COMPOUNDS FOR SITE-ENHANCED DELIVERY OF RADIONUCLIDES AND USES THEREOF

Abstract: A dihydropyridine <SIGN> pyridinium salt type of redox, or chemical, delivery system for the site-specific and/or site-enhanced delivery of a radionuclide to the brain. A chelating agent capable of chelating with a radionuclide and having a reactive hydroxyl, carboxyl, amino, amide or imide group is coupled to a carrier moiety comprising a dihydropyridine <SIGN> pyridinium salt nucleus and then complexed with a radionuclide to provide a new radionuclide pharmaceutical that, in its lipoidal dihydropyridine form, penetrates the blood-brain barrier ("BBB") and allows increased levels of radionuclide concentration in the brain, particularly since oxidation of the dihydropyridine carrier moiety in vivo to the ionic pyridinium salt retards elimination from the brain while elimination from the general circulation is accelerated. This radionuclide delivery system is well suited for use in scintigraphy and similar radiographic techniques.

Description: C0MP0UNDS FOR SITE-ENHANCED DELIVERY OF RAOIONUCLIDES AND USES THEREOF Field of the Invention The present invention relates to a dihydro- pyrid1ne * ^==_pyridiniura salt type of redox, or chemical, delivery system for the site-specific and/or site- enhanced delivery of a radionuclide to the brain and other organs. More particularly, this invention relates to the discovery that a chelating agent capable of chelating with a radionuclide and having a reactive hydroxyl, carboxyl, a ino, amide or imide group can be coupled to a carrier moiety comprising a dihydropyridine L^- rpyridinium salt nucleus and then complexed with a radionuclide to provide a new radiopharmaceutical that, in its lipoidal dihydropyridine form, penetrates the blood-brain barrier ("BSB") and allows increased levels of radionuclide concentration 1n the brain, particularly since oxidation of the dihydropyridine carrier moiety in vivo to the ionic pyridinium salt retards elimination from the brain while elimination from the general circulation is accelerated. The present radionuclide delivery system is well suited for use 1n sclntigraphy and similar radlograph c techniques. Backqround of the Invention Rad1ograph1c techniques such as scintigraphy, and the like, find application in biological and medical procedures for diagnosis as well as research. Sctntlgraphy Involves the use of radiopharmaceuticals; I.e., compounds containing (or labeled with) a radio- isotope (i.e. radionuclide) which upon introduction into a mammal become localized in specific organs, tissue, or skeletal material that are sought to be maged. When the radiophar aceutical Is so localized, traces, plates, or sdntlphotos of the existing dis¬ tribution of the radionuclide may be made by various radiation detectors known in the art. The observed distribution of the localized radionuclide can then be used to detect the presence of pathological con¬ ditions, abnormalities, and the like. Radiopharmaceuticals are thus often referred to as radiodiagnostics. In many cases, radiopharmaceutlcals are prepared using target-specific chelating agents which provide a bridge connecting a radionuclide, such as a radio¬ active metal like technet1um-99m, or the like, and a material which will temporarily localize in the organ, tissue, or skeletal material which is to be Imaged. Typical chelating agents for such purposes are: polydentate Hgands that form a 1:1 or 2:1 Hgand:radioact1ve metal complex; acrocyclic Hgands of appropriate ring size and preferably where all coordinating atoms are in a planar configuration; and blcyclic or polycycHc Hgands that can encap¬ sulate the radioactive metal. It 1s a well established fact that the delivery of drugs, Including radiopharmaceutlcals, to the brain 1s often seriously limited by transport and metabolism factors and, more specifically, by the functional barrier of the endothelial brain capillary wall deemed the blood-brain barrier. Site-spedfie delivery and/or sustained delivery of drugs to the brain are even more difficult. It has been previously suggested to deliver a drug species, specifically N-methylpyridinium- 2-carbaldox1me chloride (2-PAM), into the brain, the active nucleus of which in and of itself con¬ stitutes a quaternary pyridinium salt, by way of the dihydropyridine latentiated prodrug form thereof. Such approach is conspicuously delimited to relatively small molecule quaternary pyridinium ring-containing drug species and does not provide the overall ideal result of brain-specific, sustained release of the desired drug, with concomitant rapid elimination from the general circulation, enhanced drug efficacy and decreased toxicity. Hence, no "trapping" in the brain of the 2-PAM formed n situ results, and obviously no brain-specific, sustained delivery occurs as any consequence thereof: the 2-PAM is eliminated as fast from the brain as 1t Is from the general circulation and other organs. Compare U.S. Patents Nos. 3,929,813 and 3,962,447; Bodor et al, J. Pharm. Sc1.. 67, No. 5, pp. 685-687 (1978); Bodor et al , Science. Vol. 190 (1975), pp. 155-156; Shek, Hlguchl and Bodor, J. Hed. Chem.. Vol. 19 (1976), pp. 113- 117. A more recent extension of this approach 1s described by Brewster, Dissertation Abstracts Inter¬ national , Vol. 43, No. 09, March 1983, p. 2910B. It has also been speculated to deliver, e.g., an antltumor agent,into the brain by utilizing a dihydro- pyr1dine/pyr1d1n1um redox carrier moiety therefor, but this particular hypothesis necessarily entails derlvatizing the dihydropyridine/pyridinium carrier with a substitueπt itself critically designed to control the release rate of the active drug species from the quaternary derivative thereof, as well as being critically functionally coordinated with the particular chemical and therapeutic activity/nature of the antltumor drug species itself; Bodor et al , J. Pharm. Sci.. supra. See also Bodor, "Novel Ap¬ proaches for the Design of Membrane Transport Properties of Drugs", in Design of Biophar aceutical Properties Through Prodrugs and Analogs. Roche, E.B. (ed.), APhA Academy of Pharmaceutical Sciences, Washington, D.C., pp. 98-135 (1976). More recently, Bodor et al, Science, Vo. 214, December 18, 1981, pp. 1370-1372, have reported on s1te-spec1f1c sustained release of drugs to the brain. The Science publication outlines a scheme for specific and sustained delivery of drug species to the brain, as depicted 1n the following Scheme 1: IN THE BRAIN IN CIRCULATORY SYSTEM ID-QCI* CIRCULATORY SYSTEM LIMINATION SCHEME 1: BBB, BLOOD-BRAIN BARRIER. Accordlng to the scheme 1n Science, a drug [D] is coupled to a quaternary carrier [QC] + and the [D-QC] + which results is then reduced chemically to the lipoidal dlhydro form [D-OHC]. After administration of [D-DHC] la vivo. 1t is rapidly distributed throughout the body, including the brain. The dihydro form [D-DHC] is then 1n situ oxidized (rate constant, k.) (by the NAD^=^NADH system) to the ideally inactive original [D-QC] quaternary salt which, because of its ionic, hydrophilic character, should be rapidly eliminated from the general circulation of the body, while the blood-brain barrier should prevent its elimination from the brain (k 3 » k 2 ; k 3 » k 7 ). Enzymatic cleavage of the [D-QC] + that is "locked" in the brain effects a sustained delivery of the drug species [D], followed by its normal elimination (k ς ). metabolism. A properly selected carrier [QC] + will also be rapidly eliminated from the brain (kg » k2). Because of the facile elimination of [D-QC] + from the general circulation, only minor amounts of drug are released In the body (k 3 » k 4 ); [D] will be released primarily 1n the brain (k 4 > k 2 ). The overall result ideally will be a brain-spedfic sustained release of the target drug species. Bodor et al have reported, in Science, their work with phenylethylamlne as the drug model, which was coupled to nicotlnic acid, then quaternlzed to give compounds of the formula or CH 2 -^ which were subsequently reduced by sodium dithlonite to the corresponding compounds of the formula Testing of the N-methyl derivative ^n vivo supported the criteria set forth in Scheme 1. Bodor et al speculated that various types of drugs might possibly be delivered using the depicted or analogous carrier systems and Indicated that use of N-methylnicotinic acid esters and amides and their pyridine ring-sub- stituted derivatives was being studied for delivery of araino- or hydroxy -containing drugs, including small peptides, to the brain. No other possible specific carriers were disclosed. Other reports of Bodor et al's work have ap- peared 1n The Friday Evening Post. August 14, 1981, Health Center Communications, University of Florida, Gainesville, Florida; Chemical & Engineering News, December 21, 1981, pp. 24-25; and Science News, January 2, 1982, Vol. 121, No. 1, page 7. These publications do not suggest any carrier systems other than the specific N-methyl and N-benzyl nicotinic acid-type carriers disclosed in the Science publication. Other classes of drugs as well as a few specific drugs are mentioned as possible candidates for derivatl- zatlon; for example, steroid hormones, cancer drugs and memory enhancers are Indicated as targets for possible future work, as are β nkephalins, and specifically, dopamine and testosterone. The pub¬ lications do not suggest how to link such drugs to the carrier, except possibly when the drugs are simple structures containing a single H 2 or, perhaps, simple structures containing a single OH, of the primary or secondary type, as is the case with phenylethyla ine or testosterone. There 1s, for example, no suggestion of how one of ordinary skill in the art would form a drug-carrier combination when the drug has a more complicated chemical structure than phenylethylamlne, e.g., dopamine or an enkephaHn. For further details concerning the work with phenylethylamine, dopamine and testosterone, see also Bodor et a , J. Med. Chem., Vol. 26, March 1983, pp. 313-317; Bodor et al , J.. Med. Che .. Vol. 26, April 1983, pp. 528-534; Bodor et al , Pharmacology and Therapeutics, Vol. 19, No. 3, pp. 337-386 (April 1983), and Bodor et al , Science. Yol. 221, July 1983, pp. 65-67. In view of the foregoing, 1t 1s apparent that there has existed an acutely serious, long-standing need for a truly effective, generic but nonetheless flexible, method for the site-specific or sustained delivery, or both, of drug species to the brain. This need has been addressed in International Patent Application No. PCT/US83/00725 (filed by UNIVERSITY OF FLORIDA on May 12, 1983 and published under International Publication No. W083/03968 on November 24, 1983), which provides such a generic method for site-specific, sustained delivery of drugs to the brain utilizing a dihydropyπ * dine^ :pyridinium salt type of redox carrier system. According to the PCT application, a drug (typically having a reactive -0H, -C00H or -NH 2 group) can be coupled to a dihydro¬ pyridine.^—L pyridinium carrier; the Hpoldal dihydro form of the drug-carrier system readily crosses the blood-brain barrier; the dihydropyridine moiety is then oxidized vivo to the ideally inactive quaternary form, which Is "locked 1n" the brain, while it Is facllely eliminated from the general circulation; enzymatic cleavage of the "locked in" quaternary effects a sustained delivery of the drug itself to the brain, to achieve the desired biological effect. Diagnostic agents such as radiopharmaceuticals are generally disclosed in the PCT application as possible candidates for the carrier system, but the synthetic approach of that application, which utilizes the drug itself as the starting material, is not desirable when radioactive materials, especially relatively short-lived radionuclides, are involved. Moreover, in the case of radionuclides, the earlier objective of an ideally inactive form locked in the brain would not achieve the desired result. Thus, a serious need still exists for an effective general method for the site-spe flc and/or sustained delivery of a desired radionuclide to the brain. Summary of the Invention ∑t has now been found that a chemical delivery system based upon a dihydropyridine * ^=≥pyridinium salt type redox carrier 1s uniquely well suited for an effective site-specific and/or sustained and/or enhanced delivery of a radionuclide to the brain or li e organ, via novel carrier-containing radiopharmaceuticals, and novel carrier-containing chelating agents and novel carrier- containing precursors thereto, useful in the preparation of said radiopharmaceuticals. In one aspect, the present invention thus provides novel carrier-containing chelating agent precusors having the formula wherein the residue of a chelating agent capable of chelating with a metallic radionuclide, said chelating agent having at least one reactive func¬ tional group selected from the group consisting of amino, carboxyl, hydroxyl, amide and tmide, said functional group being not essential for the complexing properties of said chelating agent, said residue being character¬ ized by the absence of a hydrogen atom from at least one of said reactive functional groups of the chelating agent; y is 1 or 2; [QC + ] is the hydrophilic, ionic pyridinium salt form of a dihydropyridine^—__ pyri- diniu salt redox carrier; X " is the anion of a pharmaceutically acceptable organic or inorganic acid; n is the valence of the acid anion; and is a number which when multiplied by n is equal to y . In another aspect, the present invention provides novel carrier-containing chelating agents having the formula and the non-toxiiiccc ppphnnaaarrrmmaacceeui tica ly acceptable salts thereof, wherei • o- anidt y are defined as above, and [DHC] is the reduced, blooxidlzable, blood-brain barrier penetrating form of dihydropyridine ^=___pyr1- dinium salt redox carrier. In yet another aspect, the present invention provides, as an effective radionuclide delivery system, novel carrier-containing radiopharmaceuticals of the formula and the non-toxic pharmaceutically acceptable salts thereof, wherein M Is a metallic radionuclide and the remaining structural variables are defined as before; in other words, (III) is the chelated, or complexed, counterpart of (II), formed by co plexing the novel - carrier-containing chelating agent of formula (II) with a radioactive metal. When a radiopharmaceutical of formula (III) is administered, it readily pene¬ trates the BBB. Oxidation of (III) n vivo affords the corresponding pyridinium salt of the formula wherein the structural variables are as defined above. Because of its hydrophilic, ionic nature, the formula (IV) substance is "locked-in" the brain, thus allowing radiographic imaging of the radionuclide present in the complex (IV). While the quaternary "locked-in" form will gradually cleave to release the carrier moiety and the chelate portion of the molecule, such cleavage will generally occur after the most desirable period for radiographic imaging has already passed. It is generally considered most desirable, from the standpoint of patient and technician safety, to image the target area as soon as possible after ad- ministration and to use relatively short-lived radio- isotopes. Under such circumstances, the "locked-in" quaternary form will likely not degrade "to the non- carrier-containing chelate until after the radio¬ activity has decayed to a considerable extent. Thus, the present invention does not in fact provide a system for delivery and imaging of previously known radiopharmaceuticals; by the time the present delivery system degrades to a chelate of a known chelating agent and a radioactive metal, said chelate will generally no longer be sufficiently radioactive for practical Imaging. Moreover, once such degradation occurs, the known chelate may not be retained in the brain in sufficient amounts to allow imaging thereof. Thus, in contrast to the teachings of the Bodor et al publications and the aforementioned PCT application, which emphasize the desirability of an inactive quaternary form locked in the brain; the present invention pro¬ vides, and indeed requires, an active quaternary form locked in the brain in order to allow effective radionuclide imaging. The present chelate/carrier system for radio¬ nuclides is characterized by enhanced efficacy and decreased toxicity. Indeed, consistent herewith systemic toxicity is significantly reduced by ac¬ celerating the elimination of the quaternary carrier system from. the general circulation. Technetium-99m is a preferred radionuclide for diagnostic purposes because of its favorable radi- ation energy, its relatively short half-life, and the absence of corpuscular radiation, and Is preferred for use in the present Invention. Other radionuclides that, can be used diagnostically herein in a chelated form are cobaIt-57, gallium-67, gallium-68, indium-Ill, 1πd1um-lllm. and the like. Detailed Description of .the Invention The following definitions are applicable: The term "drug" as used herein means any sub- stance intended for use in the diagnosis, cure, miti¬ gation, treatment or prevention of disease in man or other animal . The term "lipoidal" as used herein designates a carrier moiety which Is lipid-soluble or lipophilic. The expression "non-toxic pharmaceutically accep¬ table salts" as used herein generally includes the non-toxic salts of products of the invention of structures (II) and (III) herelπabove formed with non-toxic, pharmaceutically acceptable inorganic or organic adds of the general formula HX. For example, the salts Include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts pre¬ pared from organic acids such as acetic, propionic, sucdnic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamdc, maleic, hydroxymaleic, phenyl- acetlc, gluta ic, benzole, salicylic, sulfanilic, fumaric, methanesul fonic, toluenesul fonic and the like. The expression "anion of a pharmaceutically acceptable organic or Inorganic add" as used herein, e.g. in connection with structures (I) and (IV) above, is in¬ tended to include anion≤ of such HX acids. It will be appreciated from the foregoing that a compound of formula (III) may be administered as the free base or in the form of a non-toxic pharma¬ ceutically acceptable salt thereof, i.e. a salt which can be represented by the formula wherein M,^}- , [DHC], y and HX are defined as before; and that, regardless of the actual form in which the compound is administered, it will be converted j_n vivo to a quaternary salt of formula (IV), the anion X being present j vivo. It is not necessary that the anion be introduced as part of the compound ad¬ ministered. Indeed, even when the compound of formula (III) is used in its salt form, the anion of the formula (IV) compound _n vivo is not necessarily the same as that present in the formula (III) compound. In fact, the exact identity of the anionic portion of the compound of formula (IV) is immaterial to the n vivo transformation of (III) to (IV). In the expression "at least one reactive functional group selected form the group consisting of a ine, carboxyl, hydroxyl, amide and imide" as used herein, the designated reactive functional groups have the following meanings: The word "amino" means any primary or secondary amino function, I.e. -NH 2 or -NHR where R is typically C j -C alkyl or is a portion of the chelating agent residue itself. The secondary amino function is also represented herein as -NH-, particularly since the exact identity of the R portion of -NHR is immaterial , just so long as it does not prevent the formation of the chelating agent residue and its linkage to the carrier moiety or otherwise interfere with the objects of this invention. The word "carboxyl" means a -C00H function. The word "hydroxyl" means an -OH function. The word "amide" means a carba oyl (-C0NH 2 ) or substituted carbamoyl (-CONHR, where R is typically C j -C 7 alky!) functional group. The -CONHR group may also be represented herein as -C0NH-, since the exact identity of the R portion of -CONHR is immaterial, just so long as it does not prevent the formation of the chelating agent residue and its linkage to the carrier moiety or otherwise interfere with the objects of this invention. The word "imide" means a functional group having the structure that is, the structure which characterizes imides (i.e. compounds such as succinimide, pathal imide and so forth). The expression "said functional group being not essential for the complexing properties of said chelating agent" 1s believed to be self-explanatory. Any functional group in the chelating agent which can be linked to the carrier moiety without destroying the chelating agent's ability to complex with the radionuclide is considered herein to be not essential for complexing properties. On the other hand, derivation of a functional group which would lead to a carrier-containing structure which would be incapable of complexing with a radionuclide is not within the ambit of this invention. In accord with the present invention, the sus¬ tained delivery of a radionuclide to the brain in sufficient concentrations for radioi aging can be. effected with much lower concentrations in the peripheral circulation afld other tissues. The present invention o f course will allow such imaging of any other organs or glands in which sufficient radio¬ activity accumulates. Thus, for example, 1t is expect¬ ed that the quaternary form (IV) which is locked in the brain will be locked in the testes as well. See the aforementioned PCT application. The novel radionuclide delivery system of this invention begins with the preparation of the novel carrier-containing chelating agent precursors of formula (I). The preparation of those precursors will be tailored to the particular chelating portion and carrier portion to be combined, and especially to the nature of the chemical bond between them, e.g. whether the linkage is an ester or amide linkage, as well as to the presence or absence of other reactive functional groups (amino, mercapto, carboxyl, Tiydroxy) in either the chelating or carrier portion. Typically, if such other reactive groups are present, they are found in the chelating portion. In any event, when such groups are present and it is desired to protect them, a step that introduces appropriate protecting groups can be Incorporated at a suitable stage of the synthetic path¬ way. Protective groups are well known in the art and Include Jt-butoxycarboπyl for amino groups, N-methyl- eπeacetamldo for mercaptans, and N-hydroxysuccinim- 1dyl for carboxyl groups. Acyl or carbonate groups are typically utilized to protect alcohol hydroxyls. When carbonate protecting groups are desired, the step of introducing the protecting groups will involve reacting the alcohol with a halocarbonate of the type R0C0C1 or ROCOBr (formed by reaction of ROH with C0C1 2 or C0Br 2 , R typicaliy being lower alkyl). For acyl protecting groups, the alcoholic hydroxyl is reacted with an acyl halide RC1 or RBr, R being -C0CH 3 or -C0C(CH 3 ) 3 . Yet other reaction schemes and reactants will be readily apparent to those skilled in the art as will the appropriate means for removing such pro¬ tective groups after they have achieved their function and are no longer needed. In forming the precursors of formula (I), at least one -C00H, -OH, primary or secondary amino, amide or imide group in a chelating agent will be bonded to [QC + ], the hydrophi.ic. ionic pyridinium salt form of a dihydro¬ pyridine ^===__pyr idiniurn salt redox carrier. It will be appreciated that by [QC ] there is intended any non-toxic carrier moiety comprising, containing or including the pyridinium nucleus, whether or not a part of any larger basic nucleus, and whether substituted or unsubstituted, the only criterion there¬ for being capacity for chemical reduction to the corresponding dihydropyridine form [DHC], BBB-penetration of [DHC] and jhi vivo oxidation of [DHC] back to the quaternary pyridinium salt carrier moiety [QC ]. As aforesaid, the Ionic pyridinium salt radio- pharmaceutical/carrier entity of formula (IV) which res.ults from n_ vivo oxidation of the dihydropyridine form (III) is prevented from efflux from the brain, while elimination from the general circulation is accelerated. Radioi aging of the radionuclide present in the "locked in" formula (IV) quaternary allows observation of the distribution of the localized radionuclide for diagnosis of pathological conditions, abnormalities, etc. Subsequently, the coupling between the parti¬ cular radioactive species lVand the quaternary carrier tQC_ + 1s likely raetaBol ica.lly cleaved which results in fac.ile elimination of the carrier moiety IQC+1. Coupling between the chelate moiety and the quaternary carrier can be a simple direct chemical bond, e.g., an amide bond or ester bond, or any other like bond, or same can even be comprised of a linking group or function as is illustrated in the Examples or the ethylenedia ine group illustrated in Schemes 3 and 4. Nonetheless, the bond is intended to be, and is hereby defined as, inclusive of all such alternatives Eventual cleavage of the formula (IV) quater¬ nary with facile elimination of the carrier moiety [QC ] is characteristically an enzymatic or chemical cleavage, e.g., by an a idase, albeit any type j_n_ brain cleavage which might result, whether enzymatic, metabolic or otherwise, of course remains within the ambit of this Invention. The many different dihydropyridine^±pyridinium salt redox carrier moieties illustrated for use here- inbelow are merely exemplary of the many classes of carriers contemplated by this invention. While the following list of carrier classes is not meant to be exhaustive (and, indeed yet other carrier classes are illustrated hereinbelow as well as in the aforemen¬ tioned PCT application, PCT/US83/00725) , the following major classes of quaternaries and the corresponding dihydro forms are prime examples of the moieties encom¬ passed hereby: (1) For linkage to a chelating agent having at least one -NH 2 , -NH- or -OH functional grouping, replacing a hydrogen atom from at least one of said functional groupings with one of the following [QC + ] groupings: C-t-NH-αlkylene-C-÷ p (C) (d) NH-αlkylene-ϋ?-÷j, or wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R Q is a radical identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R Q radicals can be the same or different; R j is CJ-C alkyl , 0-, - Cy haloalkyl or C 7 -C l0 aralkyl; R 3 is C χ to C 3 alkylene; X is -CONR'R" wherein R' and R" , which can be the same or different, are each H or C-^-Cy alkyl , or X is -CH=N0R" ' wherein R" ' is H or 0-, -C- j alkyl; the carbony -containing groupings in formulas (a) and (c) and the X substituent in formula (b) can each be attached at the 2, 3 or 4 position of the pyridinium ring; the carbonyl -containing groupings in formulas (d) and (f) and the X substituent in formula (e) can each be attached at the 2, 3 or 4 position of the quinolinium ring; and the carbonyl -containing groupings in formulas (g) and (j) and the X substituent in formula (h) can each be attached at the 1 , 3 or 4 position of the isoquinol iπiu ring; (2) For the linkage to a chelating agent having at least one -COOH functional grouping, replacing a hydrogen atom from at least one of said -COOH groupings with one of the following [QC + ] groupings: (a) When there are one or two -COOH groups to be den " vati zed: ( 11) (lv) (V) (vi) (vll) (vlli) <ix) wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 is a radical identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R Q radicals can be the same or different; Z' is C^-Cg straight or branched alkylene, preferably C^-C 3 straight or branched alkylene; Q is -0- or -NH-; R j is C j -Cy alkyl , C^-C j haloalkyl or C 7 -C 1Q aralkyl; R 3 is c ι- c 3 alkylene; X is -CONR'R" wherein R' and R' ' , which can be the same or different, are each H or C^-C 7 alkyl, or X is -CH=N0R , , , wherein R" ' is H or 0-, - C j alkyl; the X substituent in formula (ii) and the car- bony -containing groupings in formulas (i) and (iii) can each be attached at the 2, 3 or 4 position of the pyridinium ring; the X substituent in formula (v) and the carbonyl-containing groupings in formulas (iv) and (vi) can each be attached at the 2, 3 or 4 position of the quinolinium ring; and the X substituent in formula (viii) and carbonyl-containing groupings in formulas (vii) and (ix) can each be attached at the 1, 3 or 4 position of the isoquinolinium ring; (b) Alternatively, when there is only one -COOH group to be derivatized: R Vn lv (x) (xt) wherein * / is the skeleton of a sugar molecule; r\ ' v is a positive integer equal to the total number of -OH functions in the sugar molecule from which said skele¬ ton is derived; n v is a positive integer one less than the total number of -OH functions in the sugar molecule from which said skeleton is derived; each A in each of structures (xii), (xiii) and (xiv) can independently be hydroxy or D' , D' being the residue of a che¬ lating agent containing one reactive -COOH functional group, said residue being characterized by the absence of a hydrogen atom from said -COOH functional group in said chelating agent; and each R" 4 in each of struc¬ tures (x) and (xi) can independently be hydroxy, wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 is a radical identical to the corresponding portion of a natural amino add; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; D* is defined as with structure (xii), (xiii) and (xiv); Rj 1s C1-C7 alkyl , C1-C7 haloalkyl or C7«C 10 aralkyl; and the depicted carbonyl-containing groupings can be attached at the 2, 3 or 4 position of the pyridinium or quinolinium ring, or at the 1, 3 or 4 position of the isoquinollnium ring; with the proviso that at least one R*4 in each of structures (x) and (xi) is • 0 -f-H-αlkylene-NH or 0 II 0-τ-C-oIkylene-NH ' - wherein alkylene, R 0 , p and R-^ and the position of the carbonyl-containing groupings are defined as above; and with the further proviso that when more than one of the R*4 radicals in a given compound are the aforesaid carbonyl-containing groupings,, then all such carbonyl- containing groupings in said compound are identical", (3) For linkage to a chelating agent having at least one -NH- functional group which is part of an amide or imide structure or at least one ow pKa primary or secondary amine functional group, replacing a hydrogen atom from at least one of said functional groupings with one of the following [QC + ] groupings: - - NH-ol kylene-C ■ OCH- R o (1 ) C0CH- Λ-+ NH-olkylene-C- (m) (0) (P) C<J> (r) ω wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 is a radical identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R Q radicals can be the same or different; R j is C j -Cy alkyl , C-^-C haloalkyl or C 7 -C 10 aralkyl; R is hydrogen, C^-Cy alkyl , C3-C3 cycloalkyl , C1-C7 halo¬ alkyl , fury! , phenyl, or phenyl substituted by one or more halo, lower alkyl , lower alkoxy, carbamoyl , lower al koxycarbonyl , lower alkanoyloxy, lower haloalkyl , mono(lower al yl )carbamoyl , di(lower al 1 )carbamoyl , lower alkylthio, lower al kyl sul finyl or lower al y - sulfonyl; R 3 is C χ to C 3 alkylene; X is -CONR'R" wherein R' and R 1 ' , which can be the same or different, are each H or C χ -C 7 alkyl, or X 1s -CH=N0R"' wherein R"' is H or C^-Cy alkyl; the carbonyl-containing groupings in formulas (k) and (m) and the X substituent in formula (1) can each be attached at the 2, 3 or 4 position of the pyridinium ring; the carbonyl contain¬ ing groupings in formulas (n) and (p) and the X substi- tuent in formula (o) can each be attached at the 2, 3 or 4 position of the quinolinium ring; and the car¬ bonyl-containing groupings in formulas (q) and (s) and the X substituent in formula (r) can each be attached at the 1, 3 or 4 position of the isoquinol iniu ring. Here and throughout this application, the expres¬ sion " C ι- C j haloalkyl" means CJ-C7 alkyl substituted by one or more halogen atoms. Also here and throughout this application, the alkyl radicals, including alkyl and alkylene portions of other radicals, can be straight or branched unless otherwise specified. The expression "R 0 is a radical identical to the corresponding portion of a natural amino acid" is believed to be self-explanatory. Thus, for example, R 0 can be hydrogen, as in glycine; methyl, as in alanine; -CH(CH 3 ) 2 . as ιn valine; -CH 2 -CH(CH 3 ) 2 , as in leucine; - as in phenyl- alanine; -CH - , as in tryptophan; -CH 2 0H, as in serine; -CHOH-CH3, as in threonlne; -(CH 2 ) 2 -SCH , as in methionine; -CH2-C0NH 2 , as in asparagine; -CH 2 CH 2 -C0NH 2 , as in glutamine; OH as in tyrosine; -CH 2 SH, as in cysteine; -CH 2 C00H, as in aspartic acid; and -CH 2 CH C00H, as 1n glutamic acid. The expression "natural amino acid" as used herein does not encompass dopa or L-DOPA. Preferred amino acids encompassed by the R 0 term include glycine, alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine and gl utamine. The dihydro forms [DHC] corresponding to the aforementioned quaternaries are as follows: (!') For Group (1) above: HH-αl (e' ) <f) -f-NH-olkylene-έ 4 (fl'J (9") , U' ) (J") wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 is a radical identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; the dotted line in formulas (a 1 ), (b') and (c 1 ) indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring; the dotted line in formulas (d') t (e') and (f) indicates the presence of a double bond in either the 2 or 3 position of the dihydroquinoline ring; R j is C1-C7 alkyl , C1-C7 halo¬ alkyl or C7-C10 aralkyl; R3 is C j , to C 3 alkylene; X is -CONR'R' 1 , wherein R' and R' ' , which can be the same or different, are each H or C^-Cy alkyl , or X is -CH=N0R"' wherein R « " is H or C1-C7 alkyl; the carbonyl-containing groupings in formulas (a 1 ) and (c') and the X substituent 1n formula (b') can each be attached at the 2, 3 or 4 position of the dihydro¬ pyridine ring; the carbonyl-containing groupings in formulas (d 1 ) and (f) and the X substituent in formula (e') can each be attached at 2, 3 or 4 position of the dihydroquinol ine ring; and the carbonyl-containing groupings in formulas (g') and (j') and the X substi¬ tuent 1n formula (h 1 ) can each be attached at the 1, 3 o r 4 position of the dihydroisoquinol ine ring; (2 1 ) For Group (2) (a) above: • 0-2'- (V) 2*- (VU*) < lχ') <!x") wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 is a radical Identical to the corresponding portion of a natural amino add; p is 0, 1 or 2, provided that, when p Is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; the dotted line in formulas (i'), (i 1 ) and (iii') indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring; the dotted line 1n formulas (iv*), (v*) and (vi 1 ) Indicates the pre¬ sence of a double bond in either the 2 or 3 position of the dihydroquinol ine ring; V is C^-Cs straight or branched alkylene, preferably C^-C 3 straight or branched alkylene; Q is -0- or -NH-; 9.γ is C-^-C*; alkyl, C j -C 7 haloalkyl or C,-C.Q aralkyl; 3 is C,-C 3 alkylene; X is -CONR'R'' wherein R* and R' * , which can b e the same or different, are each H or C1-C7 alkyl, or X is -CH=N0R' " wherein R" • is H or -Zγ -Cη alkyl; the X substituent in formula (ii*) and the carbonyl-contain¬ ing grouping in formulas (i 1 ) and (iii') can each be attached at the 2, 3 or 4 position of the dihydropyri- dine ring; the X substituent in formula (v') and the carbonyl-containing grouping in formulas (iv') and (vi 1 ) can each be attached at the 2, 3 or 4 position of the dihydroquinol ine ring; and the X substituent in formula (viii 1 ) and the carbonyl-containing groupings formulas (vii') and (ix' ) can each be attached at the 1, 3 or 4 position of the di hydroisoquinol ine ring; (3') For Group (2) (b) above: <x*> (xi') (xiv") wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 1 s a radical identical to the corresponding portion of a natural araino add; p 1s 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; the dotted line 1n formula (xii') indicates the presence of a double bond 1n either the 4 or 5 position of the dihydropyridine ring; the dotted line in formula (xiii') Indicates the presence of a double bond in either the 2 or 3 position of the dihydroquinollne ring; ^ i 1s the skeleton of a sugar molecule; n is a positive integer equal to the total number of -OH func¬ tions in the sugar molecule from which said skeleton is derived; n v 1s a positive integer one less than the total number of -OH functions in the sugar molecule from which said skeleton is derived; each A in each of structures (xii*), (xiii'), (xiv') and (xiv") can independently be hydroxy or D', D' being the residue of a chelating agent containing one reactive -COOH func¬ tional group, said residue being characterized by the absence of a hydrogen atom from said -COOH functional group in said chelating agent; and each R4 in each of structures (x') and (xi 1 ) can independently be hydroxy, -O-f-C-αlkylene-NH ■ 0- C-αl ■ 0 or D', wherein the alkylene group can be straight or branched and can-contain 1 to 3 carbon atoms; R 0 is a radical Identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; the dotted line is defined as with structures (xii ) and (xiii*); 0* is defined as with structures (xϋ*), (xiii'), (xiv') and (xiv"); R λ is C C 7 alkyl, C C 7 haloalkyl or 7 -C 10 aralkyl; and the depicted carbonyl groupings can be attached at the 2, 3 or 4 position of the pyridinium or quinolinium ring or, except where otherwise specified, at the 1, 3 or 4 position of the isoquinol iπium ring; with the proviso that at least one R4 in each of structures (x') and (xi * ) is -O whereln alkylene, R 0 , p, R j , the dotted lines and the position of the carbonyl-containing groupings are de¬ fined as above; and with the further proviso that when more than one of the R4 radicals in a given compound are the aforesaid carbonyl-containing groupings, then all such carbonyl-containing groupings 1n said compound are identical ; (4*) For Group (3). above: (m*) (n*) (o*) (p*) - (q*) ,, (q" ) lene- -45-OCK-, (r**) ($') (s") whereln the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 is a radical identical to the corresponding portion of a natural amino add; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; R is hydrogen, Cχ-C 7 alkyl, C 3 -Cg cycloalkyl, C 1 -C 7 haloalkyl , furyl , phenyl, or phenyl substituted by one or more halo, lower alkyl, lower alkoxy, carbamoyl , lower al oxycarbonyl , lower alkanoyloxy, lower halo¬ alkyl, mono(lower alkyl )carbamoyl , di(lower alkyl)car- bamoyl , lower alkylthio, lower al kyl sul finyl or lower al yl sul fony ; the dotted line in formulas (k'), (!') and (m') indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring; the dotted line in formulas (n 1 ), (o 1 ) and (p') indi¬ cates the presence of a double bond in either the 2 or 3 position of the dihydroquinol ine ring; R j is C1-C7 alkyl , C1-C7 haloalkyl or C7-C10 aralkyl; R 3 is C to C 3 alkylene; X is -CONR'R", wherein R' and R' ' , which can be the same or different, are each H or C1-C alkyl, or X is -CH-N0R" ' wherein R' ' ' is H or C -I - C- J alkyl; the carbonyl-containing groupings in formulas (k') and (m' ) and the X substituent in formula (!') can each be attached at the 2, 3 or 4 position of the dihy¬ dropyridine ring; the carbonyl-containing groupings in formulas (n') and (p 1 ) and the X substituent in formula (o') can each be attached at the 2, 3 or 4 position of the dihydroquinol ine ring; and the carbonyl-containing groupings in formulas (q 1 ) and (s 1 ) and the X substi¬ tuent in formula (r') can each be attached at the 1, 3 or 4 position of the dihydroi soquino! ine ring. The presently preferred dihydroρyridine^__ pyri¬ dinium salt redox carrier moieties of this invention are those wherein p is 0 or 1, most preferably 0; alkylene, when present (i.e. p = 1 or 2), is -CH2-; R 0 , when present(i.e. p = 1 or 2), is H, -CH 3 , -CH(CH 3 )2, -CH 2 -CH(CH3)2, - , -(CH 2 )2-SCH 3 , -CH2-CONH2 or -CH2CH2-CONH2; Ri, when present, is -CH 3 ; R3, when present, is -CH2CH2-; X, when present, is -CONH2; the depicted carbonyl-containing groupings in formulas (a) and (c) and the X substituent in formula (b) are attached at the 3-position; the depicted car¬ bonyl-containing groupings in formulas (d) and (f) and the X substituent in formula (e) are attached at the 3- position; the depicted carbonyl-containing groupings in formulas (g) and (j) and the X substituent in formula (h) are attached at the 4-position; V , when present, is C2 or C3 straight or branched alkylene; Q, when present, is -NH-; the X substituent in formulas (ii) and (v) and the depicted carbonyl-containing groupings in formulas (i), (iii), (iv) and (vi) are attached at the 3-position; the X substituent in formula (viii) and the depicted carbonyl-containing groupings in formulas (vii) and (ix) are attached at the 4-position; and the depicted carbonyl-containing groupings encompassed by formulas (x), (xi), (xii), (xiii) and (xiv) are in the 3-position of the pyridinium or quinolinium ring and in the 4-position of the isoquinollnium ring; all R'^s in structures (x) and (xi) are -OH except for the one R4 in each structure which must be the carrier moiety; all * ~*. A's in structures (x11), (xiii) and (xiv) are -OH; * j is the skeleton of a glucose molecule; R in formulas (k), (1) and (m) is hydrogen, methyl or CC1 3 ; and the depicted carbonyl-containing groupings in formulas (k) through (s)are in the 3-position of the pyridinium or quinolinium ring and in the 4-.position of the isoquino¬ llnium ring; and the corresponding dihydro moieties. Especially preferred dihydropyridine^- pyridinium salt redox carrier moieties are the quaternaries of Group (1), structures (a), (b), (d), (e), (g) and (h); those of Group (2), structures (i), (ii), (iv), (v), (vii), (viii), (x) and (xii); and those of Group 3, structures (k), (1), (n), (o), (q) and (r); and the corresponding dihydro forms, most especially when they contain the preferred structural variables identified in the preceding paragraph. The following synthetic schemes illustrate various approaches to the preparation of the carrier- containing chelating agent precursors of formula (I), to the corresponding carrier-containing chelating agents of formula (II) and to the corresponding carrier-containing radiopharmaceuticals of formula (III). Also shown are the corresponding "locked in" quaternaries of formula (IV) formed 6y ij vivo oxidation of the formula (III) chelates, said formula (IV) quater¬ naries being the primary localized materials whose radionuclide content 1s Imaged by radiation detection means. scHεHε ∑ fore -locked (n* breia SCHEHE 3 11 12 17 SCHEHE 3, COn't . 18 Ne,S,0./base aa *- -* ■ > Coapl x of ss "TcO with *TcθJ reduction of pyridinlua ring 20 i_ vivo oxidetion Quaternary fora of rediopharae- ceutical 'locked in' brain .' 21 SCHEHE .. con' t. •» 99 Tco: N* 2 S 2 0 4 Coapiex with reduction of pyridlniua ring OH" 27 in vivo oxidation . Quaternary fora of rediopharaaceutlcal 'locked in' brain 28 SCHEHE S H 2 NCH 2 CHC00H H 2 NCH 2 CHC00C 2 H s NH, C 2 H s 0H NH, HC1 36 3S SCHEHE ~ . con't- SCHEME 6 H 2 CJHJ 43 SCHEflE 6. con't. SCHEME 7 HOOCCH—CHCOOH C 2 H $ 0H C 2 H 5 00CCH-CHC0OC 2 H s NH 2 NH 2 HC1 > NH 2 NH 2 (2,3-diaainosucclnic add) SO 49 52 S3 54 SCHEHE 7. con't . in YIVO oxidation fora 'locked in" brain Sβ fora 'locked in- brain 65 66 2_i£tE_2 67 68 73 7 . 1 HC1 dlhydrochlorlde salt of 7H SΓHFHE 9. con't . 7. 75 76 form "locked In* brain ___r__ι_ K^O^ rCHCOOHti H 2 HCH 2 O.CCX}C 2 H5 HCl NHj 30 reduction, e.g. KjHCl^CHCH^H OKNOHJCCOO^Hc, Mi til LIAlHή NH2 69 31 80 81 HCl ether 8lα SCHEME 10. COn't. 8. fora "locked in" brain ___τ_ x f β rCHjCONHj lUAlty 90 91 SCHEME 11. e.c -τ. 90 j 0 ' Quaternary form of 9. 96 ________ HO C 2 H5 m 97 98 SCHEME 12. ron'f. foπ "rocked in" brain SCHEME 12. e.net't. fora -locked in' brain -____ 1 KjHCH-jCHCHzOH t-butyl chlorofoτaαte -BOC-AKCI^CHCKjOH NH-t-EOC 31 109 thlua ^~ CKH 2 0CH 2 CH 2 OH t-B0C-NHCH 2 CKCH 2 0CH 2 CH 2 0H HH- H 2 NH-t-BOC 111 110 (1) NcHCOj (2J ClCl^COCl CH 2 CHCH20CH 2 CH 2 0H NH NH I i O-C C-0 I i CH 2 CH 2 I •** i * SH SH 11 •6b- SCHEME 13, con't. 0 f ■ r Qc-tf λ SCHEME 15/ cc-n't. form "locked in" brain SCHEME Ifi. røn'j. form "locked in" brain scHHiε 17, dl(tert-butyl) dicαrtonαte *-^>>-< * - *> _■-©- < CH-jWl-t-BOC NH 2 ( 3,4-diαaiπobenzyIαalneJ 152 151 CICH2COCI CsKc " C1CH 2 ,CCNNIH CH 2 NH-t-80C 154 153 157 $Γ-S-«F 17. con' t. ""f^" I " * NKCCH^H 1S8 NoTdy reducing agent fora -locked in" brain _£__£__. 0 CNCH 2 C00H + 7- DCC CNCH 2 C00 88 168 LIAIH 1691 170 | CH 3 I/CH 3 N0 2 17 171 SCHgflξ 18, cpn't. 172 NaTcOq/reduclπg agent Tc-99m pertechnetate and reducing agent, e.g. in Na 2 S 2 0 1 ,, In basic medlun Complex with technetlun, redox system In reduced form 173 in vivo oxidation Quaternary form of rod 1 opharmaceut leal "locked In" brain 174 SCHEME 19 CO0C 2 H 5 ClΗ^Ch^CHαXX^ C1C0CH 2 C1 NH NH i I NH 3 + CΓ O-C C-0 " I I 70 CH 2 CH, I ** - Cl Cl 40 © ■ COSNα 176 175 * 176 SCHEME 19. con*t. ______ 177 COSNα <& 63 ~ Q HERE 21, cρη 187 form "locked In" brain SCHEME 22 63 189 as in Scheme 8 66 SCHEME 23 74 17 76 74 ♦ 191 ■ 76 76 continue as in Scheme 9 ^ 79 _______ j«. s i" continue as in Scheme 14 129 SCHEME 6 1 " 192 198 199 SCHEME 26. con*t. form "locked In" brain SCHEME 2 192 203 continue as in 202 Scheme 26 198 SCHEME 2β 206 (1) NαB (2) H* SCHEME 28. coπ't. Tc-99ra pertechnetate and reducing agent, 211 e.g. Na^Oq, in basic medlun reduction, e.g. with Nσ^^, in basic medium \ lR vi o ^oxidation 212 Q uaternary form of rod i ophaπnaceut lea 1 214 "locked In" brain SCHEME 29 0 0 -. -' « 0 II Cl-C-C-CI NH 2 CH 2 CH 2 NH 2 c — NH NH CH 2 CH 2 dH 2 CH, NH, NH, in vivo oxidation Q uaternary form of rσdloohaπnaceutlcal "locked In" brain 220 Thus, Scheme 1 above Illustrates a typical synthetic route for compounds 1n which the linkage between the carrier and chelate portions Is through a -COOH function 1n the chelating agent. In the first step, the alcohol reactant can be represented generally as H0-Z«-I wherein Z' Is C -C 8 straight or branched alkylene; 1n the second step, the depicted reactant, nlcot namlde, could be readily replaced with plcoHnamlde, isonlcotlnamlde, 3-qύ-fnollnecarboxamide, 4-isoquino- Hnecarboxa lde or the like. (3-Qu1nol1necarboxam1de and 4-1soqu1nol1necarboxam1de can be prepared 1n known manner, e.g. by treating the corresponding adds with ammonia.) Other process variations will be apparent to those skilled in the art, particularly from the teachings of the aforementioned International Application PCT/US83/00725. One such alternate approach to Scheme 1 is depicted in Scheme 2. In the first step of Scheme 2, the alcohol reactant (prepared by reacting 2-iodoethanol with nicotinamide) could contain a shorter or longer alkylene bridge (C- j -Cg) than shown and the pyridinium portion could be replaced with an equivalent pyridinium carrier, prepared in analogous fashion. Thus, for example, in the first step, an alcohol of the formula wherein n « 1-8, preferably 1-3, can be reacted with or other -C00H-conta1n1ng chelating agent or pre- cursor thereof. Alternatively, an alcohol of the formula (prepared by reacting nicotinic acid with 1,2-propylene glycol 1n the presence of dicyclohexylcarbodiImide) or a position isomer or homologue thereof or correspond¬ ing derivative of a quinolinecanboxylic add or an isoquinolinecarboxylic acid can be quaternized, e.g. by reaction with methyl Iodide, and used in place of the alcohol reactant shown in Scheme 2. As yet another variation, bro oglucose can be reacted with nicotinamide, picolina ide or Isonicotina ide or ap¬ propriate quino inecarboxamide or isoquinolInecarboxa- mide " to afford a starting alcohol of the formula which can be used 1n place of the alcohol reactant used in the first step of Scheme 2. Still other varlatlons would Include reacting nicotinic acid or other suitable pyr1dine-r1ng containing add with an appropriate di- or polyhydroxy compound such as ethylene glycol, propylene. lycol , inositol or a simple sugar, linking the resultant intermediate via its free hydroxy group(s) to the carboxylic acid function of the chelating agent or the precursor thereof, and then quaternizlng that Intermediate. Schemes 3 and 4 above are illustrative of the type of procedure utilized to prepare compounds in which the 14-nkage between the carrier and chelate portions 1s through an -NH 2 or—OH function in the chelating agent or precursor thereof. The activated ester of nicotinic acid, 16, can of course be replaced with another activated estεr of that or a similar pyridlπe-ring containing acid. Equivalent activated esters, e.g. an ester in which the is replaced with (especially p-nitrophenyl ), will be apparent to those skilled in the art. The preparation of such esters proceeds according to known procedures, e.g. by reacting the acid chloride or anhydride or the add 1n the presence of OCC with N- hydroxy- succlπi ide or other alcohol, then quaternlzing the product, e.g. with methyl iodide or di ethylsulfate. Scherae 5 Illustrates another possible approach when the linkage between the carrier and chelate portions is through an -OH function 1n the chelating agent or its precursor. The first step 1n this sequence 1s described 1n Fritzberg U.S. Patent No. 4,444,690; the resultant ethyl ester 30 is then reduced to the corresponding alcohol, using an appropriate reducing agent, e.g. L1A1H 4 . The reduction thus Introduces a -CH 2 0H function 1n place of the acid function in 7. Other -COOH containing chelating agents or their precursors can be similarly converted to the corre¬ sponding -CH 2 0H containing compounds, which can then be derlvatized to the carrier-containing moieties as generally described hereinabove. One such deriva- tization is shown in Scheme 5. The conversions -_■—*3^—*3.3—*3 parallel reactions shown in Scheme 2 hereinabove as well as in the Fritzberg patent. The carrier-containing moiety can readily be intro¬ duced into the structure after obtaining 3.4 by a variety of methods, e.g. ty use of the activated quaternized ester 17 used in Schemes 3 and 4 or other activated ester;or by reaction with bromoacetyl chloride, followed by reaction with nicotinamide, isonicotinamide, 3-quinolinecarboxamide, picolinamide, 4-isoquinolinecarboxamide or the like to form 36 or similar derivative. Subsequent reduction to the dihydropyridine form as described herein and in International Application No. PCT/US83/00725 can be performed separately, or, more conveniently, can be accomplished at the same time as reduction of technetium to an appropriate oxidation state. Scheme 6 illustrates a method of particular use when the linkage between the carrier and chelate portions is through an -NH- function which is part of an amide or imide or a very low pKa primary or secondary amlπe. Conversion of an ester group to the corresponding amide is accomplished with excess ammonium. Then the chelating agent precursor 4j? having a -C0NH 2 funtlonal group is subjected to N-hydroxyalkylation, e.g. by reaction with an aldehyde [e.g. formaldehyde, beπzaldehyde, acetaldehyde or chloral(Cl 3 CCH0)3; thus, for example, in the case of chloral, the CONHΛ group becomes a CUC-CHOH 3 I CONH function and thus forms a suitable bridging group. The resultant compound is then subjected to any method described herein or in the aforementioned PCT appli¬ cation for linking the carrier to an -OH function. One such method, i.e. reacting the alcohol with nico¬ tinic acid in the presence of dicyclohexylcarbodi imide , is shown in Scheme 6. Scheme 7 is Illustrative of a process in which the -NH- group to which the carrier is to be linked is part ' of an Imide structure. The earliest steps of this Scheme are described 1n the aforementioned Fritzberg patent. Then, 51 is reacted with excess ammonia to form the corresponding succinamide which, when heated, loses ammonia to give the succinimide 52. That intermediate 1s then reacted with an aldehyde, as generally described in the preceding paragraph. and the resulting -OH containing group then derivatized, also as described previously. Scheme 8 illustrates yet another alternate to Schemes 1 and 2; 3,4-dlarainobenzoic acid is disclosed as a starting material for chelating agents in the Fritzberg patent. Scheme 8 follows the reaction sequence of Scheme 2 and could be varied in any of the many ways described in conjunction with Scheme 2 hereinabove. Moreover, 59 could alternatively be subjected to the reactions shown " in Schemes 5 and 6 and/or discussed in connection with those Schemes; i.e. the -COOH group could be converted to a -CHgOH or a -C0NH 2 group and then derivatized as shown in and discussed with respect to those Schemes. Schemes 9, 12 and 14 above illustrate typical conversion of a carboxylic acid ester group to the corresponding amide (-C0NH 2 ); reduction of the amide function to the corresponding a ine (-CH 2 NH 2 ); reaction of the -NH 2 group with an activated ester of nicotinic acid; quaternlzation with methyl iodide; and reduction of the resultant quaternary of formula (I) to the corresponding dihydro of formula (II), or conversion of (I) directly to the formula (III) radiopharmaceutical. These processes can be varied as discussed in conjunction with Schemes 3, 4 and 5 above. Schemes 10 and 15 above illustrate typical con¬ version of an alcohol (-CHgOH), which may be obtained from the corresponding carboxyl1c acid ester, to the corresponding nicotinoyl ester; reaction of the ester derivative with methyl iodide to afford the desired formula (I) quaternary; and reduction to the corresponding formula (II) dihydro or conversion directly to the corresponding formula (III) radiopharmaceutical. For process variations, see the discussion of Schemes 3, 4 and 5 hereinabove. In Scheme 11 above, there is shown a typical method for introducing a longer alkylene chain between an atom which is involved in forming the chelate structure and a pendant NH 2 group which is to be coupled to the carrier moiety. As depicted in this scheme, a secondary amino group ^NH is reacted with a halo- alkamide, e.g. BrCH 2 C0NH 2 , replacing the hydrogen of the ^NH with -CH 2 C0NH 2 . Reduction of the amide affords the corresponding ^NCH 2 CH 2 NH 2 compound. That amine can then be reacted with an activated ester of nicotinic acid, followed by quaternization and reduction as in the other schemes. For variations, see in particular Schemes 3, 4 and 5 above. Schemes 13 and 16 illustrate yet other methods for lengthening the alkylene chain, the chain here being interrupted by one or more oxygen atoms. Thus, a -CHgOH group is typically converted to the cor¬ responding lithium salt and then reacted with an iodo- alkanol, e.g. ICH 2 CH 2 0H, to convert the -CH 2 0-Li + group to a -CH 2 0CH 2 CH 2 0H group. [Obviously, the chain could be lengthened by utilizing a longer-chain iodoalkanol, or by repeating the two steps just described (in which case additional intervening oxygen atoms would be introduced.)] The -CH 2 0CH 2 CH 2 0H group is then converted to the corresponding nicotinic acid ester, which is then quaternized to form the desired quaternary salt. Again, the reaction schemes can be varied as discussed with reference to Schemes 3, 4 and 5 hereinabove. In Scheme 17 above, reaction of an -NH 2 group with an activated ester of nicotinic acid, followed by quaternizatlon, is shown. The resultant formula (I) quaternary is then reduced as shown in the other 5 schemes. Many of the earliest steps in the reaction schemes depicted above parallel reactions described in Fritz¬ berg U.S. Patent No. 4,444,690. See, for example, the conversion of 7 to 30 in Scheme 10; the conversion 10 of 30 to 40 to 41 in Scheme 12; the conversion of 113 to H2.to 113 to 114 1n Scheme 13; and so on. Scheme 18 above, like Scheme 11 which has already been discussed, shows another typical method for intro¬ ducing a longer alkylene chain between the nitrogen 5 atoms. Here the secondary amino group ✓ H is converted to the corresponding group. The resultant amine can then be reacted with an activated ester of nicotinic acid, followed by quaternizatlon and reduction as in the other schemes. As a preferred o alternative in this and many of the other reaction schemes depicted herein, the quaternary chelating agent precursor of the invention can be prepared directly from reaction of the corresponding amine with a quaternized activated ester of nicotinic acid. Other 5 variations will be apparent, e.g. from Schemes 3, 4 and 5 above. Scheme 19 represents an alternate approach to the derivatives resulting from Scheme 1. Obviously, this scheme could be varied in a number of ways, most Q notably in the fourth step, where nicotinamide could be replaced with another amide (e.g. one of those dis- cussed in Scheme 1) and where ICH2CH OH could be replaced with another compound of the type I-Z'-OH where V 1s C -Cβ straight or branched alkylene. Scheme 20 illustrates an alternate route to the derivatives of Scheme 8. This scheme represents a particularly attractive synthetic route to the pro¬ tected quaternary derivative 62. Moreover, the intermediate 17 , 6 can be varied as discussed in con¬ junction with Scheme 19; also, this process can be adapted to the preparation of derivatives of other -COOH-containing chelating agents, e.g. those of Schemes 1 and 2. In Scheme 21, the intermediate 179, prepared as in Scheme 20, is used to prepare yet other compounds of the invention derived from 3,4-diaminobenzoic acid. Scheme 22 is illustrative of yet another variation in the procedure of Scheme 8. Scheme 22 can be readily adapted to the preparation of other derivatives of this invention; see, for example, the discussions of Schemes 8 and 20 above. In Scheme 23, there are depicted two highly desi¬ rable alternate routes to the quaternary salt 76 of Scheme 9. These alternate routes utilize the quater¬ nary activated esters of nicotinic acid to prepare the quaternary derivative 7> directly from the correspond¬ ing primary amine 7__4. Use of either the succinimidyl or the phthalimidyl quaternary intermediates (17 or 1 , 91) is illustrated. Other quaternary activated esters for use in this reaction will be apparent from the various processes described herein. After formation of the formula (I) quaternary such as T > , the process of Scheme 9 can then be used to prepare the other deriva¬ tives of this invention. Scheme 24 depicts yet another highly desirable alternate route to the quaternary salt 76 of Scheme 9. In this particular preferred scheme, a protecting group is introduced prior to introduction of the car- rier function; the protecting group is then removed prior to reduction of the quaternary function to the corresponding dihydro. In the case of the chelating agent shown in this scheme, reaction with acetone protects both the secondary amino and thiol functions by formation of thiazolidine structures so that those functions do not interfere during addition of the carrier moiety. Subsequently, the secondary amino and mercapto groups are regenerated by reacting the pro¬ tected intermediate with mercuric chloride in an organic solvent such as methanol , conveniently at room temperature, and then decomposing the resulting complex with hydrogen sulfide. See, for example, British Patent Specification No. 585,250, which utilizes such a procedure for the production of esters of penicilla- mine. After preparing the quaternary salt 76 in this ' manner, the process of Scheme 9 can be used to prepare the other derivatives of this invention. Variations in the procedure used, e.g. as discussed in connection with Scheme 23, can be used to obtain yet other deriv- atives of the invention. Scheme 25 represents an alternate route to the compounds obtained via Scheme 14. The route uses the preferred route of introducing the carrier moiety in its quaternary form and can be readily adapted to the preparation of derivatives of other -COOH containing chelating agents and/or introduction of other carrier moieties disclosed herein. In Scheme 26, there 1s Illustrated a process for attaching a function or analogous carrier moiety to a pendant- primary amine function in a chelating agent. This process utilizes the thiazoli- dine structure to protect the secondary amino and thiol functions 1n the particular chelating agent depicted, as fully discussed 1n conjunction with Scheme 24 above. An alternate approach to the derivatives depicted in Scheme 26 is shown in Scheme 27, in which the pri- ary amino group in the protected primary amine is first converted to the corresponding -NHC0-R3-Br group, which is then reacted with nicotinamide or the like to afford the protected quaternary intermediate. Scheme 27 depicts a process for preparing carrier- containing derivatives of yet another type of chelating agent. The desired chelating agent in this instance contains oxime functins, which are introduced after the quaternary form of the carrier has been attached. For¬ mation of derivatives of yet another type of chelating agent 1s deplcted'in Scheme 29. Similar schemes can be shown for the. preparation of the other derivatives of this invention. The steps of introducing and removing protecting groups are only included when necessary. Also, the order of steps may be altered; in particular, quaternization may occur earlier in the reaction scheme, depending of course on the particular compounds involved. Other reaction schemes, reactants, solvents, reaction con- ditions, etc. will be readily apparent to those skilled in the art. Also, insofar as concerns the quaternary derivatives, when an anion different from that obtained is desired, the anion in the quaternary salt may be subjected to anion exchange via an anion exchange resin or, more conveniently, by use of the method of Kaminski et al , Tetrahedron, Vol. 34, pp. 2857- 2859 (1978). According to the Kaminski et al method, a ethanolic solution of an HX acid will react with • . a quaternary ammonium hal ide to produce the methyl halide and the corresponding quaternary -X salt. Reduction of the quaternary salt of formula (I) to the corresponding dihydro derivative of formula (II) can be conducted at a temperature from about -10°C to room temperature, for a period of time from about 10 minutes to 2 hours, conveniently at atmospheric pressure. Typically, a large excess of reducing agent is employed, e.g., a 1:5 molar ratio of reducing agent to starting compound of formula (I). The pro- cess is conducted in the presence of a suitable reducing agent, preferably an alkali metal dithionite su'ch as sodium dithionite or an alkali metal borohydride such as sodium borohydride or lithium aluminum boro¬ hydride, in a suitable solvent. Sodium dithionite reduction is conveniently carried out in an aqueous solution; the dihydro product of formula (II) is usually insoluble in water and thus can be readily separated from the reaction medium. In the case of sodium boro¬ hydride reduction, an organic reaction medium is employed, e.g., a lower alkanol such as methanol , an aqueous alkanol or other protic solvent. More typically, however, the quaternary of formula (I) is reduced in the same reaction mixture as the reduction of tech- netium to an appropriate oxidation state, affording the formula (III) radiopharmaceutical in one step from the formula (I) quaternary. Further details of the one-step reduction are given hereinbelow. It will be apparent from the foregoing that a wide variety of derivatives of formulas (I) through (IV) can be obtained in accord with this invention. In a particularly preferred embodiment of this invention, however, there are provided novel chelating agent precursors of the formula wherein each Rg is independently selected from the group consisting of H and C j -C 7 alkyl, or 'an R g can be combined with the represents ^.C=0; each R, is independently selected from the group consisting of H and C j -C**-, alkyl, or an Rg can be combined with the adjacent ^C-R g such is a radical o the formula ftft J k) s -A-IQC + l } wherein each R, 1s independently selected from the group consisting of H and C j -C 7 alkyl; (alk) is a straight •sip * branched lower alkylene group ( ι-C«) which additionally may contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being nonadjacent to each other and also being nonadjacent to -A'-; X" and n are as defined with formula (I); m' is a number which when multiplied by n is equal to one; s is zero or one; -A- is -NH-, -C00-, -0-, -C0NH-, wherein R 8 is C 1" C 7 alk - y1 » or -CC-N" wherein R g is CJ-C-J alkyl; R 9 when -A- is -NH-, -0- or -N-, then [QC + ] is a radical 8 of any one of formulas (a) through (j ) hereinabove; when -A- is -CONH- or -CON- or when HN NH has I R 9 the imide structure depicted above, th Ten [QC + ] is a radical of any one of formulas (k) through (s ) herein- above; and when -A- is -C00-, then [QC + ] is a radical of any one of formula (i) through (xiv) hereinabove. Preferably the salts of formula (la) have the partial structure or are position isomers and/or homologs of the first two partial structures shown. It is also preferred that when ,5 R 7 R 7 R 7 (αlk) β -A-(0C + l , then each R, is preferably H and (alk) is preferably a group, or a C j -Cg alkylene group interrupted by an oxygen atom in the chain; and that when (σlk^-A-iQC", then (alk) is preferably a C.-Cg alkylene group, or a C*.•*-C°- alkyle in the chain. then the prese l ( l ) A are -C00-, -CH 2 0-, -C0NH-, -CH 2 NH- and -CH 2 0CH 2 CH 2 0 -, Preferred values for [QC + ] in formula (la) are as given in conjunction with formula (I) hereinabove. Corresponding to the preferred novel chelating agent precursors of formula (la) are the preferred novel chelating agents of' the formula wherein R g and R g are as defined with formula (la) and HN N'H is a radical of the formula OH wherein R 7 , (alk), s and -A- are as defined with formula (la); when -A- is -NH-, -0- or -N- wherein R g is CJ-CJ alkyl, then [OHC] is a radical of any one of formulas (a') through (j'' ) hereinabove; when -A'- is -CONH- or -CON- wherein R g is CJ-C-J alkyl or when HN^ . NH R 9 DH has the imide structure depicted above, then [OHC] is a radical of any one of formulas (fc') through (s' 1 } hereinabove; and when -A- is -C00-, then [OHC] is a radical of any one of formulas (i') through (xiv 1 *) hereinabove. Preferred compounds of formula (Ila) are the dihydro derivatives corresponding to the pre¬ ferred compounds of formula (la). Likewise preferred are the novel radiopharmaceuticals in which a formula (Ila) compound is chelated with a radioactive metal, especially with technetium. Es¬ pecially preferred radiopharmaceuticals have the formula (lllα ) wherein R g and Rg are as defined with formula (la) and N .N is a radical of the formula DHC1 IDKC1 wherein R^, alk, s and -A- are as defined with formula (la) and [OHC] is as defined with formula (Ila) above; and the corresponding quaternaries, "locked in" the brain, especially those of technetium, which have the formula wherein R, m X " and n are as defined with formula (la) and fl N is a radical of the formula wherein R ? , alk, s, -A'- and [QC + ] are as defined w i th formula (la) above. The preferred complexes of formulas (Ilia) and (IVa) are those which cor ¬ respond to the preferred derivatives of formulas (la) and (Ila). Chelatlng agent precursors, chelating agents and radiopharmaceutlcals within the purview of the present Invention can also be prepared " by reacting CH 2 -NH 2 29 17 and thereafter reacting the amino group of the 5 obtained compound 2$ with the carboxyl group of compounds such as the 2-oxoρropionaldehyde bis (thiosemicarbazone) derivatives having a free carboxyl group. Illustrative of such compounds is 3-carboxy-2-oxoρropionaldehyde biS(N-methylthiosemi- carbazone), a bifunctlonal chelating agent described in Yokoyama et al U.S. Patent No. 4,287,362. The Yokoyama et al COOH- containing chelating agents also can be derivatized as generally described here¬ inabove for derivatizing COOH groups, e.g. as depicted in Schemes 1 and 2. Moreover, Yokoyama et al's chelating agents of the formula wherein R 1 , R 2 , R 3 and R 4 are each H or C j -Cg alkyl can be first converted to the corresponding esters (e.g. replacing -COOH with -COOCgHg), which can then be reduced to the corresponding alcohols (replacing -COOCgH c with -CHgOH) or converted to the corresponding amides; the alcohols or amides can then be converted to the corresponding carrier-containing derivatives; see, for example, the discussion of Schemes 9-16 above. Other process variations will be apparent from the many reaction schemes depicted hereinabove. Another bifunctional chelating agent which can be readily converted to the redox system-containing chelating agent precursors, chelating agents and radio¬ pharmaceuticals of this invention is a compound of the formula which is also known as amino DTS and which is de ¬ scribed in the literature, e.g. in Ja£. ^. Nucl. Med. ϋ ' , 610 (1982). Amino 0TS can be readily converted to the derivatives of the present invention by reacting it with an activated ester of nicotinic acid or the like and quaternizing the resulting ester to afford the corresponding precursor of formula (I), which can then be utilized as generally described herein to prepare the corresponding compound of formula (II) and radiopharmaceuticals of formulas (III) and (IV). See, for example, Scheme 30 below. Yet another group of known chelating agents which is particularly well-suited for conversion to the redox system-containing chelating agent precursors, chelating agents and radiopharmaceuticals of the present inven¬ tion can be represented by the formula wherein Rl, R 2 , R 3 and R 4 are each H or C -C3 alkyl and n' is an integer of 0 to 3. See, for example, Yokoyama et al U.S. Patent No. 4,511,550 and Australian Patent No. 533,722. An especially preferred chelating agent encompassed by this group is known as amino-PTS, or AEPM, and has the structure Amino-PTS can be converted to the derivatives of the present invention via the activated ester, as described supra in connection with amino-OTS. See, for example, Scheme 33 below. The exact structure of the resultant technetium complex 224 has not been determined; it is possible that the C=N and C=S bonds are also reduced during one of the reduction steps. One possible structure for 224 is as follows: (A similar structure could be depicted for complex lj65 of Scheme 30). A preferred alternate route to derivatives of amino-PTS, amino-DTS and the like 1s illustrated by Schemes 31 and 32 below. This route reacts a quater- nized activated ester with the ligand containing a primary amine group to form the quaternary chelating agent precursor of formula (I) in one step. Variations in this highly desirable single step, as well as in the two step alternative shown in Schemes 30 and 33 , will be apparent from the discussion of a number of reaction schemes depicted hereinabove. Also, it should be pointed out that introduction of the carrier moiety in its quaternary form, typically via a quaternlzed activated ester such as 191 or 17, is generally advantageous over the two step method, and any of Schemes 6-7 and 9-17 hereinabove could be readily modified accordingly. ______ 162 161 CHjI Q uaternary form of rodlophaπnaceutlcal -locked in- brain 166 • -f =«J re \ « t— o e »r> T i . -= < -3_= * X I I» -x SCHEME ?2 1Q_1Y_ oxidation Quaternary form of radiopharmaceutical 223 "locked In" broln 215 S_H£_E__3 222 continue as in Scheme 32 225 In a like manner, the presently contemplated car¬ rier system can be incorporated into the structure of a novel technetium-99m radiopharmaceutical whose chelate portion Is the residue of an amino- o r hydroxy-substi- tuted iminodiacetic acid, e.g., N-[3-(l-naρhthyloxy)2- hydroxypropyl ] iminodiacetic acid. Such substituted iminodiacetic a.cid chelating agents are known and are described in Loberg et al U.S. Patent No. 4,017,596; such chelating agents can be protected to the extent necessary and then the trigonell inate or other carrier structure introduced through reaction with the - H2 or -OH group in the chelating agent. Similarly, suitable chelating agents and their precursors that include a di hydropyridi ne^±pyridinium salt carrier system can be prepared by reacting Com¬ pound 17 or the like with a chelating agent which is a substituted-al kyl monophosphonic acid such as amino- butylphosphonic acid, 1 ,5-diaminopentyl phosphonic acid, and the like. Chelating agents of this general type are also known and are illustrated by those described in Kδhler et al U.S. Patent No. 3,976,762. Yet other chelating agents containing one or two carboxyl functions are described in Fritzberg U.S. Patent No. 4,444,690. Carrier-containing technetium chelates corresponding to the Fritzberg chelates can be prepared as generally described hereinabove and as illustrated by Schemes 1 and 2 above. Fritzberg U . S t Patent No. 4,444,690 describes an interesting series of 2,3-bis(mercaptoalkanoamide)- aikanoic acid chelating agents of the general formula wherein X 1s H or -COOH, and R and R 1 are H or lower alkyl, and. water-soluble salts thereof, used to pre¬ pare the corresponding radiopharmaceuticals of the formula wherein X is H or -COOH, and R and R* are H or lower alkyl. The Fritzberg chelating agents are prepared from the corresponding 2,3-d1aminoalkaπo1c acids by esterlfication with a lower alkanol containing dry HCl, followed by treating the resultant alkyl ester with a chloroalkanoyl chloride to form the bis(chloro alkanoamide)ester, followed by treating that ester with 6( ) }—CSNa, followed by alkaline hydrolysis of the resultant 2,3-bis(benzoylmercaptoalkanoamido)- aikanoic add ester to produce the 2,3-bis(mercapto- alkanoamido)alkanoic acid chelating agent. Preparation of an Analog from 3,4-diaminobenzo1c add Is also disclosed by Fritzberg. Many of Fritzberg's synthetic steps can be adapted to produce the formula (I) derivatives of this invention In which. In place of the -COOH group, in Fritzberg's chelating agent, there Is an (alfc) s -A-£QC group wherein the structural variables are as defined with formula (la) hereinabove. See, for example, Schemes 12, 13 and 16 above. Radiopharmaceuticals containing a dihydro- pyrldine^_=_:pyridin1uιπ salt carrier system can also be prepared using a novel chelating agent precursor obtained by reacting, in pyrldine as the solvent, the aforementioned Compound 29 with nitrilotrlacetic anhydride according to the known general procedure illustrated 1n Kunn et al U.S. Patent No. 4,418,208. The dlcarboxyl pyridinium salt obtained from the above reaction is obtained in purified form as follows: The volatile components of the reaction mixture are evaporated to an oily semisolid on a rotary evaporator. A solution of 10 percent aqueous sodi um hydroxide (w/v) is used to dissolve the oily semlsolid. The resulting solution is extracted with methy ene chloride to remove the remaining pyrldine from the aqueous phase. The pH value of the aqueous phase is thereafter lowered to a value of about 6-8. The resulting aqueous solution is then reduced in volume to about that of the original pyrldine solution, and about five times that volume of a saturated solution of picric acid is added to form a picrate derivative precipitate. The plcrate precipitate Is washed with cold, distilled water, and is then dissolved in a 10 percent aqueous solution of hydrochloric acid (v/v). The resulting solution Is extracted with methyl chloride until there is no more yellow color 1n the aqueous or methylene chloride phases. The resulting, colorless aqueous phase is concentrated to about the volume of the original pyrldine solution, and is then lyophyllzed to provide the chelating agent in dry form. The dried chelating agent is then dissolved in ethanol and precipitated using the diethyl ether flooding technique described in Example 4 hereinbelow. Still another useful chelating agent precursor can be prepared by reacting equimolar quantities of ethylenediarainetetracetic acid and acetic anhydride in dry pyrldine following the teachings of Nunn et al U.S. Patent No. 4,418,208, and thereafter reacting a further equimolar amount of Compound (2.9) to form the monoa ide adduct. The tridentate chelating agent salt is obtained as described Immediately above. The tridentate chelating agent precursor salt so obtained is thereafter reacted with the 99ra per- technate 1on as described 1n Example 5 below, which reduces both the technetium and the pyridinium salt, to form a 1:1 1 igandcradioactive metal ion complex drug delivery system of this invention. The complex so formed is ionically neutral inasmuch as the five valences of the reduced technetium-99m metal are taken up with one oxygen atom and three carboxylate oxygens, and the pyridinium ring is in its reduced, di ydropyridine form. As aforesaid, the preparation of the chelating agent precursors, chelating agents a-nd radiopharma¬ ceutlcals of this invention must be tailored to the particular starting materials used, especially as regards the presence of reactive functional groups in addition to the group which is to be linked to the carrier radety. The stage at which the carrier is introduced and the manner in which the carrier is Introduced will be determined accordingly. Often 10 the carrier must be introduced in quaternary form at an early stage of the synthesis as illustrated here¬ inabove. When not so required, it may be more desirable to react an appropriate starting material such as nicotinic anhydride with an NH«- or OH- containing ι _ X3 ligand or ligand precursor, and quaternize at a later stage, after coupling the ligand (chelating agent) and the 3-pyridinecarbonyl group. The processes depicted above are only intended to be illustrative. Many variations, for example, 0 can be made in the chelatirwj portions of the molecule, and such variations will naturally affect the synthetic scheme, particularly as regards the necessity for introducing protecting groups and subsequent removal thereof. 5 In order to further illustrate the present invention and the advantages thereof, the following specific examples are given, it being understood that same are intended only as illustrative and in no wise limitative. Example 1: N-(J:-butoxycarbonyl),N-(2-mercaptoethyl)- glycyl N'-(2-arainoethyl)horaocysteinaraide (Compound 14 of Scheme 3} N-(jt-butoxycarbonyl),N-(2-mercaptoethyl )glycyl ho ocysteine thiolactone (13) is prepared as described in Examples 1 and 2 of Byrne et al U.S. Patent No. 4,434,151, and is dissolved (1.0 gram; 3 raillimoles) in 25 milliliters of tetrahydrofuran (THF). The result ¬ ing solution is then cooled to about 0°C, and ethyl- enediamine (1.8 grams; 30 milli oles) is added to form a new solution. The resulting new solution is maintained for about one hour. The volatile components of the solution are thereafter removed with a rotary evaporator. n-Butanol (about 10 milliliters) is added to the "dried" solution components and the liquid components of the resulting composition are again removed by rotary evaporation. The last step is repeated until the vapors remaining in the evaporation vessel do not cause a moistened pH-indicator paper to indicate a basic pH value, thereby also Indicating that the ethylenedia ine has been substantially removed and that the N-(t-butoxycarbonyl),N-(2-mercaptάethyl}- glycyl N'-(2-aminoethyl)homocysteinamide so obtained Is substantially pure. Example 2a: Succinimidyl nicotinate (Compound 16 of Scheme 3} Nicotinic acid (12.3g;.0.1 mole) and N-hydroxy- sucdnlmide (11.5g; 0.1 mole) are dissolved in 300 millIliters of hot dioxane. Tfve mixture is cooled on an ice-bath and dicyclohexylcarbodiImide (20.6g; 0.1 mole) In 30 mlliπiters of dioxane fs added. The reaction mixture 1s stirred, with cooling, for ap¬ proximately three hours, then refrigerated for at least 2 hours. The precipitated dicyclohexylurea 1s removed by filtration, the solution is condensed under vacuum, and the yellowish solids which precipitate are recrystallized from ethyl acetate. White crystals (14g) of succinimidyl nicotinate are obtained (Yield 63. St) . Structure of the product is confirmed by NMR. Example 2b: Succinimidyl Trigonellinate (Compound 17 of Scheme 3 ) Succinimidyl nicotinate 16 (3.3 g; 15 mmole) is dis¬ solved in 50 milliliters of dioxane and 3.7 millHiters (8.2g; 60 mraole) of methyl iodide is added. The reaction mixture 1s refluxed for about 48 hours. The yellow crystals which precipitate during the reaction are removed by filtration, washed with ethyl ether and dried under vacuum at 40°C. Succinimidyl trigonellinate (5.2g) is obtained (Yield 96.3%) . Structure of the product is confirmed by NHR. An improved method for preparing Compound 17 is as fol lows: A solution of 9.0 g (41 mmol) of the ester 16 and 11:6 g (82 mmol) of methyl iodide in 40 mL of anhydrous acetone 1s heated in a pressure bottle under an argon atmosphere for 16 hours. The yellow precipitate which forms 1s removed by filtration. Yield 14 g of Compound 17, darkening at 170°C and melting at 197°C. Example 3: N- t_-butoxycarbonyl ) , N-(2-mercapto- ethyl )glycyl N* -[l-methyl-3-(2-N- ethyl )carbamoyl pyridinium iodidejhomo- cysteinamide (Compound 18 of Scheme 3) N-(_t^butoxycarbonyl ) , N-(2-mercaρtoethyl Jglycyl N'-(2-aminoethyl Jhomocysteinamide —Compound 14— (1.12 grams; 0.003 mole) and succinimidyl trigonel 1 inate — Compound 17— (0.70 gram; 0.0025 mole) are dissolved in 25 milliliters of dry pyridine with stirring. An ap¬ propriately sized, "micro" Oean-Stark trap and condens- er are added to the reaction flask and the solution is heated to and maintained at a temperature of 80°C until substantially all of the succinimidyl ester is replac¬ ed. The pyridine is removed on a rotary evaporator using jv-butanol as a "chaser" as described before for the ethyl enediamine removal. Once the pyridine is re¬ moved, the dried residue is triturated with THF and the solid is removed by filtration and washed several times with THF with care not to dry by air suction. The solid so obtained is thereafter dried in vacuo to provide Compound 18, N(_t-butoxycarbony1 ) , N-(2-mer- captoethyl Jglycyl N* -[1-methyl -3-(2-N-eth l )carbamoyl - pyridinium iodidej omocysteinamide. Example 4: N-(2-raercaptoethyl)glycyl N*-[l-methyl- 3-(2-N-ethyl)-carbamoylpyridinium iodide] homocysteinamide (Compound 19 of Scheme 3) N-(_t-butoxycarbonyl), N-(2-mercaptoethyl )glycyl N'-[l-oethyl-3-(2-N-ethyl)carbamoylpyridinium iodide] homocysteinamide —Compound 18—(1.24 grams; 0.002 mole) 1s dissolved with stirring in absolute ethanol (50 rallimters) and cooled to about 0°C in an 1ce-water bath. HCl gas 1s bubbled through the stirred solution for 15 minutes, and the solution is thereafter stirred for an additional 15 minutes. Diethyl ether (200 il- Hliters) is thereafter added to the solution to pre¬ cipitate the salt. The precipitate is filtered and washed with diethyl ether with care not to dry the precipitate by air suction. The solid is then dried in vacuo to provide N-(2-mercaptoethyl)glycyl-N'- [l-methyl-3-(2-N-ethyl)carbamoylpyridin1um iodide] homocysteinamide. Example 5: Complex Between N-(2-mercaptoethyl)glycy1- N'-Cl-methyl-S-fN-Σ-ethyUcarbamoyl-l^- d1hydropyr1dyl]homocysteinamide and the 0xotechnate-99m ion (Compound 20 of Scheme 3) N-(2-mercaρto.ethyl)-glycyl-N , -[l-methyl- 3-(2-N-ethyl)carbaraoylpyridinium iodidejhomocystein- aralde —Compound 19 — (89 milligrams; 0.17 milHπiole) is dissolved in 1.0 millillter absolute ethanol and 1.0 miliniter of IN NaOH. A 1.0 millillter generator eluant of 99m TcO^ (5 to 50 milliCuries) in saline is added. Then, 0.5 millillter of dithionite solution, prepared by dissolving 336 milligrams of Na 2 S 2 0 4 per milliliter of 1.0 NaOH, is added and the mixture heated sufficiently to reduce both the technetium and the pyridinium salt and to form the complex between N- (2-mercaptoethyl)glycyl-N'-[l-methyl-3-(N-ethyl)car- amoyl-l,4-d1hydropyr1dyl]homocysteinamide and the oxotechnate-99m 1on. The complex so prepared is buffered by the addition of 1.0 milliliter of IN HCl and 4.0 milliliter of 0.1 molar NaH 2 P0 4 , pH 4.5 buffer. Example 6: Complex Between N-(2-mercaptoethyl )glycyl- N , -Cl-methyl-3-(N-2-ethyl)carbamoyl-l,4- dihydroqu1nolyl]homocysteinamide and the 0xotechnate-99m ion A radiopharmaceutical coupled to a carrier based upon a reduced, dihydroquinol ine carrier such as the title complex can be prepared following the steps out¬ lined in Examples 1-5, but replacing the nicotinic acid in Example 2a with an equivalent quantity of 3- quinoHnecarboxyl ic acid. Example 7: N-[2-(acetamidomethy Jmercaptopropionyl] - glycyl N'-(2-aminoethyl )homocysteinamide (Compound 25 of Scheme 4) N-[2-(S-acetamidomethyl Jmercaptopropionyl ) - glycyl homocysteine thiolactone (Compound 24 of Scheme 4), prepared as described in Examples 7 and 9 of Byrne et al U.S. Patent No, 4,434,151, Is suspended (1.0 gram; 3 millimoles) in 25 milliliters of THF. The resulting suspension is cooled to a temperature of about 0°C. in an ice-water bath, and ethyl- enediamlne (1.8 grams; 30 milliraoles) is added to form a new solution. N-£2-(acetaraidoraethyl) er- captopropionyl]g1ycyl N'-(2-arainoethyl)homocysteinamide is thereafter obtained In a manner substantially similar to that described in Example 1 for the analogous compound. Example 8: N-(2-(acetamidomethyl)mercaptopropionyl]- glycyl N'-[l-methyl-3-(2-N-ethyl)carbamoy1- pyridinlura 1όd1de]hόmocysteinam1de (Compound 26 of Scheme 4) Compound 26 of synthetic Scheme 4 is obtained in a manner analogous to that used in Example 3 to prepare Compound 19, but Compounds 17 and 25 are uti l i zed as starting materials. Example 9: Complex Between N-(2-raercapt-oprop1onyl)- glycyl-N'-[l-raethyl-3-(2-N-ethyl)carbamoyl- 1,4-dihydropyrldine]homocysteinamide and the 0xotechπate-99ra ion— (Compound 27 of Scheme 4) Compound 26 of Example 8 (0.17 millimole) is dissolved in 1.0 milliliter of absolute ethanol and 1.0 milliliter of IN NaOH. The complex of this Example i s thereafter prepared in a manner analogous to that described for the complex of Example 5. Here, the basic solution frees the 2-mercaptopropionyl group from its protective N-methylene acetamido group, while the dithionite reduces both the pyridinium and technetium salts Example 10: 3,4-d1th1a-2,2.5.5-tetramethylhexane- l,6-d1one (Compound 68 of Scheme 9) To a stirred solution containing 115.6 g (1.6 mol) of Isobutyraldehyde 67 in 184 g of carbon tetra- chloride are added dropwise, at 40-50 β C, 108. (0.8 mol) of 97* sulfur monochloride. The addition Is carried out during a 2.5 hour period, under a nitrogen atmosphere, with occasional cooling. The solution is maintained at 30-45°C, with stirring, for an ad- ditional 48 hour period, under a current of nitrogen, to remove the hydrogen chloride liberated. The solution 1s distilled under vacuum to give 72 g of the desired 3,4-d1thia-2,2,5,5-tetramethylhexane-l,6-dione, i.e. Compound 6.8 of Scheme 9. NMR(C0C1 3 ) $ 9.1(s,2-CJH0), Example 11: Ethyl 2,3-(diammonium)propionate dichloride (Compound.70 of Scheme 9) To 10 g (0.07 mol) of ethyl cyanoglyoxylate-2- oxime 69 are added 125 ml of absolute ethanol, 15 g of hydrogen chloride gas and 1 g of platinum oxide. The mixture is hydrogenated using a Parr-hydrogenation apparatus. Hydrogen uptake is complete in 3 hours. The product 1s removed by filtration and taken up in 75 mL of hot 95* ethanol. The ethanol solution is filtered. The filtrate is then cooled and the crystalline product which separates on standing is removed by filtration. There is thus obtained ethyl 2^3- (diammonlum)propionate dichloride, i.e. Compound 70 of Scheme 9. Yield 5 g (35%), melting point 164-f66°C (Ht. 164.5-165 β C); H NMR(0 2 0) δ 4.5(m,3,-NCHCO-, -0CH 2 CH 3 ). 3.5(m,2,-NCH 2 CH-) f 1.3(t,3,-0CH 2 CH 3 ). Example 12: 5,8-diaza-l,2-dith1a-6-ethoxycarbonyl- 3,3,10,10-tetramethylcyclodeca- ,8-diene (Compound 71 of Scheme 9) Procedure I 5 To 1.0 g (5 mmol) of the b1saldehy< * e 68 is added dropwise a solution of 1.0 g (5 mmol) of the ester 70 and 0.9 m of pyridine in 30 mL of methanol at 0°C wTiile under a nitrogen atmosphere. The addition takes place during a 10 minute period. The solution is 10 then allowed to stand for 1 hour, after which time 10 L of water 1s added. The solution turns turbid and warms to 26 β C. The solution is stirred for an additional 20 minute period, after which time the white precipitate which forms settles out of solution. 15 The precipitate is removed by filtration and then taken up in chloroform. The chloroform solution is dried.over sodium sulfate. Removal of the solvent and trituratlon of the residue with petroleum ether gives white plate-like crystals of the desired product, Z0 5,8-diaza-l,2-d1thia-6-ethoxycarbonyl-3,3,10,10-tetra¬ methylcyclodeca-4,8-diene, i.e. Compound 71 of Scheme 9, In 53* yield (1 g), melting point 98-99 β C. IR (thin film) 3450, 1740. 1650 cm" 1 ; NMR(C0C1 3 ) ύ 6.9(m,2,C-N=CH-) 3.0-4.6(m,5,-0Cϋ 2 CH 3 , -NCHgCji-N-), 1.5[m,15,2^C(CJi 3 ) 2 , -0CH 2 CH 3 ]. 5 Procedure II To 1.0 g (5 mmol) of the bisaldehyde 68 in 10 L of methanol is added dropwise 1.0 g (5 mmol) of the ester 70 and 1 g (12 mmol) of sodium bicarbonate in 20 mL of a 50:50 by volume mixture of methanol and water. the mixture Is stirred at 0°C for 10 minutes, after which time 10 L of water 1s added. The re ¬ sultant mixture Is maintained at room temperature, with stirring, for 2 hours. Water is added until the white precipitate which forms separates out of solution. The precipitate is removed by filtration and taken up 1n chloroform. Removal of the solvent by rotary evaporation affords 0.4 g (21% yield) of Compound 71, having a melting point and H NMR spectrum Identical to the product of Procedure I. Procedure III A solution of 8 g of the ester 70 and 7 mL of pyridine 1n 200 mL of methanol 1s added dropwise over a two hour period to a solution of 8 g of bisaldehyde 68 in 25 mL of methanol. The reaction mixture 1s cooled in an ice bath after the addition for 1 hour, then is allowed to remain at room temperature for 1 hour. The reaction mixture is then placed in a freezer (-20°C) overnight. The solution is concentrated to one-third volume, water is added and the aqueous solution is extracted with chloroform. The chloroform extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Removal of the solvent leaves a viscous mass, which is dissolved in 20 mL of hexane. The hexane solution is cooled in an acetone/dry ice bath until a white powder separates. The product 1s removed by filtration and taken up in chloroform. The chloroform solution is concentrated. White crystals of Compound 7JL a re formed on standing. Yield 7 g, melting point 95-96°C. NMR and IR as in Procedure I . -130- Example 13: 6-carbamoyl-5,8-d1aza-l,2-d1thia-3,3,10,10- tetramethylcyclodeca-4,8-diene (Compound 72 of Scheme 9) Procedure I: A solution of 5 g of the ester 71 in 20 L of -***_ tetrahydrofuran and 20 mL of aqueous ammonia is stirred at room temperature for 2 hours, after which time it is allowed to stand at room temperature for 24 hours. Removal of solvent leaves a white powder which is removed fay filtration. The product, 6-carbamoyl- 5,8-diaza-l,2-dithia-3,3,10,10-tetramethylcyclodeca- 4,8-diene, i.e. Compound 72 of Scheme 9, is crystallized from a mixture of isopropanol and water. Yield 4 g (88%) , melting point 181-183 β C. IR ( Br) 3300, 3100, 1650 cm ~ 1 ; 1 H NMR(C0C1 3 ) 6 7.0(m,2,-jiC=N-), 6.4(broad .6[m,3, -NCH 2 -CH(N-)C0-], 1.5, Procedure II: A solution of 5 g of the ester 71 in 20 mL of tetrahydrofuran, 20 mL of ethanol and 20 L of aqueous ammonia (28%) is stirred at room temperature for 16 hours. Removal of the solvent leaves Compound 72 as a white powder, which crystallizes from toluene as white plates. Yield 4 g, melting point 193-194°C. IR and NMR as in Procedure I. Example 14: 5-carbamoyl-5,8-diaza-l,2-d1th1a-3,3,l0,l0- tetramethylcyclodecane (Compound 73 of Scheme 9) To 3.7 g of the amide 7 _2• in 25 mL of 95% ethanol 5 Is added 2 g of sodium borohydride. The mixture is stirred at room temperature for 2 hours, then 1s heated at reflux for 2 hours. The solution is thereafter concentrated J^ vacuo and water is added to precipitate the product. The white crystalline product 1s removed * by filtration. Recrystallization from a mixture of isopropanσl and water affords 6-carbamoyl-5,8-diaza- 1,2-d1thia-3,3,10,10-tetramethylcyclodecane, i.e. Compound 73 0 f Scheme 9, as fine white needles melting at 138-139 * °C. Yield 3 g. X H NMR(C0CL 3 ) 6 2.3-4.0[m,7, -NCϋ 2 Cϋ-N-, 2-N H 2 -C(CH 3 )-S-], 1.8(broad band, 2, 5 -C0NH 2 ), 1.3[m,14, C(CH 3 ) 2 , -CNH-CH 2 -]. Example 15: 5-aminomethyl-4,7-diaza-2,9-dimethyldecane- 2,9-d1th1ol (Compound 74 of Scheme 9) 0 A solution of 1.8 g of the amide 73 in 50 L of dry tetrahydrofuran Is added dropwise to a slurry of 1 g of lithium aluminum hydride in 100 mL of dry tetrahydrofuran. The addition takes place over a g 30 minute period. The mixture is then heated at the reflux temperature for 20 hours. At the end of that time, the reaction mixture 1s first cooled and then quenched with saturated Na- tartrate solution. The aqueous phase Is extracted with chloroform. The com¬ bined organic phase is then dried over sodium sulfate. Removal of the solvent by rotary evaporation affords, as a viscous oil, 5-aminomethyl-4,7-diaza-2,9-dimethvl- decane-2,9-dithiol , i.e. Compound 74 of Scheme 9; H NMR (C0C1 3 ) ζ 2.8[m,9,-NCH 2 CH-C(CH 2 )NH-, " 2- CJi 2 -C(CH 3 ) 2 S-], 1.5[m,14, .C(CH 3 ) 2 , -SH]. - 132- Example 16: 5,8-d1aza-l,2-dithia-3,3,l0,l0-tetra- methylcyclodeca-4,8-diene (Compound 87 of Scheme 11) To 3.15 g of the dialdehyde 68 is added 4.0 g of ethylenedia ine, with stirring and * cooling, over a period of 10 minutes. The thick mass which results 1s stirred for an additional one minute period, then allowed to stand for 1 hour at room temperature and subsequently cooled for 16 hours in a freezer (-20°C). The solid is removed by filtration and washed with 500 mL of water. The white product is then taken up in chloroform and the chloroform solution is dried over sodium sulfate. Removal of the chloroform gives 2.5 g of 5,8-diaza-l,2-dithia-3,3,10,10-tetra- methylcyclodeca-4,8-dieπe, i.e. Compound 87 of Scheme 11, as a white crystalline product, melting at 168- 170°C (lit. 162-164°C, 163-166 β C). X H NMR(C0C1 3 ) -5 6.9(s,2.-HC«=N-), 4.2,3.0(doublet of doublet. 2, 2-CH 2 -CH 2 ), 1.40[s,6,-C(CH 3 ) 2 -]. AnaL.Calcd. for C 10 C 18 N 2 S 2 : C » 52 - 13 5 H » 7 ~ e8 ' ~ H ~ 2- 6; S. 27.83. Found: C, 52.20; H, 7.90; N, 12.14; S, 27.74. Example 17: 5,8-diaza-l,2-dithia-3,3,10,10-tetra- raethylcyclodecane (Compound 88 of Scheme 11) A solution of 0.5 g of 87 and 0.3 g of sodium borohydride in 23 mL of ethanol 1s stirred at room temperature for 1 hour, then is heated at the reflux temperature for 20 minutes. Then, 10 mL of water are added and the mixture is heated for an additional 10 minutes. The solvent is partially removed fay rotary evaporation -133- and the residue is extracted three times with 10 mL portions of chloroform. The chloroform extract is dried over sodium sulfate and the solvent is removed by rotary evaporation. The resultant liquid solidifies on cooling. Flash chromatography (eluent hexanes/di- chloromethane/lsopropanol 5:1:1 by volume) gives 5,8- diaza-l,2-d1thia-3,3,l0,l0-tetramethylcyclodecane, I.e. Compound 88 of Scheme 11, as a solid, melting at 52-53 β C. 1 H * NMR(C0C1 3 ) 6 3-2.1(m,10 ring protons), l.l,1.2(s,6 CH 3 , CH 3 ). Example 18: N-C(4,7-diaza-2,9-dimercapto-2,9-dimethyldec- 5-yl)raethyl]nicotinamide (Compound 75 of Scheme 9) A solution of 9 mmol of the activated ester 16 in 30 mL of dimethoxyethane is added dropwise over a period of one hour to 8.4 mmol of the amine 74 in 70 L of dimethoxyethane. Thin layer chromatog aphy after one hour, using a solvent system of petroleum ether/acetone/dichloromethane/isopropyl alcohol (10:5:5:1 fay volume), indicates a major component has been obtained. The solvent 1s removed by evap¬ oration .and the residue is treated with water. The resultant mixture is extracted with chloroform and dried over sodium sulfate. Removal of the solvent affords the desired product, Compound 75 of Scheme 9. -134- Example 19: 3-{N-£(4',7'-diaza-2',9'-dimercapto- 2',9'-dimethyldec-S • -yl)methyl]carbamoyl}- 1-methylpyridinium iodide (Compound 76 of Scheme 9) Compound 75 is reacted with methyl iodide according to the general procedure described in Example 2b above. Prepared in this manner is the desired quaternary salt, i.e. Compound 76 of Scheme 9. Example 20: Complex formation The general procedure of Example 5 can be repeated to convert the other quaternary salts of formula (I) to the corresponding radiopharmaceuticals, e.g. to convert Compound 76 to Complex 78 , Compound 83 to Complex 85 and so forth. Example 21: 5-am1nomethyl-4,7-d1aza-2,9-dimethyl- decane-2,9-dith1ol (Compound 74 of Scheme 9) To a slurry of 11 g of lithium aluminum hydride in 00 mL of ry tetrahydro furan 1s added dropwise, over a 2 hour period and under an argon atmosphere, 13 g of the amide 7 1n 150 mL of dry tetrahydrofuran. After the addition is complete, the reaction mixture 1s heat¬ ed at reflux for 30 hours, then quenched with satur- ated Na- tartrate solution. Treatment with 3N hydro¬ chloric acid and then with saturated sodium carbonate solution, followed by filtration and extraction of the filtrate with dichloromethane, affords an organic solu¬ tion which is dried over magnesium sulfate. Removal of the solvent affords the desired amine, Compound 74 of Scheme 9, as a viscous oil. A sample of the free amine thus obtained is dis¬ solved in diethyl ether and hydrogen chloride gas is added. The white powder which separates is removed by filtration and purified from ethanol/water to give the corresponding hydrochloride salt melting at 225-228°C. l H NMR (D 2 0) 6 3.3-4.2(m,9H,HCl,NH 2 CH 2 , -HCl NHCJ * ^), 1.5Cm,12H,C(CH3) 2 ]. Anal . Calcd. for C 11 H 30 C1 3 3 S 2 * * H 2 0: C33.63; H.8.21; N,10.69; Cl ,27.07 ; S.16.32. Found: C,33.93; H,7.94; N.10.60; Cl.27.05; S,16.25. Example 22 Comound 192 of Scheme 24 A mixture of 1 g of the amine 74, 75 mL of acetone and a catalytic amount of p-toluenesul fonic acid is heated at reflux for 24 hours. The solvent is removed by rotary evaporation and the residue is taken up in chloroform and treated successively with saturated aqueous sodium bicarbonate solution, aqueous sodium hydroxide solution (10%) and saturated aqueous sodium chloride solution. The solution is dried owe r magnes¬ ium sulfate. Removal of the solvent leaves a viscous mass. Thin layer chromatography (CHCl 3 /methanol , 2:1) indicates two major components having Rf values of 0.13 and 0.73. The component with the lower Rf value shows a positive niπhydrin test, confirming that it is the desired primary amine 192, while the component with the higher R f value is negative. 1 H NMR of the R f 0.73 component (CDC1 3 ): ' 2.9, 2.5, 1.3-1.5. *H NMR of the R 0.13 component (CDC1 3 ): ~ 3.0, 2.8, 2.3, 1.2-1.7. Obtained in this manner is the desired bisthi azol idine primary amine, Compound 192 of Scheme 24. Example 23: Compounds 193 and 76 of Scheme 24 Reaction of the bisthiazol idine primary amine 192 with the quaternized activated ester 17 or 191 affords the corresponding bisthlazol idine quaternary, i.e. Com¬ pound ljJ3 of Scheme 24, which can then be de-protected, e.g. by reaction with mercuric chloride, followed by treatment with hydrogen sulfide, to give the unpro¬ tected quaternary, Compound 76 of Scheme 24. Example 24: Compound 81 of Scheme 10 A solution of 7 g (3 mmol) of the ester 71 in 50 mL of dry tetrahydrofuran is added dropwise over a period of 1 hour to 1.8 g (47 mmol) of lithium aluminum hydride in 200 mL of dry tetrahydrofuran. The mixture 1s heated at reflux for 16 hours, after which time the reaction is quenched with -Na tartrate solution. The organic phase is dried over sodium sulfate. Removal of the solvent leaves a yellow viscous mass. Yield 4 g (65%) of the desired alcohol , Compound 8 of Scheme 10. *H NMR (C0C1 3 ) θ 2.2-2.8, 3.5, 2.3, 1.5. Example 25 Compound 83 of Scheme 10 Following the general procedure of Example 22, but substituting an equivalent quantity of the alcohol 81 1n place of the amine 74, affords the bisthiazol idine alcohol , i.e. the protected counterpart of Compound 81 of Scheme 10.. That protected alcohol can then be sub¬ jected to the procedures detailed in Example 23 above to ultimately give the corresponding unprotected qua- ternary, Compound 83 of Scheme 10. Example 26: Compound 32 of Scheme 5 A solution of 17 mL of 2N Hthium borohydride 1n tetrahydrofuran is added to 300 L of dry tetrahydro¬ furan under an argon atmosphere. To that solution are added 10 g (0.035 mol) of the ester 40 in 100 mL of dry tetrahydrofuran. The resultant cloudy solution 1s heated at reflux for 1.5 hours. The reaction is quenched with water and the organic phase 1s washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Removal of the solvent leaves, as a white powder which is very soluble in water, the corresponding primary alcohol , Compound 32 of Scheme 5. Yield 2 g (24%); melting point 85-90°C; 1 H NMR (acetone-d 6 ) δ 7-8, 4.15, 3.3-4.0. Example 27: Compound 33 of Scheme 5 To 1 g of the alcohol 32 in 40 mL of dry ethanol is added a solution of sodium thiobenzoate prepared from 0.2 g of sodium in 10 mL of ethanol and 1.26 g of thiobenzolc acid 1n 5 mL of ethanol. The reaction mixture is stirred at room temperature for 10 minutes, then is heated at 45°C for an additional 10 minutes. The mixture becomes very thick and difficult to stir and a yellow product separates. The product, Compound 33 of Scheme 5, is removed by filtration and washed with water. Yield 1.2 g, melting point 151-152°C; X H NMR (0MS0-d 6 /acetone-d 6 ) 6 7.4-8.3, 3.85, 3.1-3.6. Example 28: Compound 168 of Scheme 18 Cyanoacetlc a d (8.5 g; 0.1 mol) and N-hydroxy- succinimide (11.5 g; 0.1 mol) are combined in 150 mL of dry tetrahydrofuran. To the cooled suspension 1s added dropwise a solution of 20.6 g (0.1 mol) of dicyclo- hexylcarbodϋmide in 50 L of dry tetrahydrofuran over a period of 2 hours. The mixture is allowed to warm to room temperature overnight. The white precipitate which forms is removed by filtration and washed with 50 mL of tetrahydrofuran. The combined filtrates are con¬ centrated to give 8 g (44% yield) of the ester 167. The product crystallizes from isopropyl alcohol as white needles, m.p. 140-142°C. A solution of the ester 167 (0.62 g, 3.4 mmol) in 10 mL of dry dimethoxyethane is added dropwise to a stirred solution of the cyclic diamine 88 (0.8 g, 3.4 mmol) in 20 mL of dry dimethoxyethane at room temperature. The solution is stirred for an additional 2 hours, after which 1t 1s allowed to stand for 16 hours. The dimethoxyethane 1s removed by rotary evaporation and the brown residue is suspended in water to remove N-hydroxysucc1n1mide. The product 1J58 1s removed by filtration and crystallized from toluene/ hexanes as fine brown needles; yield 0.9 g (88%); m.p. 142-143°C; IR (thin film) 3450, 2250, 1675 cm - " 1 1 .; 1HNMR (CDC1 3 ): <5 3.7, 2.4-3.6, 3.5, 1.3, 1.25. Anal . Calcd. for C 13 H 23 N 3 0S 2 : C, 51.79; H, 7.69; N, 13.94; S, 21.27. Found: C, 51.99; H, 7.12; N, 14.01; S, 21.34. Example 29: Compound 169 of Scheme 18 A solution of 3 g of the nitrile 168 in 50 mL of dry tetrahydrofuran 1s added dropwise over a 30 minute period to a stirred slurry of 1.2 g of lithium alumi¬ num hydride 1n 100 mL of dry tetrahydrofuran, under a nitrogen atmosphere. The pale yellow solution is heated at reflux for 7 hours, then stirred at room temperature for 50 hours. The slurry is hydrolysed with a saturated Na-K tartrate solution, the aqueous phase 1s extracted with dichloromethane and the com¬ bined organic extracts are dried over sodium sulfate. Rotary evaporation of the solution leaves the amine 1 9 as a viscous yellow oil. Example 30: Compound 170 of Scheme 18 A solution of the activated ester 1 (2 g, 9 mmol) in 30 mL of dimethoxyethane is added dropwise over a period of 1 hour to the amine 169 (2.6 g, 8.9 mmol) in 70 mL of dimethoxyethane. After 1 hour, thin layer chro otography (eluent: petroleum ether/acetone/ dichloromethane/isopropyl alcohol, 10:5:5:1) indicates one major component having an Rf of 0.6. The solvent is removed by evaporation, the residue is treated with water and the mixture 1s extracted with chloroform and dried over sodium sulfate. Removal of the solvent leaves HO as a viscous yellow mass, yield 2.1 g; HNMR (C0C1 3 ) <S 7.3-9.3, 2.6-3.6, 1.5. Example 31: Compound 40 of Scheme 19 To a mixture of 10 g of sodium bicarbonate in 50 mL of water and 200 mL of toluene 1s added the ester 70 (2 g, 0.01 mol), with cooling 1n an 1ce-bath. Chloro- acetyl chloride (5 g, 0.44 mol) solution is added drop- wise, then the mixture is allowed to warm to room tem¬ perature. The organic phase 1s extrated with ethyl acetate, washed with water and brine and then dried over magnesium sulfate. Removal of the solvent leaves 40 as a white mass; yield 2 g (70%); m.p. 85-87°C. *HNMR (CDC1 3 ): δ 7.12, 7.6, 4.67, 4.2, 4.07, 3.75, 1.3. Example 32: Compound 41 of Scheme 19 A solution of the ester 40 (2 g, 9 mmol) in 20 mL of dry ethanol is prepared under argon. To this 1s added a solution of sodium thiobenzoate in dry ethanol (prepared from 0.45 g of Na in 20 L of ethanol to form sodium ethoxide, which is reacted with 2.5 g of 97% thiobenzoic acid). Precipitation occurs immediately. The reaction mixture is heated at reflux for 5 minutes, then is diluted with ethyl acetate. The aqueous phase is extracted with ethyl acetate. The combined organic extracts are washed with water and brine and dried over magnesium solvent. Removal of the solvent leaves 4.1 g of a creamy white powder. Crystallization from toluene gives 2.4 g of white product, 41, m.p. 125-127°C (Lit. 129.5-131°C) . NMR is consistent with structure. Example 33: Compound 176 of Scheme 19 A mixture of lodoethanol (7.5 g, 43 mmol), nicotinamide (5.2 g, 43 mmol) and 150 mL of acetone 1s heated at reflux for 18 hours. The mixture 1s cooled and the product 176 1s removed by filtration. Yield 1.5 g (12%); m.p. 87°C. Example 34: Compound 177 of Scheme 20 To a mixture of 10 g of potassium carbonate in 20 mL of water and 200 mL of toluene is added 5 g(32 mmol) of 3,4-diaminobenzoic acid. To the cooled mixture is added 14.4 g (127 mmol) of chloroacetyl chloride in 10 mL of toluene over a period of 1 hour. After the addi¬ tion is complete, the mixture is stirred at room temperature for 30 minutes. The brown product is removed by filtration and crystallized from ethanol. Yield 8 g(82%) of 177, m.p. 240-241°C. Example 35: Compound 178 of Scheme 20 To 25 mL of ethanol is added 0.17 g of sodium metal , followed by 1.1 g (7.4 mmol) of thiobenzoic acid. To the resultant yellow-brown solution is added 1.16 g (3.7 mmol) of the acid \ TJ . The mixture turns yellow Immediately and thickens. The mixture is diluted to 200 mL with dry ethanol and heated at reflux for 2 hours. The product is removed by filtration and crystallized from Isopropyl alcohol /tetrahydrofuran . Yield 1 g (53%) of 178, m.p. 244-245°C Example 36: Compound 179 of Scheme 20 To 15.2 g (0.03 mol) of the acid 178 and 3.45 g (0.03 mol) of N-hydroxysuccinimide 1s added 500 mL of dry tetrahydrofuran. To the resultant suspension is added 6 g (0.03 mol) of dicyclohexylcarbodlimide 1n 50 mL of dry tetrahydrofuran, over a period of 1 hour. The resulting mixture is stirred at room temperatre for 16 hours. The white precipitate of dicyclohexylurea which forms is removed by filtration and the filtrate in concentrated in vacuo to give a brown product. Flash chromatography of a small sample (eluent: dichloromethane/aetone, 3:1) gives the ester 1^ , m.p. 117-118°C. Example 37: Compound 183 of Scheme 21 A solution of 2-bromoethyl amine hydrobromide (10.2 g, 0.05 mol) and nicotinamide (6 g, 0.05 mol) in 150 mL of dry dimethyl formamide 1s heated at 140°C for 16 hours. The precipitate which forms is removed by filtration and washed with ether. Yield 14 g (88%), m.p. 280°C (decomp.) of 183. Example 38: Compound 75 of Scheme 9 A solution of the amine 74 (2 g, 7.5 mmol) and the activated ester 16 (1.65 g, 7.5 mmol) 1n 100 mL of dry dimethoxyethane is stirred at room temperature for 24 5 hours. The solvent 1s removed by rotary evaporation and the residue is treated with water. The viscous product 1s extracted with chloroform and dried over magnesium sulfate. Removal of the solvent leaves 75 as a viscous mass. NMR is consistent with structure. The 0 compound 1s used without further purification. Example 39: Compound 76 of Scheme 9 A solution of the amide 7 (0.5 g), 5 mL of methyl iodide and 20 mL of nitromethane is stirred at room temperature for 7 days under argon. After the second 5 day, a precipitate begins to form. The precipitate is removed by filtration and treated with acetone. Yield 150 mg of the quaternary salt 76, m.p. 210-215°C (decomp.) 1 HNMR (0MS0-d 6 ) δ 8.3-9.5, 4.5, 3.0-4.0, 1.2- 1.5. Example 40: Compound 77 of Scheme 9 o To a solution of 0.5 g (1 mmol) of the quaternary salt 76 in 10 mL of water is added 0.25 g (3 mmol) of sodium bicarbonate and 0.61 g (3 mmol) of sodium dithionite. Ether (50 mL) is added and the mixture is stirred under a nitrogen atmosphere for 30 minutes whlle being cooled in an ice-water bath. The aqueous phase is extracted with dichloromethane. The combined organic phase 1s dried over magnesium sulfate. Obtained in this manner is the dihydro derivative 77. Example 41: Compounds 81 and 81a of Scheme 10 A solution of the ester 71 (10 g, 35 mmol) in 100 mL of dry tetrahydrofuran is added dropwise over a priod of 30 minutes to a slurry of lithium aluminum hydride (4 g, 94 mmol) in 300 mL of dry tetrahydro- furan, with cooling in an ice-bath. The slurry is then heated at reflux for 24 hours. The reaction is quenched with saturated Na-K tartrate solution, then with 3N hydrochloric acid and finally with sodium carbonate. The aqueous phase is extracted with chloroform. The combined organic phase is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Removal of the solvent leaves the alcohol 81 as a viscous mass. The product is taken up in ether saturated with hydrogen chloride, with cooling in an ice-bath. Yield 6 g of the salt 81a, m.p. 190-191°C. NMR and elemental analysis consistent with structure. Example 42: Compound 190 of Scheme 23 To 24.6 g (0.17 mol) of nicotinic acid and 32 g (0.19 mol) of N-hydroxyphthal imide in 300 mL of tetra¬ hydrofuran are added 41 g of di cycl ohexyl carbodi imide 1n 200 mL of tetrahydrofuran voer a period of 2 hours. The reaction mixture 1s stirred at room temperature for 24 hours. The white precipitate of dicycl ohexylurea which forms is removed by filtration. The filtrate is concentrated, leaving a white mass which Is crystall- lized twice from ethyl acetate, once from Isopropyl- alcohol , and again from ethyl acetate. The various batches of 190 thus obtained melt at 132-135°C and 148- 150°C. X HNMR (C0C1 3 ) δ 8.4-9.5 (m, 3H, Py-H); 7.95 (s, 4H, Ar-H); 7.5-7.7 (m, 1H, Py-H). Example 43: Compound 191 of Scheme 23 A solution of the ester 190 (5 g, 18.6 mmol) and methyl iodide (6 g, 42.4 mmol) in 40 mL of acetone is placed in a pressure bottle and heated in an oil bath (bath temperature 65°C) for 12 hours. The product is removed by filtration. Yield 4.5 g (59%) of the quaternized activated ester 191. The product darkens at 175°C and melts at 185°C. l H M (OMSO-dg) δ 8.2-9.9 (m, 4H, Py-J*); 8.1 (s, 4H, Ar-H} ; 4.52 (s, 3H, N-CH3). Example 44: Compound 180 of Scheme 21 To the activated ester 179 (9 g, 14.9 mmol) in 100 mL of dimethoxyethane is added ethanolamine (0.918 g, 15.4 mmol) in 50 mL of dimethoxyethane. The reaction mixture is stirred at room temperature for 48 hours; the white precipitate which forms is then removed by filtration. Concentration of the solvent gives an additional 2 g of the product. Yield 4 g (49%) of 180, melting at 205-210°C. ^NMR (DMS0-d 6 ): δ 7.5-10, 4.8 * , • - ~ * tj / ^ « _> • Example 45: Compound 179 of Scheme 25 The acid 178 (8 g) and N-hydroxysuccinimide (1.8 g) are combined in 200 mL of tetrahydrofuran. To that suspension is added dicyclohexylcarbodiimide (3.16 g) in 25 mL of tetrahydrofuran over a period of 2 hours. The mixture is then stirred at room temperature for 16 hours. The white precipitate is removed by filtration and the filtrate is concentrated in vacuo. The product, the activated ester 179, is crystallized from toluene. Exmaple 46: Compound 194 of Scheme 25 To 4.7 g (8 mmol) of the activated ester 179 is added a solution of 0.14 g (8 mmol) of ammonia in 150 mL of dimethoxymethane. The reaction mixture is stir¬ red at room temperature for 16 hours. The solution is concentrated _i____n_ —va_c_______—uo to give 3 g of the amide 1^9 ^ 4 as a white product. Example 47: Compound 76 of Scheme 23 To 6.12 g (23 mmol) of the amine 74 in 100 L of anhydrous dimethyl formamide is added dropwise, over a period of 4 hours, 2.2 g (6 mmol) of the activated ester 17 in 80 mL of anhydrous dimethyl formamide. The . reaction is carried out at -47°C (aceton1tr1le/dry 1ce) while under an argon atmosphere. The reaction mixture is stirred for an additional 2 hours at -47°C, then is placed in a freezer (approximately -20°C) overnight. The dimethyl formamide is removed in vacuo. To the residue is added 150 mL of xylene and the solvent is again removed in vacuo. The residue is taken up in 75 mL of benzene and triturated with petroleum ether, after which a gummy product separates. This process is repeated twice. The resultant gummy residue is suspended in the same solvent. HPLC data indicate one major peak with some amine being present. Flash chromatography (eluent, methanol) of a small sample of the reaction mixture gives a product which by HPLC Indicates two components, the residual amine and the desired quaternary salt 76. Example 48: Compound 76 of Scheme 23 To 1.5 g (5.7 mmol) of the amine 74 in 20 mL of dimethyl formamide is added 0.5 g (1.4 mmol) of the quaternary compound 1 **9* * *1 in 20 mL of dimethyl forma- mide. The reaction is carried out at -47°C over a two hour period, under an argon atmosphere. The solvent is removed in vacuo and the residue is treated 5 times with benzene/petroleum ether. HPLC data again indi¬ cates most of the amine has been removed, leaving the desired quaternary salt 76. Example 49: 1-methyl-3-[N-{ (β- {4-Cl ' ,2' -bis(4* *- met ylthiosemicarbazono)prop-l' -yl]- phenyl }ethyl }}carbamoyl ]pyr1din1um iodide hemlhydrate (Compound 222 of Scheme 32) Amino-PTS hydrochl oride monohydrate (100 mg , 0.238 mmol) 1n dry pyridine (15 mL) with the quaternized activated ester 1 * 9_*•*1 (200 mg , 0.488 mmol) is heated at gentle reflux. After 2 hours, no amino-PTS remains and the mixture is set aside to cool. Volatiles are removed in vacuo and the residue is washed with water (10 mL) and taken into chloroform (40 mL). The aqueous layer is re-extracted with chloroform (20 mL) and the combined, dried (MgSO /j ) organic layers are evaporated to dryness, leaving an orange oil. The oil is taken into a minimum of warm ethanol. Trituration results in precipitation of a pale yellow powder. Yield 75 mg (51%) of the quaternary salt 222, melting at 214- 216°C. IR (KBr) 3000-3600, 1670, 1535, 1470 cm "1 ; X HNMR (DMS0-d 6 ) δ 9.5, 8.1-9.4, 7.1-7.6, 4.5, 2.3- 3.8. Analysis calculated for C 2 2H29 8l0S- 1/2H 2 0: C, 42.51: H, 4.86; N, 18.01; S, 10.31. Found: C, 42.70; H, 4.77; N, 17.74; S, 10.42. Example 50: l-{ {4'- {β-[N-( I' ■ -methyl-1' • , "- dihydropyridin-3' '- l )carbon l amino]- eth l }phenyl }}propane-l,2-d1one bis(4- ethylthiosemicarbazone) , hydrated with 1/4 mole H 2 0 (Compound 223 of Scheme 32) The quaternary salt 222 (104 mg, 0.17 mmol) in ice-cold deaerated water (30 mL) is treated with sodium bicarbonate (140 mg, 1.7 mmol) and sodium dithionite (30 mg, 1.7 mmol). Ethyl acetate (50 mL) is added to - the stirred solution, and nitrogen gas (scrubbed free of oxygen by passing through a basic pyrogallol solution) is bubbled through the reation mixture. After 45 minutes, the organic and aqueous layers are separated, and the aqueous layer is re-extractd with ethyl acetate (30mL). The combined organic layers are dried ove r magnesium sulfate and the volume of solvent is reduced to half by evaporation in vacuo. The product is eluted through a short column of neutral alumina (Aldrich, 150 mesh, Brockmaπ 1). Evaporation of the solvent affords the dihydro derivative 223 as a yellow powder. Yield 57 mg (70%). The product darkens at 130°C and decomposes at 185°C. ^ MR (CDC1 3 /DMS0- d 6 ) δ 8.0-8.3, 7.1-7.5, 6.95, 6.0-6.4, 5.6-5.8, 4.5- 4.8, 3.4-3.7, 3.2, 2.8-3.4, 2.3. Analysis calculated for C22H3θ 8θS2*l/4H 2 0: C, 53.80; H, 6.41; N, 22.82; S, 13.04. Found: C, 53.80; H, 6.27; N, 22.63; S, 13.02. The foregoing reaction schemes and examples illustrate the preparation of a wide variety of deriva¬ tives of this Invention in which the dihydropyri¬ dine * - *** ±pyridinium salt redox carrier moieties can be one of the [DHC]/[QC + ] groupings depicted on pages 19 to 38 hereinabove wherein p is zero. The preparation of yet other derivatives of this type will be readily apparent to those skilled 1n the art from the teachings hereinabove, particularly in light of the illustrative synthetic methods detailed in the PCT application referred to hereinabove, i.e. PCT/US83/00725. More¬ over, it is possible to adapt the methods of PCT/US83/00725 and of the present specification to the preparation of the instant derivatives containing the carrier moieties depicted on pages 19 to 38 above wherein p = 1 or 2. Some illustrative methods for preparing the compounds of this invention in which the carrier comprises a CNH-al ] p group as depicted hereinabove wherein p = 1 or 2 are set forth below. It should be noted that just as the p = 1 or 2 derivatives can be made by methods analogous to those depicted in the reaction schemes for the p = 0 derivatives, so, too, the p = 0 derivatives can be prepared by methods analogous to those specifically described below for the p = 1 or 2 derivaties. The methods described below must of course be adapted to the particular chelating agent selected for derivation, in analogous fashion to the reaction schemes depicted above. ILLUSTRATIVE SYNTHETIC METHODS I. Methods for Derivatizing -NH 2 or -NH- Functions METHOD A The chelating agent or its protected counterpart (e.g. 7 _4 in Scheme 9 or 1«*9*••2 in Scheme 24 or 2•**2*•»1 in Scheme 32) is reacted with nicotinuric acid chloride, with nicotinuric acid anhydride, or with nicotinuric acid in the presence of a suitable coupling agent such as dicyclohexylcarbodiimide, in an appropriate organic solvent, to afford the corresponding glycyl nicotina¬ mide, or nicotinuramide. The nicotinuramide is then quaternized, typically by treatment with methyl iodide in a suitable organic solvent, to afford the quaternary derivative, which is then de-protected if necessary and reduced by treatment with sodium dithionite or sodium borohydride as generally described hereinabove. Alternatively, glycine may be first reacted with a reagent capable of introducing an amino protecting group such as benzyloxycarbonyl or t-butoxycarbonyl and the N-protected glycine then reacted with the chelating agent or its protected counterpart in the presence of a coupling agent such as dicyclohexylcarbodiimide, followed by removal of the N-protecting group, followed by reaction with nicotinoyl chloride or nicotinic anhydride, or with nicotinic acid in the presence of dicyclohexylcarbodiimide or other suitable coupling agent, to afford the nicotinuramide. The nicotinura¬ mide may then be quaternized and the quaternary de- protected if necessary and reduced as described in the preceding paragraph. The procedure of the second paragraph of this method may be repeated using picolinlc add or its acid chloride or anhydride, or isonicotlnic add or its acid chloride or anhydride, in place of nicotinic acid or its acid chloride or anhydride, respectively, to con¬ vert chelating agents or their protected counterparts to the corresponding glycyl picol inamides and glycyl isonicotinamides and then to the corresponding quaternary and dihydro derivatives. The procedure of the first paragraph of this method may be similarly adapted. Moreover, any of these procedures may be repeated, substituting a different amino acid or nicotinic acid derivative thereof for the glycine or nicotinuric acid used above, e.g. replacing glycine with alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine. Alternatively, the chelating agent or its pro¬ tected counterpart may be reacted with an activated ester of nicotinuric acid or the like, e.g. a sudnlmidyl ester such as and the product quaternized, de-protected if necessary and then reduced as described in the first paragraph of this method to afford the identical products. As yet another and highly desirable alternative, the activated ester, e.g. the siccinimidyl ester depicted above, may be quaternized (e.g. by treatment with methyl iodide) and the quaternized activated ester then reacted with the drug. The quaternary compound thus obtained may then be de-protected if necessary and reduced as described in the first paragraph of this method. METHOD B This method is of particular use when the -NH- function is part of an amide or imide or a very low pKa primary or secondary amine. The chelating agent (e.g. 52 in Scheme 7) is first reacted with an aldehyde [e.g. formaldehyde, benzalde- hyde, acetaldehyde or chloral (CI3CCHO)]; for example, in the case of formaldehyde, one converts the -NH- function to a CH OH l c -N- function and thus forms a suitable bridging group. The resultant compound is then reacted with nicotinuric acid in the presence of a suitable dehydrating agent, or with nicotinuric acid chloride or nicotinuric acid anhydride, to form the corresponding nicotinuric acid ester of the partial formula The resultant Intermediate is then quaternized and reduced as in Method A. The alternative process utilizing an activated ester or quaternary derivative thereof which is described in Method A may be utilized to * advantage here as well. Alternatively, the steps subsequent to formation of the CH-OH -N- function may be replaced with steps analogous to those detailed in the second paragraph of Method A. The procedure of the preceding paragraph may be repeated using picolinic acid or its acid chloride or anhydride, or isonicotinic acid or its acid chloride or anhydride, in place of nitotlnic acid or its acid chloride or anhydride, respectively (as called for in the second paragraph of Method A), to convert chelating agents to the corresponding glycyl picolinic acid esters and glycyl isonicotlnic acid esters and then to the corresponding compounds of this invention. Deri- vatives of amino acids other than glycine may be similarly prepared. See Method A, last paragraph. As yet another alternative, the intermediate compound containing the CH OH 1 •** group or the like may be reacted with thionyl chloride to afford the corresponding compound containing a CH 2 C1 -N- or similar group. That derivative may then be reacted with a metallic salt (especially a silver or thallous salt) of nicotinuric acid or the like (formed, e.g. by reacting nicotinuric acid or the like with fresh silver hydroxide or oxide or with thallous ethoxide). The resultant nicotinuric acid ester of the partial formula or like derivative is then quaternized and subsequently reduced as in Method A. METHOD C The procedure of the second paragraph of Method A is followed, except that removal of the N-protecting group is followed by reaction with 3-quinol inecar- boxylic acid or its acid chloride or anhydride instead of nicotinic acid, or its acid chloride or anhydride. The procedure of the first paragraph of Method A may be similarly adapted to the production of the 3- quinol inecarboxyl ic acid derivatves. Moreover, Method C may be combined with Method to afford the corres¬ ponding 3-quinol inecarboxyl ic acid derivatives of the type of chelating agent used in that method. The procedure of the first paragraph of this method may be repeated using 4-isoquinol inecarboxyl ic acid or its acid chloride or anhydride to convert chelating agents such as those mentioned with Methods A and B to the corresponding 4-isoquinol inecarboxyl ic acid derivatives. The procedure of the first or third paragraph of this method may be repeated, substituting a different amino acid, e.g. alaniπe, valine, leucine, phenyl¬ alanine, isoleucine, methionine, asparagine or glutamine, for the glycine used in the first step.. (See Method A, second paragraph). The general procedures described above may be utilized to provide the 1,2-dihydro derivatives as well as the 1 ,4-dihydros. METH00 D The procedure of the second paragraph of Method A s followed, except that a reactant of the formula C00CH 2 C00H cor is used place of nicotinic acid. (That starting material may be prepared by reacting nicotinic anhydride, nicotinoyl chloride or nicotinic add with glycol ic acid.) The foregoing procedure can be repeated using picolinic acid or its acid chloride or anhydride, or isonicotlnic acid or its acid chloride or anhydride, in place of nicotinic acid or its acid chloride or an¬ hydride, respectively, in the preparation of the reactant depicted above. This variation affords a reactant of the formula -./QV- COOCH.COOH which can then be used in place of nicotinic acid to prepare derivatives of chelating agents or their protected counterparts such as those mentioned with Method A. METHOD E The procedure of the second paragraph of Method A s followed, except that a reactant of the formula -CONHJ (iH 2 ) n C00H wherein n *■ *• 1-3, preferably 2, is used in place of nicotinic acid. (That reactant may be prepared from nicotinamide, e.g. when n = 2 , by reacting 3- iodopropionic acid with nicotinamide.) The quaternary salt thus obtained may then be de-protected if necessary and reduced as described in Method A. See also Scheme 26. The procedure described above can be repeated using picolinamide or isonicotinamide in place of nicotinamide in the preparation of the reactant depicted above. This variation affords a reactant of the formula which can then be used in place of nicotinic acid in the procedure of the first paragraph of this method. II. Methods for Derivatizing -OH Functions METHOD F The chelating agent or its protected counterpart (e.g. 81 of Scheme 10, or the corresponding bisthiazo- lidine) is reacted with nicotinuric acid chloride, with nicotinuric acid anhydride, or with nicotinuric acid in the presence of a suitable coupling agent such as dicyclohex lcarbodiimide, in an appropriate organic solvent, to afford the corresponding glycyl nicotinate, or nicotinurate. The nicotinurate is then quaternized, de-protected if necessary and subsequently reduced as described above in Method A. The alternative process utilizing an activated ester or quaternary derivative thereof which is described in Method A may be utilized to advantage here as well. Alternatively, glycine may be first reacted with a reagent capable of introducing an amino protecting group such as benzyl oxycarbonyl or t-butylcarbonyl and the N- protected glycine then reacted with the chelating agent or its protected counterpart in the presence of a coupling agent such as dicyclohexylcar¬ bodiimide, followed by removal of the N- protecting group, followed by reaction with nicotinoyl chloride or nicotinic anhydride, or with nicotinic acid in the presence of dicyclohexylcarbodiimide or other suitable coupling agent, to afford the nicotinurate. The nicotinurate may then be quaternized, de-protected if necessary and the quaternary reduced as described in the preceding paragraph. The procedure of the second paragraph of this method may be repeated using picolinic acid or its acid chloride or anhydride, or isonicotiπic acid or its acid chloride or anhydride, in place of nicotinic acid or its acid chloride or anhydride, respectively, to con¬ vert chelating agents to the corresponding glycyl picolinic acid esters or glycyl isonicotinic acid esters and then to the corresponding compounds of the invention. The procedure of the first paragraph of this method may be similarly adapted. Moreover, any of these procedures may be repeated, substituting a different amino acid or nicotinic acid derivative thereof for the glycine or nicotinuric acid used above, e.g. replacing glycine with alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine. METHOD G The procedure of the second paragraph of Method F is followed, except that a reactant of the formula wherein n * * * 1-3, preferably 2 (prepared as described in Method E), is used in place of nicotinic acid. The quaternary salt thus obtained may then be de-protected if necessary and reduced as described in Method A. Method G is of particular use in preparing deriva¬ tives of chelating agents in which the hydroxy function is hindered. Alternatively, Method G may follow Method F, second paragraph, except that it employs a reactant of the formula H (prepared as described in Method E) in place of nicotinic acid. The procedures of this method may be repeated, substituting a different amino add, e.g. alanine, valine, leucine, phenylalanine, isoleucine, methionine, asparagine or glutamine, for the glycine used in the first step. (See Method A, second paragraph). METHOD H The procedure of Method F, second paragraph, is followed, except that removal of the N- protecting group is followed by reaction with 3-quinolinecar- boxylic acid or its acid chloride or anhydride instead of nicotinic acid or its acid chloride or anhydride. The procedure of the first paragraph of Method F may be similarly adapted to the production of the 3- quinolinecarboxylic acid derivatives. The procedure of Method H may be repeated using 4- isoqulnol inecarboxyl ic acid or its acid chloride or anhydride in place of 3-quinolinecarboxyl1c acid or its acid chloride or anhydride. 3-Quinol inecarboxyl ic acid or its acid chloride or anhydride or 4-1soquinolinecarboxyl ic acid or its acid chloride or anhydride can also be substituted for nicotinic acid or its acid chloride in Method B, fourth paragraph, to afford the corresponding derivatives. The general procedures described above may be utilized to provide the 1,2-dlhydro derivatives as well as the 1 ,4-dihydros. METHOD I The procedure of the second paragraph of Method F is followed, except that a reactant of the formula C0OCH 2 C0OH @ is used in place of nicotinic acid. A starting material of the formula set forth immediately above can also be substituted for nicotinic acid in Method B, paragraph 4, to afford the corres¬ ponding derivatives. Alternatively, Method I may follow Method F, second paragraph, except that it employs a reactant of the formula (prepared as described in Method D ) . These alternative Method I starting materials may be substituted for nicotinic acid in Method B, fourth paragraph, to give the corresponding derivatives. The procedure of the first or third paragraph of this method may be repeated, substituting a different amino acid, e.g. alanine, valine, leucine, phenyl¬ alanine, isoleucine, methionine, asparagine or glutamine, for the glydne used in the first step. (See Method A, second paragraph). III. Methods for Derivatizing -COOH Functions METH00 J Nicotinuric acid (N-nicotinoyl glycine) or an activated ester thereof is reacted with an a inoal kanol H 2 N-Z*-0H wherein Z' is C -C β straight or branched alkylene, e.g. 2-aminoethanol , to afford the corresponding inter¬ mediate alcohol, e.g. in the case of 2-aminoethanol , an intermediate of the formula That alcohol is then reacted with a chelating agent containing one or more -COOH functions, in the presence of a suitable coupling agent such as dicyclohexylcar¬ bodiimide. The compound thus obtained is then quaternized and subsequently reduced as described above in Method A. Nicotinuric acid is commercially available. However, it and analogous starting materials can be readily prepared by reacting the selected amino acid with the acid chloride of nicotinic acid, of picolinic acid, of isonicotinic acid, of 3-quiπol Inecarboxylic acid, of 4-isoquinolinecarb'oxyl ic acid or the like to afford the desired N-substituted amino acid, which can then be reacted with an a inoal anol as described above. METHOD K The chelating agent is first reacted with ethylene glycol (or other dihydroxyal kanol having up to 8 carbon atoms), in the presence of a suitable coupling agent such as dicyclohexylcarbodiimide, to convert the -COOH function(s) to the corresponding -C00CH 2 CH 2 0H 0 (or other -C-O-Z'-OH) group(s). Then, a N-protected amino acid, such as N-benzy oxycarbonylg ycine, which has been prepared as described in Method A, is reacted therewith in the presence of dicyclohexylcarbodiimide or other appropriate coupling agent. Removal of the protecting group, e.g. by catalytic hydrogenation , af¬ fords a derivative of the chelating agent in which the original -COOH group(s) has/have, in the case of utilizing ethylene glycol and glycine, been converted to the structure • C00CH 2 CH 2 0CCH 2 NH2 That I ntermedi ate 1 s then reacted with a compound of the formul a or the like, prepared as described in Method E, in the presence of a coupling agent such as dicyclohexylcar¬ bodiimide, to give the desired quaternary derivative. Subsequent reduction to the corresponding dihydro derivative proceeds as described in Method A. The procedure described above may be repeated utilizing a reactant of the formula K or the like, prepared as described in Method E, in place of the intermediate of the formula METHOD L A chelating agent containing one -COOH function is reacted with an equivalent amount of Inositol , In the presence of dicyclohexylcarbodiimide or other suitable coupling agent, to convert the -COOH function to a group of the structure Reaction of that intermediate with nicotinuric acid, in the presence of a suitable coupling agent, or with an activated ester of nicotinuric acid, affords an inter¬ mediate in which the original -COOH has been converted to (OR}* wherein each R is H or - the number of original hydroxy groups esterified varying with the amount of nicotinuric acid employed. Subsequent qua- ternization and reduction are carried out as 1n Method A. Alternatively, the above procedure may be repeat- ed, replacing nicotinuric acid with an analogous start¬ ing material , prepared by reacting the selected amino acid with the acid chloride of nicotinic acid, of pico- linlc acid, or isonicotlnic acid, of 3-quinolinecar- boxylic acid, of 4-isoquinolinecarboxyl1c acid or the like. Repetition of the procedure of the first paragraph of this method utilizing a greater amount of the chelating agent (e.g. 2 to 5 or more moles per mole of inositol) provides an intermediate containing from 2 to 5 acid residues and from 4 to 1 hydroxyl groups. That intermediate is then reacted with nicotinuric acid to convert at least one hydroxyl group to the corresponding -O group. Subsequent formation of the quaternary and reduction proceed as in Method A. METHOD M The chelating agent is first reacted with 1,2- propylene glycol (or other dihydroxyalkanol having up to 8 carbon atoms), in the presence of a suitable coupling agent such as dicyclohexylcarbodiimide, to convert the -COOH functioπ(s) to the corresponding -COOCHpCHOH c 1 CH 3 0 or other -C-O-Z'-OH) group(s). The resultant inter- mediate is then reacted with nicotinuric acid, in the presence of an appropriate coupling agent, or with an activated ester of nicotinuric acid, to give an inter¬ mediate of the partial formula Subsequent quaternization and reduction are carried out as in Method A. Alternatively, the above procedure may be repeat¬ ed, replacing nicotinuric acid with an analogous start- ing material , prepared by reacting the selected amino acid with the acid chloride of nicotinic acid, of pico¬ linic acid, of isonicotlnic acid, of 3-quinol inecar- boxylic acid, of 4-isoqui nol i necarboxl ic acid or the like. METHOD N Glucosamine, of the structural formula is reacted with nicotinuric acid, using equimolar amounts of the reactants, in the presence of a suitable coupling agent such as dicyclohexylcarbodiimide, or . wi th an acti vated ester of ni coti nuri c acid The resul tant i ntermedi ate of the formul a is then reacted with a chelating agent containing one reactive -COOH function, in the presence of dicyclo¬ hexylcarbodiimide or other appropriate coupling agent, replacing one or more of the hydroxy groups with acid residue(s), the number of groups replaced varying with the relative amounts of reactants used. Alternatively, the above procedure may be repeat¬ ed, replacing nicotinuric acid with an analogous start¬ ing material , prepared by reacting the selected amino acid with the acid chloride of nicotinic acid, of pico¬ linic acid, of isonicotinic acid, of 3-quiπol inecar- boxylic acid, of 4-isoquinolinecarboxylic acid or the like. - 171 - Suitable nontoxic pharmaceutical y acceptable diluents or vehicles for use with the present complexes of formula (III) will be appareπt-to those skilled in this art. See, for example, Remington's Pharma¬ ceutical Sciences, 4th Edition (1970). Obviously, the choice of suitable diluents or vehicles will depend upon the exact nature of the particular dosage form selected. The dosage ranges for administration of the com¬ plexes according to this invention will vary with the size and species of the subject, the objective for which the -complex is administered, the particular dosage form employed, and the like, as discussed below. The quantity of given dosage form needed to deliver the desired dose of the radiopharmaceutical, of course, depends upon the concentration of the complex in any given pharmaceutical composition/dosage form thereof and the radioactivity thereof. By way of example only, a 5-50 mg/kg dose of formula (III) radiopharmaceutical, injected into the tail vein or carotid vein of rats, due to the "lock ' in" mechanism will exhibit a very significant difference between brain and peripheral levels of radioactivity, with- consequent ready radioimagiπg of the brain; imaging at approximately 60 to 90 minutes after administration will be most effective, since it will take advantage of this brain/peripheral differential. The instant radiopharmaceuticals are generally administered intravenously. Sustained release ad¬ ministration, typically by slow intravenous Infusion, will further enhance the s1te-specif1city of the instant redox system. " The rate of release of the formula (HI) radiopharmaceutical from the sustained release system should be comparable to the rate of j^ vivo oxidation of the dihydro form (III) to the quaternary form (IV) in order to achieve the greatest degree of enhancement of specificity. In a further aspect, the present invention also provides a process for the manufacture of a diagnostic agent for the visualization of an organ such as the brain. To that end, the blood-brain barrier penetrating form, formula (III), is admixed with an aqueous buffer medium having a pH value of about 4 to about 8 preferably of about 6.5 to about 7.5, in an effective radloi aging amount. Preparation of the radiopharmaceutical can be carried out in the hospital or like location where the patient is found in order to minimize losses of radioactivity caused by the decay of the radioactive metal. Inasmuch as the preparation for visualization is 1n- jectable, it must be sterile arid pyrogen-free; preferably, it is also Isotonic. To this end, a so-called labeling kit can be provided that permits a simple, rapid and safe labeling of the solution to be injected with the radioactive metal, e.g., techπetium-99m. Such kits are especially desirable when a short-lived radio- isotope such as technetium 99-m is used. The kit Includes a collecting vial for receiving and/or containing an aqueous medium in which the com¬ plexing reaction can be effected. Additionally, the kit includes the chelating agent of formula (II) or chelating agent precursor of formula (I) and a pharma¬ cologically acceptable reducing agent for reducing the radioactive element to an appropriate oxidation state for complexing with the chelating agent [and also for reducing the pyridinium carrier moiety to the corresponding dihydropyridine form, when a chelating agent precursor of formula (I) is present]. In the case of technetium-99m, the radioactive element is received from a radionuclide generator as an aqueous pertechnetate (TcoT) solution such as an eluate in isotonic saline, as is well-known in the art. The amount of Tc-99m required to produce a quantity of formula (III) radiopharmaceutical suf¬ ficient for diagnostic purposes is generally from 0.01 m1lliCur1e ( Ci ) to about 500 Ci per ml of 99m- pertechnetate solution. The reducing agent for the pertechnetate can be a thiosulfate or dithionite if the reducing reaction 1s to be carried out in a basic medium, or a tin (II) salt such as SnCl 2 if the reducing reaction 1s to be carried out 1n an acid medium. A kit for preparing an injectable radiopharma¬ ceutical, e.g., for complexing an organ-specific agent labeled with a radioactive metal, Includes, in separate containers: (1) a biologically compatible, sterile aqueous medium suitable for complex formation with a radioactive metal, (2) a d1hydropyridine^==-≥pyr1d.inium salt carrier-containing complexing agent of formula (I) or (II) compatible therewith, and (3) a pharma¬ ceutically acceptable reducing agent for the radio¬ active metal. The dihydropyridine-—^pyridinium salt carrier moiety may be present in the kit either in its oxidized or Its reduced state, as desired. The reducing agent for the. radioactive metal can be selected to reduce also the oxidized carrier moiety, if present, as the radioactive metal is. reduced to form the complex pre¬ paratory to Injection of the radiopharmaceutical into a test animal or a patient. In a preferred embodiment of this invention, a reducing agent capable of reducing both the oxidized form of the carrier moiety and the radioactive metal is chosen and the chelating agent precursor , of formula (I) is present in the kit. In an especially preferred embodiment the kit comprises, in separate containers (preferably aseptically and hermetically sealed vials of approximately 5-25 ml volume), (1) a biologically compatible, sterile aqueous medium, (2) a chelating agent precursor of formula (I), (3) a pharmacologically acceptable reducing agent capable of reducing the chelating agent precursor of formula (I) to a chelating agent of formula (II) and also capable of reducing the radioactive metal to an oxidation state in which it is capable of complexing with the formula (II) chelating agent to form a radio¬ pharmaceutical of formula (III). Most preferably, the reducing agent 1s sodium dithionite; also most preferably, the radioactive metal is technetium. The dithionite reduction is preferably carried out in basic medium; this may be accomplished by providing that the aqueous medium (1) above is of basic pH, or by adding an appropriate base (e.g. NaOH, Na^0 3 ) when combining the kit components and the pertechnetate solution. As yet another alternative, the kit could comprise only two separate components: (1) the bio¬ logically compatible, sterile aqueous medium of es- 5 sentially neutral pH containing the. chelating agent precursor of .formula (I); and (2) the reducing agent and the base, e.g. sodium dithionite and sodium carbonate. Radioactive metal ions are typically not provided with the kit due to the relatively short half-lives 10 of commonly utilized radionuclides. Rather, the radio¬ nuclide is provided separately as described earlier , and admixed with the components of the kit shortly before use, as is known for other radiopharmaceutical delivery systems. In the ca_e of technetium-99m , j5 the pertechnetate solution and the basic aqueous medium may be first combined and then heated, e.g. from 40 to 95°C. for 10 to 20 minutes, in the presence of the reducing agent,then cooled to about room temperature or below prior to addition of the formula (I) precursor. Q In this instance, the technetium will be reduced prior to reduction of the quaternary moiety to the correspond¬ ing dihydro form 1n which case a substantial portion of the quaternary salt (I) will likely chelate with the reduced technetium to form the quaternary complex 5 ( v ) in the reaction mixture as an intermediate to the dihydro complex (III), rather than the quaternary salt (I) being first converted to the dihydro chelating agent (II) and then to the dihydro complex (III). Alternatively, if only minimal or no heating is done, 0 tne Precursor may be present in the initial mixture made from the kit, and it is likely in this instance that the formula (I) quaternary will be first reduced - 1 76 - to the formula (II) dihydro, which will then chelate with the reduced technetium to form the complex (III). If the mixture is mildly basic, e.g. pH 8 to 9, it may be administered as is, after the reduction and chelation have occurred to form the formula (III) radiopharmaceutical, or the pH may be adjusted to about 7. If the mixture is more strongly basic, e.g. pH 13, it is generally desirable to adjust the pH to a slightly alkaline or neutral value. Whatever the exact configuration σ ' f the kit, it-is preferable for it to contain excess chelating agent precursor (I) or chelating agent (II) with respect to the radionuclide to be co plexed therewith, e.g a 1:2 molar excess. The reducing agent is present in a large excess with respect to the chelating agent precursor (I), e.g. 1:5 to 1:10. When the chelating agent (II) rather than the precursor (I) 1s present, then the reducing agent i s preferably present in a slight excess with respect to the radionuclide. To effect visualization, the diagnostic agent is administered to a patient, typically intravenously, with or without further dilution by a carrier vehicle such as physiological saline, phosphate-buffered saline, plasma, or the like. Generally, the unit dose to be administered has a radioactivity of about 0.01 milliCurie (mCi) to about 100 milliCuries, preferably about l mCi to about 20 mCi. The solution to be injected into an adult patient per unit dosage is about 0.01 millillter (ml) to about 1 milliliter. After-intravenous administration. Imaging of the organ J_n vivo can take place after a few minutes. If desired. Imaging can also take place hours after the Injection, depending upon the half-Hfe of the radioactive material that has been introduced into the patient and upon the amount of such material introduced Preferably, imaging takes place 60 to 90 minutes after intravenous administration. Any conventional method of imaging for diagnostic purposes can be utilized when practicing the present invention. In summary, then, in its broadest aspects the present invention can be seen to provide compositions of matter comprising: (1) the residue of a chelating agent having at least one reactive functional group selected from the group consisting of amino, carboxyl, hy oxyl, amide and imide, said functional group being not essential for the complexing properties of said chelating agent " , said residue being characterized by the absence of a hydrogen atom from at least one of said reactive functional groups of said chelating agent, said chelating agent being either (a) capable of chelating with a metallic radionuclide or (fa) chelated with a metallic radionuclide; and (2) a dihydro- pyridine ; ~_pyridin1um salt redox carrier moiety; said chelating agent residue and said carrier moiety being coupled to each Other to form a hydrolytically cleavable linkage between. While the invention has been described in terms of various preferred embodiments, the skilled artisan will appreciate that various modifications, substi¬ tutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it i s Intended that the scope of the present invention be limited solely by the scope of the following claims.

Claims: WHAT IS CLAIMED IS: 1- A composition of matter comprising: (1) the residue of a chelating agent having at least one reactive functional group selected from the group consisting of amino, carboxyl, hyd oxyl, amide and imide, said functional group being not essential for the complexing properties of said chelating agent, said residue being characterized by the absence of a hydrogen atom from at least one of said reactive functional groups of said chelating agent, said chelating agent being either (a) capable of chelating with a metallic radionuclide or (b) chelated with a metallic radionuclide; and (2) a dihydropyridine^--±:pyridinium salt redox carrier moiety; said chelating agent residue and said carrier moiety being coupled to each other to form a hydrolytically cleavable linkage there¬ between. 2. A salt having the structural formula wherein -is the residue of a chelating agent capable of chelating with a metallic radionuclide, said chelating agent having at least one reactive functional group selected from the group consisting of amino, carboxyl, hydroxyl, amide and imide, sai functional group being not essential for the complexing properties of said chelating agent, said residue being characterized by the absence of a hydrogen atom from at least one of said reactive functional groups ot the chelating agent; y is 1 or 2; [QC ] is the hydrophilic, ionic pyridinium salt form of a dihydropyridine ^==-ipyridinium salt redox carrier; X " is the anion of a pharmaceutically acceptable organic or inorganic acid; n is the valence of the acid anion; and is a number which when multiplied by n is equal to y. 3. A salt as defined by Claim 2, wherein said residue 1s characterized by the absence of a hydrogen atom from at least one amino or hydroxyl reactive functional group of the chelating agent. 4. A salt as defined by Claim 3, wherein y is ι- 5. A salt as defined by Claim 3, wherein [QC + ] is a radical of the formula (a ) (b) 0 0 C-f-NH-αlkylene-C-fp (c) (d) 180- wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 1s a radical Identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; R-^ is CJ-C alkyl, Cι-C 7 haloalkyl or Cy-C^ aralkyl; R 3 is C χ to C 3 alkylene; X is -CONR'R" wherein R » and R' ' , which can be the same or different, are each H or C1-C7 alkyl, or X is -CH=N0R* ' ' wherein R'*' is H or C- ^ alkyl; the carbonyl-containing groupings in formulas (a) and (c) and the X substituent in formula (b) can each be attached at the 2, 3 or 4 position of the pyridinium ring; the carbonyl-containing groupings in formulas (d) and (f) and the X substituent in formula (e) can each ' be attached at the 2, 3 or 4 position of the quinolinium ring; and the carbonyl-containing groupings in formulas (g) and (j) and the X substituent 1n formula (h) can each be attached at the 1 , 3 or 4 position of the isoquinollnium ring. 6. A salt as defined by Claim 5, wherein p is zero. 7. A salt as defined by Claim 5, wherein p 1s one, alkylene 1s -CH 2 - and R Q 1s H, -CH 3 , -CH(CH 3 ) 2 , CH. ,-CH(CH 3 ) 2 , , -(CH 2 ) 2 - SCH- -CH 2 -C0NH 2 or -CH 2 CH 2 -C0NH 2 . 8. A salt as defined by Claim 2 t wherein said residue is characterized by the absence of a hydrogen atom from an -NH- moiety which is part of an amide or imide functional group or which is part of a low pKa primary or secondary amino functional group. 9. A salt as defined by Claim 8 , wherein y is l. 10. A salt as defined by Claim 8, [QC ] is a radical of the formula NH-ol <o) ( P ) (q) (r) (s) wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 1s a radical identical to the corresponding portion of a natural amino add; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R Q radicals can be the same or different; R is C!-C 7 alkyl, C j -C 7 haloalkyl or C 7 -C Q aralkyl; R is hydrogen, Cι«C 7 alkyl, C 3 -C 8 cycloalkyl, Cι-C 7 halo¬ alkyl, furyl, phenyl, or phenyl substituted by one or more halo, lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl , lower alkanoyloxy, lower haloalkyl, mono(lower alkyl )carbamoyl , di(lower alkyl )carbamoyl , lower alkylthlo, lower alkylsulflnyl or lower alkyl- sulfonyl; R 3 1s C x to C 3 alkylene; X 1s -CONR'R*' wherein R' and R 1 ', which can be the same or different, are each H or C j -C; alkyl , or X 1s -CH=N0R" ' wherein R ' ' is H or C ~C 7 alkyl; the carbonyl-containing groupings 1n formulas (k) and (m) and the X substituent in formula (1) can each be attached at the 2, 3 or 4 position of the pyridinium ring; the carbonyl contain¬ ing groupings 1n formulas (n) and (p) and the X substi¬ tuent In formula (o) can each be attached at the 2, 3 or 4 position of the quinolinium ring; and the car- bonyl-coritaining groupings in formulas (q) and (s) and the X substituent in formula (r) can each be attached at the 1, 3 or 4 position of the isoquinollnium ring. 11. A salt as defined by Claim 10, wherein p 1s zero. 12. A salt as defined by Claim 10, wherein p is one, alkylene is -CH 2 - and R Q 1s H, -CH 3 , -CH(CH 3 ) 2 , 5 -CH 2 -CH(CH 3 ) 2 , -(CH 2 ) 2 -SCH 3 , -CH 2 -CONH 2 or -CH 2 CH 2 -C0NH 2 . 13. A salt as defined by Claim 2, wherein said residue is characterized by the absence of a hydrogen atom from at least one carboxyl reactive functional 0 group of the chelating agent. 14. -A salt as defined by Claim 13, wherein y Is 1. 15. A salt as defined by Claim 13, wherein [QC + ] is a radical of the formula HH-αl 0-Z*- on (iv) 184- (vi) (vJ R 3 -C _-NH-αlkyIcne-24 p Q -Z' (vll) (viii) (ix) wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 is a radical Identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R Q radicals can be the same or different; Z' is C -Cg straight or branched alkylene; Q 1s -0- or -NH-; R j 1s C^Cy alkyl, Cι-C 7 haloalkyl or C 7 -CIQ aralkyl; R 3 is .C!-C 3 alkylene; X 1s -CONR'R" wherein R' and R' ' , which can be the same or different, are each H or C ~C 7 alkyl, or X is -CH=N0R' * ' wherein R'*' 1s H or C- ^ - C j alkyl; the X substituent in formula (ii) and the car¬ bonyl-containing groupings in formulas (1) and (iii) can each be attached at the 2, 3 or 4 position of the pyridinium ring; the X substituent In formula (v) and the carbonyl-containing groupings in formulas (Iv) and (vi) can each be attached at the 2, 3 or 4 position of the quinolinium ring; and the X substituent 1n formula (v11i) and carbonyl-containing groupings in formulas (v11) and (1x) can each be attached at the 1,-3 or 4 position of the isoquinollnium ring . 16 - A salt as defined by Claim 14, wherein CQC + ] is a radical of the formula (x) (xl) [ +-C -t-HH-αlkylene-C -} p NH- ** 7 (A) n v whereln ' ,ι is the skeleton of a sugar molecule; n 1s a positive integer equal to the total number of -OH functions in the sugar molecule from which said skele¬ ton 1s derived; n v is a positive integer one less than the total number of -OH functions 1n the sugar molecule from which said skeleton 1s derived; each A in each of structures (x1i), (x111) and (x1v) can Independently be hydroxy or D', 0' being the residue of a che ¬ lating agent containing one reactive -COOH functional group, said residue being characterized by the absence of a hydrogen atom from said -COOH functional group in said chelating agent; and each R' 4 in each of struc¬ tures (x) and (xi) can independently be hydroxy, or 0', whereln the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 is a radical Identical to the corresponding portion of a natural amino add; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; D' 1s defined as with structure (x11), (xiii) and (xiv); Ri * is Cι-C 7 alkyl, C1-C7 haloalkyl or C7-C 10 aralkyl; and the depicted carbonyl-containing groupin-gs can be attached at the 2, 3 or 4 position of the pyridinium or quinolinium ring, or at the 1, 3 or 4 position of the isoquinollnium ring; with the proviso that at least one R'4 in each of structures (x) and (xi) is •O-f-ϊ-αlkylene-NH→ p - 1— (Q R o 1 wherein alkylene, R 0 , p and R j and the position of the carbonyl-containing groupings are defined as above; and with the further proviso that when more than one of the R * 4 radicals 1n a given compound are the aforesaid carbonyl-containing groupings ,. then all such carbonyl- containing groupings in said compound are identical . 17. A salt as defined by Claim 15, wherein p is zero. 18. A salt as defined by Claim 16, wherein p is zero. 19. A salt as defined by Claim 15 or 16, wherein P 1s one, alkylene is -CH 2 - ' and R Q is H, -CH 3 , 20. A compound havi ng the structural formul a or a non-toxic pharmaceutically acceptable salt thereof, wherein ( J" is the residue of a chelating agent cap¬ able of chelating with a metallic radionuclide, said chelating agent having at least one reactive func¬ tional group selected from the group consisting of amino, carboxyl, hydroxyl, amide and imide, said functional group being not essential for the complexing properties of said chelating agent, said residue being character- ized by the absence of a hydrogen atom from at least one of said reactive functional groups of the chelating agent; y is 1 or 2; and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating form of dihydropyridine pyridinium salt redox carrier. 21. A compound as defined by Claim 20, wherein said residue is characterized by the absence of a hydrogen atom from at least one amino or hydroxyl reactive functional group of the chelating agent. 22. A compound as defined by Claim 21, wherein y is 1. 23. A compound as defined by Claim 21, wherein [DHC] is a radical of the formula ( α'J (b*) («*> if) (h*) 0 iene-<.4- p ( J *) (J * *} wherein the alkylene group can be straight or branched, and can contain 1 to 3 carbon atoms; R 0 is a radical identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; the dotted line in formulas (a*), (b € ) and (c*) indicates the presence of a double bond 1n either the 4 or 5 position of the dihydropyridine ring; the dotted line in formulas (d 1 ), (e') and (f*) indicates the presence of a double bond in either the 2 or 3 position of the dihydroquinol1ne ring; R is C »C 7 alkyl, C -C 7 halo¬ alkyl or C 7 -C j o aralkyl; R 3 is C j to C 3 alkylene; X is -CONR'R'-, wherein R* and R* * , which can be the same or different, are each H or C -C 7 alkyl, or X is -CH=N0R , , t wherein R"* 1s H or C1-C7 alkyl; the carbonyl-containing groupings in formulas (a') and (c 1 ) and the X substituent 1n formula (b*) can each be attached at the 2, 3 or 4 position of the dihydro¬ pyridine ring; the carbonyl-containing groupings in formulas (d * ) and (f) and the X substituent in formula (e 1 ) can each be attached at 2, 3 or 4 position of the dihydroquinoline ring; and the carbonyl-containing groupings in formulas (g') and (j') and the X substi¬ tuent in formula (h*) can each be attached at the 1, 3 or 4 position of the dihydroisoquinoline ring. 24. A compound as defined by Claim 23, wherein p is zero. 25. A compound as defined by Claim 23, wherein p 1s one, alkylene is -CH 2 - and R Q is H, -CH 3 , -CH(CH 3 ) 2 , 26. A compound as defined by Claim 20, wherein said residue Is characterized by the absence of a hydrogen atom from an -NH- ra ety which is part of an amide or imide functional group or which Is part of a low pKa primary or secondary amino functional group. 27. A compound as defined by Claim 25, wherein y 1s l. 28. A compound as defined by Claim 26, wherein [DHC] 1s a radical of the formula (n'J (m'J C0CH 2 £-f-NK-αlkylene-l! p— CH -. H-αlkylene-2-4 ιr 0CH- J (o*) (P*} - ( q'J (r"J (s*) 0 NH-olkyJ<ne-C 4**r OCH-, (s") 193- whereln the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 1s a radical identical to the corresponding portion of a natural amino acid; p Is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; R is hydrogen, C -C7 alkyl, C 3 -Cg cycloalkyl, C j -Cy haloalkyl, furyl, phenyl, or phenyl substituted by one or more halo, lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl , lower alkanoyloxy,- lower halo¬ alkyl, mono(lower al kyl)carbamoyl , di(lower alkyl )car- bamoyl , lower alkylthio, lower al kylsul finyl or lower alkylsulfonyl ; the dotted line 1n formulas (k*), (V) and (m 1 ) indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring; the dotted line in formulas (n*), (o 1 ) and (p*) indi¬ cates the presence of a double bond 1n either the 2 or 3 position of the dihydroquinol 1ne ring; R is Cι-C alkyl , Cι-C 7 haloalkyl or C7-C10 aralkyl; R3 is Ci to C 3 alkylene; X is -CONR'R *, wherein R* and R 4 *, which can be the same or different, are each H or C » C 7 alkyl, or X is -CH-N0R"' wherein R'* is H or C χ -C 7 alkyl; the carbonyl-containing groupings in formulas (k 1 ) and (m') and the X substituent in formula (1') can each be attached at the 2, 3 or 4 position of the dihy¬ dropyridine ring; the carbonyl-containing groupings in formulas (n 1 ) and (p*) and the X substituent in formula (o') can each be attached at the 2, 3 or 4 position of the dihydroquinol ine ring; and the carbonyl-containing groupings i n formula (q') and (s 1 ) and the X substi¬ tuent 1n formula (r 1 ) can each be attached at the 1, 3 or 4 position of the dihydroisoquinol ine ring. -194- 29. A compound as defined by Claim 28, wherein p 1s zero. 30. A compound as defined by Claim 28, wherein p 1s one, alkylene is -CH - and R 0 1s H, -CH3, -CH(CH3)2» 31. A compound as defined by Claim 20, wherein said residue is characterized by the absence of a hydrogen atom from at least one carboxyl reactive functional group of the chelating agent. 32. A compound as defined by Claim 31, wherein y is 1. 33 ^ A compound as defined by Claim 31, wherein . [OHC] is a radical of the formula -tj-α-Z'- (v'l <vil') (v!li"J wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 is a radical identical to the corresponding portion of a natural amino acid; p is 0, l or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; the dotted line in formulas <1 « ), (i'j and (iii') indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring; the dotted line In formulas (iv*), (v*) and (vi*) Indicates the pre¬ sence of a double bond 1n either the 2 or 3 position of the dihydroquinol1ne ring; V 1s Ci-Cg straight or branched alkylene; Q 1S _ 0 - or -NH-; R χ is C j -C 7 alkyl, C 1~ C 7 haloalkyl or 7 -C. Q aralkyl; R 3 is j -C 3 alkylene; X 1s -CONR'R" wherein R* and R*', which can be the same or different, are each H or C1-C7 alkyl, or X is -CH-N0R'** wherein R* * ' is H or -Cy alkyl; the X substituent in formula (11*) and the carbonyl-contain¬ ing grouping in formulas (i*) and (iii*) can each be attached at the 2, 3 or 4 position of the dihydropyri¬ dine ring; the X substituent in formula (v*) and the carbonyl-containing grouping in formulas (i.v*) and (vi * ) can each be attached at the 2, 3 or 4 position of the dihydroqulnoline ring; and the X substituent in formula (viii*) and the carbonyl-containing groupings in formulas (v11*) and (ix*) can each be attached at the 1, 3 or 4 position of the d1hydro1soqu1noline ring.- 34. A compound as defined by Claim 32, wherein [OHC] 1s a radical of the formula < W v_r- * -• _✓- (x*J (xi') -197- ( iv") wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 1s a radical identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; the dotted line 1n formula (xii') indicates the presence of a double bond 1n either the 4 or 5 position of the dihydropyridine ring; the dotted Hne in formula (xiii*) indicates the presence of a double bond in eithe e flog is a positive Integer equal to the total number of -OH func¬ tions in the sugar molecule from which said skeleton is derived; n v 1s a positive integer one less than the total number of -OH functions in the sugar molecule from which said skeleton 1s derived; each A 1n each of structures (xii*), (xiii*), (x1v*) and (xiv") can independently be hydroxy or 0', D' being the residue of a chelating agent containing one reactive -COOH func¬ tional group, said residue being characterized by the absence of a hydrogen atom from said -COOH functional group in said chelating agent; and each R4 in each of structures (x*) and (xi*) can Independently be hydroxy, or Q wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 1s a radical Identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, provided that, when p 1s 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; the dotted line is defined as with structures (x11*) and (xiii * ); 0* 1s defined as with structures (xiT), (xiii 1 ). (x1V) and (xiv**); R Is -CJ- alkyl, C C 7 haloalkyl or C 7 -C-, 0 aralkyl; and the depicted carbonyl groupings can be attached at the 2, 3 or 4 position of the pyridinium or quinolinium ring or, except where otherwise specified, at the 1, 3 or 4 position of the isoquinollnium ring; with the proviso that at least one R in each of structures (x*) and (xi*) is -04- 0 i-α! whereln alkylene, R 0 , p, R j , the dotted lines and the position of the carbonyl-containing groupings are de¬ fined as above; and with the further proviso that when more than one of the radicals in a given compound are the aforesaid carbonyl-containing groupings, then all such carbonyl-containing groupings In said compound are identical. 35. A compound as defined by Claim 33, wherein p is zero. 36. A compound as defined by Claim 34, wherein p is zero. 37. A compound as defined by Claim 33 or 34, wherein p is one, alkylene 1s -CH 2 - and R Q 1s H, -CH 3 , -CH(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , -(CH 2 ) 2 -SCH 3 , -CH 2 -C0NH 2 38. A radiopharmaceutical having the structural for u a or a non-toxic pharmaceutically acceptable salt thereof, wherein ( Y-1s the residue of a chelating agent capable of chelating with a metallic radionuclide, said chelating agent having at least one reactive functional group selected from the group consisting of amino, carboxyl,. hydroxyl , amide and imide, said functional group being not essential for the complexing properties of said chelating agent, said residue being characterized by the absence of a hydrogen atom from at least one of said reactive functional groups of the chelating agent; y 1s 1 or 2; [DHC] 1s the reduced, biooxldizable, blood-brain barrier penetrating form of dihydropyridine ^=_-r pyri¬ dinium salt redox carrier; and M is a metallic radio¬ nuclide; said radiopharmaceutical of formula (III) being a ohelate of said metallic radionuclide with a compound of the formula whereiin( -, [OHC] and y are defined hereinabove 39. A radiopharmaceutical as defined by Claim 38, wherein said residue is characterized by the absence of a hydrogen atom from at least one amino or hydroxyl reactive functional group of said chelating agent. 40. A radiopharmaceutical as defined by Claim 39, wherein y is 1. 41. A radiopharmaceutical as defined by Claim 39, wherein [OHC] is a radical of the formula ( 0 * 3 to' ) in the presence of a double bond 1n either the 4 or 5 position of the dihydropyridine ring; the dotted line in formulas ( d ' f , (e*) and (f*) indicates the presence of a double bond In either the 2 or 3 position of the dihydroquinoHne ring; R j 1s C ~C alkyl , C ] _-C 7 halo¬ alkyl or C 7 -C 1Q aralkyl; R 3 is C-, to C 3 alkylene; X is -CONR'R'', wherein R' and R' ' , which can be the same or different, are each H or Cι~C 7 alkyl, or X Is -CH- s NOR'" wherein R*** 1s H or C1-C7 alkyl; the carbonyl-containing groupings In formulas (a*) and (c*) and the X substituent 1n formula (b*) can each be attached at the 2, 3 or 4 position of the dihydro¬ pyridine ring; the carbonyl-containing groupings in formulas (d 4 ) and (f) and the X substituent In formula (e 1 ) can each be attached at 2, 3 or 4 position of the dihydroquinol ine ring; and the carbonyl-containing groupings in formulas (g*) and (j') and the X substi¬ tuent in formula (h'J can each be attached at the 1, 3 or 4 position of the dihydroisoquinol ine ring. 42. A radiopharmaceutical as defined by Claim 41, wherein p is zero. 43. A radiopharmaceutical as defined by Claim 41, wherein p is one, alkylene is -CH 2 - and R Q is H, -CH 3 , -CH(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , -(CH 2 ) 2 -SCH 3 , -CH 2 -C0NH 2 44. A radiopharmaceutical as defined by Claim 38, wherein said residue is characterized by the absence of a hydrogen atom from an -NH- moiety which is part of an amide or imide functional group or which is part of a low pKa primary or secondary amino functional gorup. 45. A radiopharmaceutical as defined by Claim 44, wherein y is 1. 46. A radiopharmaceutical as defined by Claim 4; wherein [DHC] is a radical of the formula , (n'J (β*) (o'J (o'J. -206- whereln the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 1s a radical identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups cari be the same or different and the R 0 radicals can be the same or different; R 1s hydrogen, C!~C 7 alkyl, C 3 -C 8 cycloalkyl, C χ -C 7 haloalkyl, furyl, phenyl, or phenyl substituted by one or more halo, lower alkyl, lower alkoxy, carbamoyl, lower alkoxycarbonyl , lower alkaπoyloxy, lower halo¬ alkyl, mono(lower al y1)carbamoyl , di(lower alkyl )car- bamoyl , Iλwer alkylthio, lower al kylsul finyl or lower alkylsulfonyl ; the dotted line in formulas (k 1 ), (I 4 ) and (m 1 ) indicates the presence of a double bond 1n either the 4 or 5 position of the dihydropyridine ring; the dotted line in formulas (n'), (o') and (p*) Indi¬ cates the presence of a double bond in either the 2 or 3 position of the dihydroqulnoline ring; Ri 1s C ~C alkyl, Cι«C 7 haloalkyl or C7-C10 aralkyl; R3 1s Ci to C 3 alkylene; X 1s -CONR'R", wherein R' and R", which can be the same or different, are each H or C1-C7 alkyl, or X is -CH-N0R"* wherein R'" 1s H or C 1 -C 6 alkyl; the carbonyl-containing groupings in formulas (k*) and (m*) and the X substituent in formula (!') can each be attached at the 2, 3 or 4 position of the dihy¬ dropyridine ring; the carbonyl-containing groupings in formulas (n*) and (p 1 ) and the X substituent in formula (o') can each be attached at the 2, 3 or 4 position of the dihydroqulnoline ring; and the carbonyl-containing groupings in formulas (q 4 ) and (s 4 ) and the X substi¬ tuent in formula (r') can each be attached at the 1, 3 or 4 position of the dihydroisoquinol ine ring. 47. A radiopharmaceutical as defined by Claim 46, wherein p is zero. 48. A radiopharmaceutical as defined by Claim 46, wherein p is one, alkylene 1s -CH 2 - and R Q is H, -CH 3 .-CH(CH 3 )2, -CH 2 -CH(CH 3 ) 2 , - % -(CH 2 ) 2 -SCH 3 , -CH 2 -C0NH 2 or -CH 2 49. A radiopharmaceutical as defined by Claim 38, wherein said residue 1s characterized by the absence of a hydrogen atom from at least one carboxyl reactive functional group of said chelating agent. 50. A radiopharmaceutical as defined by Claim 49, wherein y 1s 1. 51. A radiopharmaceutical as defined by Claim 49, wherein [OHC] is a radical of the formula (V) (vlD (lx'J <ix'*J wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 is a radical identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; the dotted line 1n formulas (i') t (i') and (iii * ) indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring; the dotted Hne in formulas (1v*), (v*) and (vi*) Indicates the pre¬ sence of a double bond in either the 2 or 3 position of the dihydroqulnoline ring; Z' is C -Cβ straight or branched alkylene; Q is -0- or -NH-; x Is C 1 -C alkyl, C j -Cy haloalkyl or C 7 -C. 0 aralkyl; 3 Is C j ,-C 3 alkylene; X is -CONR'R** wherein R* and R* * , which can he the same or different, are each H or C 1 -C 7 alkyl, or X 1s -CH«N0R"* wherein R"* is H or C 1 -C 7 alkyl; the X substituent in formula (11') and the carbonyl-contain¬ ing grouping in formulas (i*) and (iii*) can each be attached at the 2, 3 or 4 position of the dihydropyri- dine ring; the X substituent in formula (v*) and the carbonyl-containing grouping in formulas (iv*) and (vi 1 ) can each be attached at the 2, 3 or 4 position of the dihydroqulnoline ring; and the X substituent in formula (viii*) and the carbonyl-containing groupings 1° formulas (v11*) and (ix*) can each be attached at the 1, 3 or 4 position of the dihydrolsoquinoHne ring- 52. A radiopharmaceutical as defined by Claim 50, wherein [OHC] is a radical of the formula (X*J (xD tn tn en wherein the alkylene g and can contain 1 to 3 identical to the corre amino acid; p is 0, 1 5 then the alkylene group and the R 0 radicals can dotted line is defined (xiii'); 0* is defined (xiii'), (xiv') and (xi 10 haloalkyl or C 7 -C 1Q ara groupings -can be attach the pyridinium or quino otherwise specified, at isoquinollnium ring; wi 15 R4 in each of structure - 4-C-.I *1 wherein alkylene, R 0 , p, R χ . the dotted lines and the position of the carbonyl-containing groupings are de¬ fined as above; and with the further proviso that when more than one of the R radicals in a given compound are the aforesaid carbonyl-containing groupings, then all such carbonyl-containing groupings in said compound are Identical . 53. A radiopharmaceutical as defined by Claim 51, wherein p 1s zero. 54. A radiopharmaceutical as defined by Claim 52, wherein p is zero. 55. A radiopharmaceutical as defined by 51 or 52, wherein p is one, alkylene is -CH 2 - and 0 is H, -CH 3j -CH(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , - } -(CH 2 ) 2 -SCH 3 , -CH 2 -C0NH 2 or -CH 2 56. A radiopharmaceutical as defined by Claim 38, wherein M is technetium-99m. 57. A radiopharmaceutical having the structural formula wherein ( )"is the residue of a chelating agent capable of chelating with a metallic radionuclide, said chelating agent having at least one reactive functional group selected from the group consisting of amino, carboxyl , hydroxyl, amide and imide, said functional group being not essential for the complex¬ ing properties of said chelating agent, said residue being characterized by the absence of a hydrogen atom from at least one of said reactive functional groups of the chelating agent; y is 1 or 2; [QC + ] is the hydro- philic, ionic pyridinium salt form of a dihydro¬ pyridine - *■* --■=pyridinium salt redox carrier; X " is the anion of a pharmaceutically acceptable organic or in¬ organic acid; n is the valence of the acid anion; m is a number which when multiplied by n is equal to y; and H 1s a metallic radionuclide; said radiopharma¬ ceutical of formula (IV) being a chelate of said metallic radionuclide with a salt of the formula wherein (" " » y * CQ c+ 3. X " . n and y are defined as above. 58. A radiopharmaceutical as defined by Claim 57, wherein said residue is characterized by the absence of a hydrogen atom from at least one amino or hydroxyl reactive functional group of the chelating agent. 59. A radiopharmaceutical as defined by Claim 58 , wherein y is 1. 60. A radiopharmaceutical as defined by Claim 58, wherein [QC + ] is a radical of the formula -4- KH-αl k !yl ene-C-k P, (α) (t>) (c) (d) wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 1s a radical identical to the corresponding portion of a natural amino acid; p 1s 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R Q radicals can be the same or different; R j 1s C j -C 7 alkyl, C j _-C 7 haloalkyl or 7 -C 10 aralkyl; R 3 is C 1 to C 3 alkylene; X is -CONR'R" wherein R 4 and R" , which can be the same or different, are each H or C j -C alkyl, or X 1s -CH=N0R 4 * * wherein R" * is H or C 1 -C 7 alkyl; the carbonyl-containing groupings 1π formulas (a) and (c) and the X substituent 1n formula (b) can each be attached at the 2, 3 or 4 position of the pyridinium ring; the carbonyl-containing groupings in 5 formulas (d) and (f) and the X substituent 1n formula (e) can each be attached at- the 2, 3 or 4 position of the quinolinium ring; and the carbonyl-containing groupings in formulas (g) and (j) and the X substituent in formula (h) can each be attached at the 1, 3 or 4 Q position of the isoquinollnium ring. 61. A radiopharmaceutical as defined by Claim 60, wnerein p is zero. 62. A radiopharmaceutical as defined by Claim 60, wherein p is one, alkylene is -CH 2 - and R Q s H, -CH 3 ,-CH(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , - , -(CH 2 ) 2 -SCH 3 , -CH 2 -C0NH 2 or -CH 2 63. A radiopharmaceutical as defined by Claim 57, wherein said residue is characterized by the ab¬ sence of a hydrogen atom from an -NH- moiety which is part of an amide or imide functional group or which is part of a low pKa primary or secondary amino func¬ tional group. 64. A radiopharmaceutical as defined by Claim 63, wherein y is 1. 65. A radiopharmaceutical as defined by Claim 63, [QC + ] is a radical of the formula (1 ) (o) (P) ( qJ (r) (s> wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 is a radical identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R Q radicals can be the same or different; R j is C ] ,-C 7 alkyl, C j _-C 7 haloalkyl or C 7 -C 10 aralkyl; R is hydrogen, C j -C 7 alkyl , C 3 -C 8 cycloalkyl , C j -C halo¬ alkyl, furyl, phenyl, or phenyl substituted by one or more halo, lower alkyl , lower alkoxy, carbamoyl, lower al oxycarbonyl , lower alkanoyloxy, lower haloalkyl, mono(lower al kyl )carbamoyl , di(lower al yl )carbamoyl , lower alkylthio, lower al yl sul f1nyl or lower alkyl- sulfonyl; R 3 1s C x to C3 alkylene; X 1s -CONR'R" wherein R* and R' 1 , which can be the same or different, are each H or C χ -C 7 alkyl, or X is -CH-sNOR* ' ' wherein R'" Is K or c l" c 7 a, * < y 1 ϊ the carbonyl-containing groupings in formulas (k) and (m) and the X substituent in formula (1) can each be attached at the 2, 3 or 4 position of the pyridinium ring; the carbonyl contain¬ ing groupings in formulas (n) and (p) and the X substi- tuent in formula (0) can each be attached at the 2, 3 or 4 position of the quinolinium ring; and the car¬ bonyl-containing groupings 1n formulas (q) and (s) and the X substituent in formula (r) can each be attached at the 1, 3 or 4 position of the isoquinollnium ring. 66. A radiopharmaceutical as defined by Claim 65, wherein p is zero. 67. A radiopharmaceutical as defined by Claim 65, wherein p is one, alkylene is -CH 2 - and R Q is H, -CH 3 ,-CH(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , - , -(CH 2 )2-SCH3, -CH2-CONH2 or -CH2 68. A radiopharmaceutical as defined by Claim 57, wherein said residue is characterized by the absence of a hydrogen atom from at least one carboxyl reactive functional group of the chelating agent. 69. A radiopharmaceutical as defined by Claim 68, wherein y is 1. 70. A radiopharmaceutical as defined by Claim 68, wherein [QC + ] is a radical of the formula KH-αI (11) KH-αlkylene -C4- 0 O-Z'- (lv) 4- 0 0-Z'- ( v) ( vIJ ( vll) (vlJl) UxJ wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 1s a radical Identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, provided that, when p 1s 2, then the alkylene groups can be the same or different and the R Q radicals can be the same or different; V is C 1 ' C 8 straight or branched alkylene; Q Is -0- or -NH-; ~ \ is C j -Cy alkyl, C j -^ haloalkyl or 7 -C 1Q aralkyl; R 3 is C χ -C 3 alkylene; X 1s -CONR'R" wherein R' and R' ' , which can be the same or different, are each H or C j^ -C 7 alkyl, or X is -CH=N0R 4 * ' wherein R" 4 is H or C 1 -C 6 alkyl; the X substituent in formula (ii) and the car¬ bonyl-containing groupings in formulas (i) and (iii) can each be attached at the 2, 3 or 4 position of the pyridinium ring; the X substituent in formula (v) and the carbonyl-containing groupings in formulas (iv) and (vi) can each be attached at the 2, 3 or 4 position of the quinolinium ring; and the X substituent in formula (viii) and carbonyl-containing groupings in formulas (v11) and (ix) can each be attached at the 1, 3 or 4 position of the isoquinollnium ring. 71. A radiopharmaceutical as defined by Claim 69, wherein [QC + ] is a radical of the formula (x) <xl) wherein \ 1 is the skeleton of a sugar molecule; n is a positive integer equal to the total number of -OH functions in the sugar molecule from which said skele¬ ton 1s derived; n v is a positive integer one less than the total number of -OH functions 1π the sugar molecule from which said skeleton is derived; each A in each of structures (x1i), (x111) and (xiv) can Independently be hydroxy or 0', 0' being the residue of a che¬ lating agent containing one reactive -COOH functional group, said residue being characterized by the absence of a hydrogen atom from said -COOH functional group 1n said chelating agent; and each R* 4 1n each of struc¬ tures (x) and (xi) can independently be hydroxy, - • 04-?-αlkylene -NH or D', wherein the alkylene group can be straight or branched and can contain 1 to 3 carbon atoms; R 0 1s a radical identical to the corresponding portion of a natural amino acid; p is 0, 1 or 2, provided that, when p is 2, then the alkylene groups can be the same or different and the R 0 radicals can be the same or different; D 4 1s defined as with structure (xi1), (xiii) and (xiv); R * 1s C1-C7 alkyl, C1-C7 haloalkyl or C7-C 10 aralkyl; and the depicted carbonyl-containing groupings can be attached at the 2, 3 or 4 position of the pyridinium or quinolinium ring, or at the 1, 3 or 4 position of the Isoquinollnium ring; with the proviso that at least one R*4 in each of structures (x) and (xi) 1s •223- wherein alkylene, R 0 , p and R j and the position of the carbonyl-containing groupings are defined as above; and with the further proviso that when more than one of the R' radicals 1π a given compound are the aforesaid carbonyl-containing groupings ,. then all such carbonyl- containing groupings in said compound are Identical. 72. A radiopharmaceutical as defined by Claim 70, wherein p 1s zero. 73. A radiopharmaceutical as defined by Claim 71, wherein p 1s zero. 74. A radiopharmaceutical as defined by Claim 70 or 71, wherein p 1s one, alkylene 1s -CH 2 - and R 0 is H, -CH 3 ,-CH(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , t -(CH 2 ) 2 -SCH 3 , -CH 2 -C0NH 2 or -CH H 2 75. A radiopharmaceutical as defined by Claim 57, wherein M is technetium-99m. 76. A chemical entity as defined by Claim 5, 23, 41 or 60, wherein is methyl . 77. A chemical entity as defined by Claim 5, 23, 41 or 60, wherein R3 is -CH2CH2-. 78. A chemical entity as defined by Claim 5, 23, 41 or 60, wherein X is -C0NH 2 . 79. A chemical entity as defined by Claim 5, 23, 41 or 60, wherein the X and carbonyl-containing group¬ ings whose ring positions can vary are located in the 3 position of the pyridinium or dihydropyridine rings, in the 3 position of the quinolinium or dihydroquinol ine ring systems, or in the 4 position of the isoquinolin- 1um or dlhydroisoquinoline ring systems. 80. A chemical entity as defined by Claim 5, 23, 41 or 60, wherein the carrier moiety is a radical of formul a (a) or (a* ) . 81. A chemical entity as defined by Claim 80, wherein the carrier moiety is a radical of the formula 82. A chemical entity as defined by Claim 10, 28, 46 or 65, wherein R χ is methyl . 83« A chemical entity as defined by Claim 10, 28, 46 or 65, wherein the X and carbonyl-containing group ¬ ings whose ring positions can vary are located in the 3 position of the pyridinium or dihydropyridine rings, in the 3 position of the quinolinium or di hydroquinol ine ring systems, or in the 4 position of the isoquinolin- ium or dlhydroisoquinoline ring systems. 84. A chemical entity as defined by Claim 10, 28, 46 or 65, wherein R is hydrogen, C -C 7 alkyl , C 3 -Cg cycloalkyl , C 1 -C 7 haloalkyl, furyl or phenyl. 85. A chemical entity as defined by Claim 15, 33, 51 or 70, wherein V is C j^ -C^ straight or branched al ylene. 86. A chemical entity as defined by Claim 85, wherein Z 4 is C 2 -C 3 straight or branched alkylene. 87. A chemical entity as defined by Claim 15, 33, 51 or 70, wherein the X and carbonyl-containing group¬ ings whose ring positions can vary are located in the 3 position of the pyridinium or dihydropyridine rings, in the 3 position of the quinolinium or dihydroqulnoline ring systems, or in the 4 position of the isoquino- liniu or dlhydroisoquinoline ring systems. 88. A chemical entity as defined by Claim 16, 34, 52 or 71, wherein the carbonyl-containing groupings encompassed by the definitions of R 4 and R' 4 are located in the 3-position of the pyridinium or dihydropyridine rings, in the 3 position of the quinolinium or dihydroquinoline ring systems, or in the 4 position of the isoquinollnium or dihydroi soqui no! ine ring systems. 89. A salt as defined by Claim 5, 6 or 7, having the structural formula wherein each R g is independently selected from the 5 group consisting of H and C.-C 7 alkyl, or an R g can be combined with the adjacent -R such that ^ C. \ represents ^ .C=0; each Rg is independently selected from the group consisting can be combined with the adjacent ^C-Rg such that 10 -C- represents 0; Hfl ^NH is a radical of κ 6- Q the formula R R 7 R 7 filfcl g -A j -tQC*! wherein each R 7 is independently selected from the group consisting of H and C.-C 7 alkyl; (alk) is a *ι ■ *_ straight or branched lower alkylene group which ad¬ ditionally may contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being nonadjacent to each other and also being nonadjacent to -A.-; X " 1s the anion of a pharmaceutically acceptable organic or inorganic acid; n is the valence of the acid anion; m* is a number which when multiplied by n is equal to one; s is zero or one; -A,- is -NH-, -0- or -N- * I R 8 wherein R g is C j -C 7 alkyl; and [QC + ] is as defined in Claim 5., 6 or 7. 90. A salt as defined by Claim 10, having the structural formula wherein each Rg is independently selected from the group consisting of H and 0-, -C- j alkyl, or an Rg can be combined with the adjacent i-R such that ,C. R S represents ^C=0; each Rg is independently selected from the group consisting of H and C- ^ -C j alkyl, or an Rg can be combined with the adjacent ^C- g such that is a radical of the formula - . °-ζ -QC + J -A2-fQC + l wherein each R, is independently selected from the group consisting of H and C j -C 7 alkyl; (alk) is a straight or branched lower alkylene group which ad¬ ditionally may contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being nonadjacent to each other and also being nonadjacent to -A 2 -; X " is the anion of a pharmaceutically acceptable organic or inorganic acid; n is the valence of the acid anion; m* is a number which when multiplied by n is equal to one; s is zero or one; -A - is -CONH- or -C0N- 9 wherein R g is C j -Cy alkyl; and [QC + ] is as defined in Claim 10. 91. A salt as defined by Claim 15 or 16, having the structural formula wherein each Rg is independently selected from the group consisting of H and C,- be combined with the adjacent represents yC^O ; each R β is independently selected from the group consisting of H and C^-Cy alkyl,.or an R can be combined with the adjacent ^.C-Rg such that is a radical of the formula wherein each Ry is independently selected from the group consisting of H and C.-C 7 alkyl; (alk) is a straight or branched lower alkylene group which ad- ditionally may contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being nonadjacent to each other and also being nonadjacent to -A 3 -; X " is the anion of a pharmaceutically acceptable organic or inorganic acid; n is the valence of the acid anion; m* is a number which when multiplied by n is equal to one; s is zero or one; -A 3 - is -C00-; and [QC ] is as defined in Claim 15 or 16. 92. A salt as defined by Claim 5, 6 or 7, having the structural formula wherein R 1 and R 2 are each H or * c 1 -c 3 alkyl, n* is an integer of 0 to 3 and [QC + ] is as defined in Claim 5, 6 or 7. 93. A salt as defined by Claim 5, 6 or 7, having the structural formula (lb') wherein [QC + ] is as defined in -Claim 5, 6 or 7. 94. A compound as defined by Claim 23, 24 or 25, having the structural formula wherein each Rg is independently selected from the group consisting of H and C.-C 7 alkyl, or an Rg can be combined with the adjacent ,C-Rg such that C. represents ^C=0; each Rg is independently selected from the group consisting of H and C,-C 7 alkyl, or an Rg can be combined with the adjacent A ,c-R 6 such that A represents ^C-=0; HN NH is a radical of the formula OH <αlW s -A r tD«Cl wherein each Ry is independently selected from the group consisting of H and C,-Cy alkyl; (alk) is a straight or branched lower alkylene group which ad¬ ditionally may contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being nonadjacent to each other and also being nonadjacent to -Aι~; s is zero or one; -A-, - is -NH-, -0- or -N- wherein R„ is C } -C 7 alkyl; and [DHC] is as defined in Claim 23, 24 or 25 95. A compound as defined by Claim 28, having the structural formula represents ^C=0; each Rg. is independently selected from the group consisting of H and C j -Cy alkyl, or an Rg can be combined with the adjacent C-R fi such that / represents ^C*=0; HN NH is a radical of the formula DH wherein each Ry is independently selected from the group consisging of H and C j -Cy alkyl; (alk) is a straight or branched lower alkylene group which ad¬ ditionally may contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being nonadjacent to each other and also being nonadjacent to -A 2 -; s is zero or one; -A 2 - is -CONH- or -CON- wherein R-. is C j -Cy R 9 alkyl; and [OHC] is as defined in Claim 28. 96. A compound as defined by Claim 33 or 34, having the structural formula wherein each Rg is independently selected from the group consisting of H and C j -Cy alkyl, or an Rg can be combined with the adjacent C-R O ς such that *v represents ^C=0 each R g . is independently selected from the group consisting of H and C 1 -Cy alkyl, or an Rg can be combined with the adjacent ^C-R c such that C 0 ' \ R 6 -**. \ / represents ^C=0; H ^ ^NH is a radical of the formula DH (αlk) s -A*5-tDHCl , wherein each R is Independently selected from the group consisting of H and C j -Cy alkyl; (alk) is a straight or branched lower alkylene group which ad¬ ditionally may contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being nonadjacent to each other and also being nonadjacent to -A 3 -; s is zero or one; -A 3 - is -C00-; and [DHC] is as defined in Claim 33 or 34. 97. A compound as defined by Claim 23, 24 or 25, having the structural formula lDHCl-NH-(CH 2 ) π , -ff Vc-W-NH-I-NHR 1 (lib) ^ = ^ C-H-NH-C-NHR 2 CH 3 S wherein R 1 and R 2 are each H or CJ-C-J alkyl, n' is an integer of 0 to 3 and [OHC] 1s as defined in Claim 23, 24 or 25. 98. A salt as defined by Claim 23, 24 or 25,hav¬ ing the structural formula wherein [OHC] is as defined in Claim 23, 24 or 25 -234* 99. A radiopharmaceutical as defined by Claim 41, 42 or 43, said radiopharmaceutical being a chelate of a metallic radionuclide with a compound of the structural formula wherein each Rg is independently selected from the group consisting of H and C -^ -Cy alkyl, or an Rg can be combined with the adjacent ,C-R such that ,C. represents ^C=0; each Rg is independently selected from the group consisting of H and C^-Cy alkyl, or an Rg can be combined with the adjacent ^C-R g such that / ,C. represents .C=0; HN NH is a radical of 6 the formula ≤ -A r (DIICI , wherein each Ry is independently selected from the group consisting of H and C χ -C 7 alkyl; (alk) is a straight or branched lower alkylene group which ad- ditionally may contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being nonadjacent to each other and also being nonadjacent to -A.-; s is zero or one; -A.- is -NH-, -0- or -N- wherein Rg is , R 8 C,-C 7 alkyl ; and [DHC] is as defined in Claim 41, 42 or 43. 100. A radiopharmaceutical as defined by Claim 46, said radiopharmaceutical being a chelate of a metallic radionuclide with a compound of the structural formul a wherein each Rg is independently selected from the group consisting of H and C j -Cy alkyl, or an Rg can be combined with the adjacent C-R c such that R 5 represents -C=0; each R g is independently selected from the group consisting of H and C j -Cy alkyl, or an R g can be combined with the adjacent Jc-R g such that =0 ; HN H i s a radical of DH the fo rmu l a wherein each Ry is independently selected from the group consisting of H and C,-Cy alkyl; (alk) is a straight or branched lower alkylene group which ad¬ ditionally may contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being nonadjacent to each other and also being nonadjacent to -A^-; s is- zero or one; -A 2 - is -CONH- or -CON- wherein R g is _ C j -Cy alkyl; and [DHC] is as defined in Claim 46. 101. A radiopharmaceutical as defined by Claim 51 or 52, said radiopharmaceutical being a chelate of a metallic radionuclide with a compound of the structural formula wherein each Rg is, independently selected from the group consisting of H and C,-Cy alkyl, or an Rg can be combined with the adjacent - -Rg such that represents ^C=0; each Rg is independently selected from the group consisting of H and C j -Cy alkyl, or an R fi can be combined with the adjacent ^C-R g such that „C/ 6 represents C=0; HN NH is a radical of 6 DH the formula R 7 R 7 R 7 (αlk) s -A j -lDHCl or (αlk) r A r lDHCl , wherein each y is independently selected from the group consisting of H and C j -Cy alkyl; (alk) is a straight or branched lower alkylene group which ad- ditionally may contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being nonadjacent to each other and also being nonadjacent to -A 3 -; s is zero or one; -A 3 - is -C00-; and [DHC] is as defined in Claim 51 or 52. 102. A radiopharmaceutical as defined by Claim 99, wherein said metallic radionuclide is the oxo- technate-99m ion. 103. A radiopharmaceutical as defined by Claim 100, wherein said metallic radionuclide is the oxo- technate-99m ion. 104. A radiopharmaceutical as defined by Clai 101, wherein said metallic radionuclide is the oxo- technate-99m Ion. 105. A radiopharmaceutical as defined by Claim 41, 42 or 43, said radiopharmaceutical being a chelate of a metallic radionuclide with a compound of the structural formula (DHC--NH-(CH 2 ) n , ( lib) wherein R 1 and R 2 are each C-^-C β alkyl , n' is an integer of 0 to 3 and [OHC] is as defined in Claim 41, 42 or 43. 106. A radiopharmaceutical as defined by Claim 105, wherein said metallic radionuclide is the oxo- technate-99m ion. 107. A radiopharmaceutical as defined by Claim 41, 42 or 43, said radiopharmaceutical being a chelate of a metallic raidonuclide with a compound of the structural formula wherein [DHC] is as defined in Claim 41, 42 or 43. 0 108. A radiopharmaceutical as defined by Claim 107, wherein said metallic radionuclide is the oxotechnate-99m ion. 109. A radiopharmaceutical as defined by Claim 60, 61 or 62, said radiopharmaceutical being a chelate of a 5 metallic radionuclide with a salt of the structural formula wherein each Rg is independently selected from the group consisting of H and C,-C 7 alkyl, or an Rg can o be combined with the adjacent -C-Rg such that rep resents ^ C=0 ; each R g i s i ndepe nde ntl y se l ected from the g roup cons i sti ng of H and C , -C 7 a l kyl , or an R g can be combined with the adjacent -C-R g such rep dical of the formula wherein each R 7 is independently selected from the group consisting of H and C j -Cy alkyl; (alk) is a straight or branched lower alkylene group which ad¬ ditionally may contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being nonadjacent to each other and also being nonadjacent to -A-^-; X " is the anion of a pharmaceutically acceptable organic or inorganic acid; n is the valence of the acid anion; m is a number which when multiplied by n is equal to one; s is zero or one; -A,- is -NH-, -0- or -N- 8 wherein R g is C j -Cy alkyl; and [QC + ] is as defined in Claim 60, 61 or 62. 110. A radiopharmaceutical as defined by Claim 65, said radiopharmaceutical being a chelate of a metallic radionuclide with a salt of the structural formula - 240 - whereln each Rg i_ independently selected from the group consisting of H and C j -Cy alkyl, or an Rg can be combined with the adjacent C-R ς such that represents ^C=0 each Rg is independently selected from the group consisting of H and C- j -Cy alkyl, or an R g can be combined with the adjacent ^C-R g such that .C is a radical of the formula wherein Ry is independently selected from the group consisting of H and C-, -0-, alkyl; (alk) is a straight or branched lower alkylene group which additionally may contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being nonadjacent to each other and also being nonadjacent to -A 2 - X " is the anion of a pharma¬ ceutically acceptable organic o r inorganic acid; n is the valence of the acid anion; m' is a number which when multiplied by n is equal to one; s is zero or one; -A * 2 - is -CONH- or -CON- wherein R g is C j -C-, alkyl; and [QC ] is as defined in Claim 65. 111. A radiopharmaceutical as defined by Claim 70 or 71, said radiopharmaceutical being a chelate of a metallic radionuclide with a salt of the structural formula wherein each Rg is independently selected from the group consisting of H and C,-Cy alkyl, or an Rg can be combined with the adjacent -Rg such that represents „C=0; each Rg is independently selected from the group consisting of H and C j -Cy alkyl, or an R g can be combined with the adjacent * C-R g such that «0; HN NH is a radical of the formula R 7 R 7 R 7 (filk) s -A 3 -lQC + l wherein each R 7 is independently selected from the group consisting of H and C.-C 7 alkyl; (alk) is a straight or branched lower alkylene group which additionally may contain 1, 2 or 3 oxygen atoms in the chain, said oxygen atoms being nonadjacent to each other and also being nonadjacent to -A 3 ~; X " is the anion of a pharma¬ ceutically acceptable organic or inorganic acid; n is the valence of the acid anion; m' is a number which when multiplied by n is equal to one; s is zero or one; -A 3 - is -C00-; and [QC + ] is as defined in Claim 70 or 71. 112. A radiopharmaceutical as defined by Claim 109, wherein said metallic radionuclide is the oxo- technate-99m ion. 113. A radiopharmaceutical as defined by Claim 110, wherein said metallic radionuclide is the oxo- technate-99m ion. 114. A radiopharmaceutical as defined by Claim 111, wherein said metallic radionuclide is the oxo- technate-99m ion. 115. A radiopharmaceutical as defined by Claim 60, 61 or 62, said radiopharmaceutical being a chelate of a metallic radionuclide with a salt of the structural formula [QC + 1-NH-(CH 2 ) n , (lb) wherein R 1 and R 2 are each H or CJ-C-J alkyl , n" is an integer of 0 to 3 and [QC + ] is as defined in Claim 60, 61 or 62. 116. A radiopharmaceutical as defined by Claim 115, wherein said metallic radionuclide is the oxotechnetate-99m ion. 117. A radiopharmaceutical as defined by Claim 60, 61 or 62, said radiopharmaceutical being a chelate of a metallic radionuclide with a salt of the structural formula (lb') wherein [QC + ] is as defined in Claim 60, 61 or 62. 118. A radiopharmaceutical as defined by Claim 117, wherein said metallic radionuclide is the oxotechnate-99m 1on. 119. A salt as defined by Claim 2 , having the structural formula 3 121. A radiopharmaceutical as defined by Claim 33 ^ said radiopharmaceutical being a complex of the oxotechnate-99m ion with a compound of the formula 250- 122. A radiopharmaceutical as defined by Claim 57, said radiopharmaceutical being a complex of the oxotechnate-99m ion with a salt of the formula 123. A method for rad1o1mag1ng of the brain, said method comprising administering to a patient a radio¬ pharmaceutical as defined by Claim 38 1n a quantity sufficient to deliver an effective radio1mag1ng amount of a radionuclide to the brain, and thereafter imaging the brain by radiation Imaging means. 124. A kit for preparing an In ectable radio¬ pharmaceutical comprising, in separate containers: (1) a compound of formula (II) as defined by Claim 20; (2) a pharmaceutically acceptable reducing agent capable of reducing a radioactive metal to an oxidation state in which said metal is capable of complexing with said compound of formula (II); and (3) a biologically compatible, sterile aqueous medium. 125. A kit for preparing an injectable radio¬ pharmaceutical comprising, in separate containers: (1) a salt of formula (I) as defined by Claim 2 (2) a pharmaceutically acceptable reducing agent capable of reducing said salt to the corresponding compound of the formula ( VCDHC], (II) wherein f Vand y are as defined in Claim 2 and [DHC] is the reduced, biooxidi zable , blood-brain barrier penetrating form of a dihydropyridi ne^±rpyridi niu salt redox carrier, said reducing agent also being capable of reducing a radioactive metal to an oxidation state in which said metal is capable of complexing with said compound of formula (II); and (3) a bio¬ logically compatible, sterile aqueous medium. 126. A kit as claimed in Claim 25» wherein the radioactive metal which said reducing agent is 'capable of reducing is technetium. 127. A kit as claimed in Claim 1 5. wherein said reducing agent is sodium dithionite. 128. A kit as claimed ,in Claim 25» wherein said aqueous medium is of basic pH. 129> A kit for preparing an injectable radio ¬ pharmaceutical comprising, in separate containers: (1) a salt of formula (I) as defined by Claim 2, in a biologically compatible, sterile aqueous medium; and (2) a pharmaceutically acceptable reducing agent capable of reducing said salt to the corres ¬ ponding compound of the formula f VEDHC], (ID wherei y are as defined in Claim 2,and [OHC] is the reduced, bioox idizable, blood-brain barrier penetrating form of a salt redox carrier, said reducing agent also being capable of reducing a radioactive metal to an oxidation state in which said metal is capable of complexing with said compound of formula (II). 130. A kit as claimed in Claim 129, wherein the radioactive metal which said reducing agent is capable of reducing is technetium. 131. A kit as claimed in Claim 129, wherein said reducing agent is sodium dithionite. 132. A kit as claimed in Claim 129, wherein said aqueous medium is of approximately neutral pH. 133. A kit as claimed in Claim 129, wherein (2) contains a base in addition to said reducing agent. 134. A process for preparing a salt of formula (I) as defined by Claim 2, said process comprising: reacting a chelating agent or protected derivative thereof having at least one reactive functional group selected from the group consisting of amino, carboxyl, hydroxyl , amide and imide, said functional group being not essential for the complexing properties of said chelating agent, with a reagent capable of replacing a hydrogen atom from at least one of said reactive functional groups with a [QC + ] radical , or with a radical capable of being quaternized to afford a [QC ] radical; followed by quaternizatlon, when said hydrogen atom has been replaced with a radical capable of being quaternized to afford a [QC ] radical; followed by, when said protected derivative has been used as the starting material , removal of the protecting group or groups to afford the corresponding salt of formula (I). 135. A process for preparing a compound of for¬ mula (II) as defined by Claim 20, said process compris- ing reducing a salt of formula (I) as defined by Claim 2. 136. A process for preparing a radiopharmaceuti¬ cal of formula (III) as defined by Claim 38, said process comprising complexing a metallic radionuclide with a compound of formula (II) as defined by Claim 20. 137. A process for preparing a radiopharmaceuti¬ cal of formula (III) as defined by Claim 38, said pro¬ cess comprising reducing a radiopharmaceutical of for¬ mula (IV) as defined by Claim 57. 138. A process for preparing a radiopharmaceuti¬ cal of formula (IV) as defined by Claim 57, said pro¬ cess comprising: (a) complexing a metallic radionuclide with a salt of formula (I) as defined by Claim 2; or (b) oxidizing a radiopharmaceutical of formula (III) as defined by Claim 38.

Inventors: BODOR NICHOLAS S, BODOR, NICHOLAS, S.
Applicants: UNIV FLORIDA, UNIVERSITY OF FLORIDA
Application year: 1985
Main classification: C07D213
IPC codes: A61K51, C07B59, C07D207, C07D211, C07D213, C07D215, C07D277, C07D285, C07D401, C07K5, C09K3