BICYCLOPOLYAZAMACROCYCLOPHOSPHONIC ACID COMPLEXES, THEIR PREPARATION, CONJUGATES AND RADIOPHARMACEUTICALS

Abstract: Complexes of bicyclopolyazamacrocyclophosphonic acid compounds with a metal ion, e.g. <153>Sm, <177>Lu, <159>Gd, <149>Pm, <140>La, <175>Yb, <166>Ho, <90>Y, <47>Sc, <186>Re, <188>Re, <142>Pr, <99m>Tc, <67>Ga, <68>Ga, <105>Rh, <97>Ru, <111>In, <113m>In or <115m>In ion, are disclosed. The complexes can be covalently attached to a biologically active molecule, e.g. an antibody or antibody fragment, to form conjugates. The complexes and conjugates are useful as radiopharmaceutical agents for therapy and/or diagnostic purposes. Processes for preparing the complex and conjugate are discussed.

Description: BICYCL0P0LYAZAMACR0CYCL0PH0SPH0NIC ACID COMPLEXES, THEIR PREPARATION , CONJUGAT E AND RADIOPHARMACEUTICALS This invention concerns complexes that contain bicyclopolyazamacrocycio- 5 phosphonic acid ligands with metal ions, and conjugates thereof, for use as radiopharmaceuticals, especially for the treatment and/or diagnosis of cancer. The process for the preparation of both the complexes and conjugates is provided. The delivery of radionuclides to different organ and tissue targets has been the objective of many research efforts for both diagnostic and therapeutic purposes. Various 10 molecules have been tried that would carry the active component to the desired site and yet be stable at least until the site has been reached by the delivery system. Halogenated (e.g. -'I and 88m Br) organic molecules have been used. Thus iodinated hippuran has been used to study renal function, e.g. J. Nucl. Med. 23, 377-380 (1982). Also labeling a monoclonal antibody with ,3 'l has been proposed for the detection and therapy of cancer, e.g Cancer Res. 44, 5744-5751 15 (1984) Metallic radionuclides offera variety of nuclear properties and chemistries. Thus, for example, 20 , TI, 67 Cu, 99m Tc, 90 Y and various isotopes of In and Ga are only a few examples of radioisotopesthat have been used for diagnostic imaging and/or therapy. Of these metals, the chemistry of 99m Tc has been explored the most for use as a radiopharmaceutical. For example, 20 Tc-diphosphonates are used to image the skeletal system [see Subramanian et al., Radiology 149, 823-828 (1983)]. Loberg et al. [J. Nucl. Med. 16, 533 (1975)] were able to study liver function with lipophilic "Tc complexes in which the Tc existed in a + 3 oxidation state and the overall charge of the iminodiacetic acid complex was -1. Deutsch et al. [Science 213, 85 (1981 )] was able to prepare Tc complexes with As and P containing ligands that localized in the heart 25 These compounds contained a Tc(lll) core with an overall charge of the complex of + 1. Also Volkert et al. [Int'l. J. Appl. Rad. lsotopes 35, 467-470 ( 1974)] were successful in delivering Tc(lll) to brain tissue. However, since 99m Tc is a pure gamma emiter, it is limited only to diag-OS * -«. applications Therefore, there has been a need for particle emitting radioisotope co. - υ xe- and/or conjugates which would be useful in therapy- Deutsch etal. [Corina Int'L, Veronai and Raven Press, pp.733-740 (1990)] have used the combination of 186 Re and a diphosphonate to treat bone tumors- Also Simon et al. (U.S. Patent 4,898,724) teach the use of 153 Sm and other rare earth radionuclides in combination with aminophosphonic acids forthe treatment of bone 5 pain and tumors- The development of bone metastasis is a common and often catastrophic event for a cancer patient. The pain, pathological fractures, frequent neurological deficits and forced immobility caused by these metastatic lesions significantly decrease the quality of life for the cancer patient- The number of patients that contract metastatic disease is large since nearly 10 50% of all patients who contract breast, lung or prostate carcinoma will eventually develop bone metastasis. Bone metastasis are also seen in patients with carcinoma ofthe kidney, thyroid, bladder, cervixand othertumors, but collectively, these represent less than 20% of patients who develop bone metastasis. Metastatic bone cancer is rarely life threatening and occasionally patients live for years following the discovery ofthe bone lesions. Initially, 15 treatment goals center on relieving pain, thus reducing requirements for narcotic medication and increasing ambulation. Clearly, it is hoped that some of the cancers can be cured The use of radionuclides for treatment of cancer metastatic to the bone dates back to the early 1950's. It has been proposed to injecta radioactive particle-emitting nuclide in a suitable form for the treatment of calcif ic lesions. It is desirable that such nuclides be 0 concentrated in the area ofthe bone lesion with minimal amounts reaching the soft tissue and normal bone. Radioactive phosphorus (P-32 and P-33) compounds have been proposed, but the nuclearand biolocalization properties limitthe use of these compounds- (E. Kaplan, etal., J. Nucl. Med 1(1), 1, (1960); U.S- Patent 3,965,254). Another attempt to treat bone cancer has been made using phosphorus 5 compounds containing a boron residue. The compounds were injected into the body (intravenously) and accumulated in the skeletal system- The treatment area was then irradiated with neutrons in order to activate the boron and give a therapeutic radiation dose- (U.S- Patent 4,399,817). The use of Re-186 complexed with a diphosphonate has also been proposed. 0 [L Mathϊeu et al., Int. J. Applied Rad. <S Isotopes, 30, 725-727 (1979); J. Weinenger, A. R. Ketring etal.,.. Nucl. Med., 24(5), P125 (1983)]. However, the preparation and purification needed forthis complex limits its utility and wide application. Strontium-89 has also-been proposed for patients with metastatic bone lesions. However, the long half-life (50.4 days), high blood levels and low lesion to normal bone 5 ratios limitthe utility. [N. Firusian, P. Mellin, C. G. Schmidt,-/. Urology, 116, 764 (1976); C. G. Schmidt, N. Firusian, Int. J. Clin. Pharmacol., 93, 199-205, (1974)] A palliative treatment of bone metastasis has been reported which employed I- 131 labeled α-amino-(3-iodo-4-hydroxybenzylidene)diphosphonate [M. Eisenhut, J. Nucl Med., 25(12), 1356-1361 (1984)]. The use of radioiodine as a therapeutic radionuclide is less than desirable due to the well known tendency of iodine to localize in the thyroid. Eisenhut lists iodide as one ofthe possible metabolites of this compound The use of radionuclides for calcific tumor therapy or relief of bone pain is discussed in published European patent application 176,288, where the use of Sm-153, Gd- 159, Ho-166, Lu-177 or Yb-175 complexed with a ligand such as ethylenediaminetetraacetic acid (EDTA) or hydroxyethylenediaminetriacetic acid (HEEDTA) is disclosed. A macrocydic system having a 1,4,7,10-tetraazacyclododecane moiety complexed with Sm-153, Gd-159, Ho-166, Lu-177 or Yb-175 for calcific tumor therapy or relief of bone pain is discussed in U.S. Patent 5,059,412 which complex is very stable and hasa lower charge than the complex disclosed in published European patent application 176,288. Functionalized chelants, or bifunctional coordinators, are known to be capable of being covalently attached to an antibody having specificity for cancer or tumor cell epitopes or antigens. Radionuclide complexes of such antibody/chelant conjugates are useful in diagnostic and/or therapeutic applications as a means of conveying the radionuclide to a cancer or tumor cell. See, for example, Meares etal., Anal. Biochem. 142, 68-78, (1984); and Krejcarek et al., Biochem. andBiophys. Res. Comm. 77, 581-585 (1977). Aminocarboxylic acid chelating agents have been known and studied for many years. Typical of the aminocarboxylic acids are nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), trans- 1,2-diaminocyclohexanetetraacetic acid (CDTA) and 1, 4,7,10-tetraazacyclododecanetetraacetic acid (DOTA). Numerous bifunctional chelating agents based on aminocarboxylic acids have been proposed and prepared For example the cyclic dianhydride of DTPA [Hnatowich et al. Science 220, 613-615, (1983), U.S. Patent 4,479,930] and mixed carboxycarbonic anhydrides of DTPA [Gansow, U.S. Patents 4,454,106 and 4,472,509; Krejcarek et al., Biochem. and Biophys.Res. Comm 77, 581-585, (1977)] have been reported. When the anhydrides are coupled to proteins the coupling proceeds via formation of an amide bond thus leaving four of the original five carboxymethyl groups on the diethylenetriamine (DETA) backbone [Hnatowich et al. Int. J. Appl. Isot. 33, 327- 332, (1982)]. In addition, U.S. Patents 4,432,907 and 4,352,751 disclose bifunctional chelating agents useful for binding metal ions to "organic species such as organic target molecules or antibodies." As in the above, coupling is achieved via an amide group through the utilization of dia'minotetraacetic acid dianhydrides. Examples of anhydrides include dianhydrides of EDTA, CDTA, propylenediaminetetraacetic acid and phenylene 1 ,2-diaminetetraacetic acid. A recent U.S. Patent 4,647,447 discloses several complex salts formed from the anion of a complexing acid for use in various diagnostic techniques. Conjugation via a carboxyl group of the complexing acid is taught which gives a linkage through an amide bond. In the J. Radioanal. Chem. 57(12), 553-564 (1980), Paik et al. disclose the use of p-nitrobenzylbromide in a reaction with a "blocked" diethylenetriamine, i.e. bis-(2- phthaIimidoethyl)amine followed by deblocking procedures and carboxymethylation using chloroacetic acid, to give N ' -p-nitrobenzyfdiethylenetriamine N,N,N",N"-tetraacetic acid. Again, since the attachment is through a nitrogen, a tetraacetic acid derivative is obtained- Conjugation ofthe bifunctional chelating agentand chelation with indium is discussed. Substitution on the nitrogen atom is also taught by Eckelman, etal. in the/ Pharm. Sci. 64(4), 704-706 (1975) by reacting amines such as "ethylenediamfne or diethylenetriamine with the appropriate alkyl bromide before carboxymethylation." The compounds are proposed as potential radiopharmaceutical imaging agents. Another class of bifunctional chelating agents based on aminocarboxylic acid functionality is also well documented in the literature. Thus, Sundberg, Meares, et al. in the J. Med. Chem.17(12), 1304 (1974), disclosed bifunctional analogs of EDTA. Representative of these compounds are 1-(p-amϊnophenyl)-ethylenediaminetetraacetic acid and 1-(p- -benzenediazonium)ethylenediaminetetraacetic acid. Coupling to proteins through the para- substituentand the binding of radioactive metal ions to the chelating group is discussed. The compounds are also disclosed in Biochem. and Biophys. Res. Comm. 75(1), 149 (1977), and in U.S. Patents 3,994,966 and 4,043,998. It is important to note thatthe attachment ofthe aromatic group to the EDTA structure is through a carbon ofthe ethylenediamine backbone. Optically active bifunctional chelating agents based on EDTA, HEDTA and DTPA are disclosed in U.S.4,622,420. In these compounds an alkylene group links the aromatic group (which contains the functionality needed for attachment to the protein) to the carbon ofthe polyamine which contains the chelating functionality. Other references to such compounds include Brechbiel et al., Inorg. Chem.25^2772-2781 (1986), U.S. Patent 4,647,447 and International Patent Publication No. WO 86/06384. More recently, certain macrocydic bifunctional chelating agents and the use of their copper chelate conjugates for diagnostic or therapeutic applications have been disclosed in U.S. Patent 4,678,667 and by Moi et a!., Inorg. Chem.26,, 3458-3463 (1987). Attachment of the aminocarboxylic acid functionality to the rest of the bifunctional chelating molecule is through a ring carbon ofthe cyclic polyamine backbone. Thus, a linker, attached at one end to a ring carbon ofthe cyclic polyamine, is also attached at its other end to a functional group capable of reacting with the protein. Another class of bifunctional chelating agents, also worthy of note, consists of ' compounds wherein the chelating moiety, i.e. the aminocarboxylic acid, ofthe molecule is attached through a nitrogen to the functional group ofthe molecule containing the moiety capable of reacting with the protein. As an example, Mikola etal. in patent application (WO 84/03698, published 9/27/1984) disclose a bifunctional chelating agent prepared by reacting p- nitrobenzyl bromide with DETA followed by reaction with bromoacetic acid to make the aminocarboxylic acid. The nitro group is reduced to the corresponding amine group and is then converted to the isothiocyanate group by reaction with thiophosgene. These compounds are bifunctional chelating agents capable of chelating lanthanides which can be conjugated to bio-organic molecules for use as diagnostic agents. Since attachment of the linker portion of the molecule is through one of the nitrogens of tie aminocarboxylic acid, then one potential aminocarboxyl group is lost for chelation. Thus, a DETA-based bifunctional chelant containing four (not five) acid groups is prepared. In this respect, this class of bifunctional chelant is similar to those where attachment to the protein is through an amide group with subsequent loss of a carboxyl chelating group. Recently Carney, Rogers, and Johnson disclosed (3rd. Int'l. Conf. on Monoclonal Antibodies For Cancer: San Diego, California - 2/4-6/88) abstracts entitled "Absence of Intrinsically Higher Tissue Uptake from lndium-1 1 1 Labeled Antibodies: Co-administration of lndium-1 11 and lodine-125 Labeled B72.3 in a Nude Mouse Model" and "Influence of Chelator Denticity on the Biodistribution of lndium-11 1 Labeled B72.3 Immunoconjugates in Nude Mice". The biodistribution of indium-111 complexed with an EDTA and DTPA bifunctional chelating agent is disdosed. Attachment of the aromatic ring to the EDTA/DTPA moieties is through an acetate methylene. Also at a recent meeting D.K. Johnson et al. [Florida Conf. on Chem. in Biotechnology, April 26-29 (1988), Palm Coast, FL] disclosed bifunctional derivatives of EDTA and DTPA where a p-isothiocyanatobenzyl moiety is attached at the methylene carbon of one of the carboxymethyl groups. Previously Hunt et al. in U.S. Patents 4,088,747 and 4,09 .88 (1978) disclosed ethylenediaminediacetic acid (EDDA) based chelating agents wherein attachment of an aromatic ring to the EDDA moiety is through the alkylene or acetate methylene. The compounds are taught to be useful as chelates for studying hepatobiliary function. The preferred metal istechnetium-99m. lndium-11 1 and indium-1 13m are also taught as useful radionuclides for imaging. Such uses of other complexes are known using radio frequency to induce hyperthermia (Japanese Kokai Tokkyo Koho JP 61, 158,931) and fluorescent-lmmunoguided therapy (FIGS) [K. Pettersson et al., Clinical Chem. 29(1), 60-64 (1983) and C. Meares et al., Ace. Chem. Res. 17, 202-209 (1984)]. Consequently, it would be advantageous to provide a complex that does not readily dissociate, that exhibits rapid whole body clearance except from the desired tissue, and conjugates with an antibody to produce the desired results. Advantageously; the present invention provides a new type of a stable metal complex, especially with metals that are rare earths or pseudo-rare earths in their chemistry. The present invention teaches the use of these complexes and that the variance of their charge and lypophilic character may favorably altertheir biodistribution when introduced into an animal. The conjugates of these complexes with a biologicai.y active material, such as an antibody, are also a part of this invention. These complexes and conjugates may be formulated with suitable pharmaceutical carriers and administered to a mammal for diagnosis and/or therapy The present invention is directed to novel complexes which have a ligand that is a bicyclopolyazamacrocyclophosphonic acid compound ofthe formula 5 wherein: 15 f R = - (C) n -T; I y where: 2Q Xand Y are independently H, OH, C^ alkyl or COOH; n is an integer of 1 , 2 or 3; with the proviso that: when n is 2, then the sum of X and Y must equal two or more H; and when n is 3, then the sum of X and Y must equal three or more H; ?1 - T is H, C.-C 18 alkyl, COOH, OH, S0 3 H, where: R 1 is -OH, C.-ς-alkyl or -0-(C C s alkyl); 0 R 4 is H, N0 2 , NH 2 , isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or carboxyl; R 2 is H or OH; with the proviso that when R 2 is OH, then the R term containing the R 2 must have all Xand Y equal to H; with the proviso that at least one T must be P(0)R * OH and with the proviso that when one T is then oneXorY of that Rterm may be COOH and all other Xand Y terms of that Rterm must be H;2 A is CH, N, C-Br, C-CI, C-OR 3 , C-OR 8 , N + -R 5 X " , R 3 is H, C^C,. alkyl, benzyl, or benzyl substituted with at least one R 4 ; R 4 is defined as above; R 5 is C.-C 16 alkyl, benzyl, or benzyl substituted with at least one R 4 ; R 8 is C^C alkylamino; X is C|-, BrM- or H 3 CC0 2 " ; Q and Z independently are CH, N, N + -R 5 X " , C-CH 2 -OR 3 or C-C(0)-R 6 ; R 3 and R 5 are defined as above; R 6 is -0-(C.-C 3 alkyl), OH or NHR 7 ; R 7 is C l -C 5 alkyl or a biologically active material; X ' is defined as above; or pharmaceutically-acceptable salts thereof; with the proviso that: a) when Q, A or Z is N or N + -R 5 X " , then the othertwo groups must be CH; b) when A is C-Br, C-CI, C-OR 3 or C-OR 8 , then both Q and Z must be CH; c) the sum of the R 4 , R 7 and R 8 terms, when present, may not exceed one; and d) only one of Q or Z can be C-C(0)-R 6 and when one of Q or Z is C-C(0)-R 6 , then A must be CH; and complexed with a metal ion of 153 Sm, 177 Lu, 159 Gd, 1 9 Pm, 140 La, 175 Yb, 166 Ho, 90 Y, 47 Sc, 186 Re, 188 Re, 142 Pr, 99 Tc, 67 Ga, 68 Ga, 105 Rh, 97 Ru, l1 , ln, 1,3m ln or 1l5m ln. The complexes of Formula (I) use various metal ions, usually in the + 3 state, selected from: samarium ( 153 Sm), lutetium ( 177 Lu), holmium ( 166 Ho), yttrium ( 90 Y), scandium ( 47 Sc), rhenium ( 186 Re) or ( ,88 Re), praseodymium ( 142 Pr), technetium ( 99 Tc), gallium ( 67 Ga) or ( 68 Ga), or indium ( l11 ln) or ( 115m ln); with 153 Sm, 177 Lu, 159 Gd, 1 9 Pm, ,40 La, 175 Yb, 166 Ho, 90 Y, 47 Sc, 142 Pr, 99 Tc, 67 Ga, 68 Ga, '"In, 113m ln or 115m ln being preferred; with 153 Sm, 177 Lu, 66 Ho, 9 °Y, 99 Tc, 67 Ga, 68 Ga, 11, ln, 113m ln or 115m ln being especially preferred; and with ,53 Sm, 177 Lu or 166 Ho being most preferred. Complexes having gamma emissions, such as 99 Tc, 68 Ga, 67 Ga, • * n, ' 13 ln, or 97 Ru, are useful as diagnostic agents. Complexes having particle emissions, such as 9 Pm, 42 Pr, 90 Y, or ,75 Yb, are useful as therapeutic agents. Complexes having both gamma and particle emissions, such as 153 Sm, 177 Lu, 159 Gd, ,40 La, 166 Ho, 47 Sc, 186 Re, 88 Re, ,Q5 Rh, or ' 15m ln, are useful as both diagnostic and therapeutic agents- The complexes so formed can be used by themselves or can be attached, by being covalently bonded, to an antibody or fragment thereof and used for diagnostic ortherapeutic purposes. Such conjugates and complexes are useful as diagnostic and/or therapeutic agents. Particularly preferred are those complexes of Formula (I) where * Xand Y are H; n is 1 ; or A, Q and Zare CH. Bifunctional complexes of Formula (I) are desirable to prepare the conjugates of this invention. Such complexes contain a ligand which must have: one R term where the T moiety is where R 2 and R 4 are defined as above, especially where in the two Rterms not containing an R 4 term, both T terms are P(0)R'OH, where R 1 is defined as above or where in the two Rterms not containing an R 4 term, one Tterm is a COOH and the other Tterm is P(0)R'OH, where R 1 is defined as above; preferably that moiety of the above Tterm where one ofX or Y of thatterm is COOH; and also preferred are those ligands where n is 1 and/or the remaining X and Y terms are H; or A is C-OR 3 or C-OR 8 , where R 3 and 8 are defined as above or where R 4 is defined as above; or A is CH, and one of Q or Z is CH and the other is C-C(0)-R 6 , where R 6 is defined as above; especially those ligands where R 6 is NHR 7 , where R 7 is a biologically active material. Use ofthe complexes or conjugates of this invention for diagnosis ortherapy of disease states such as cancer is possible. The complexes and conjugates of this invention can be designed to provide a specific overall charge which advantageously influences the in vivo biolocalization. For example, when the metal ion is + 3 the following can be obtained: (A) an overall charge of -2 or more - when in three R terms T is PfOJR'OH, where R 1 is OH, and n is 1 ; or in two R terms T is P(0)R'OH, where R 1 is OH, in the third R term T is COOH, and n is 1 ; or in two R terms T is P(0)R'OH, where R 1 is OH, in the third R term T is PfO^OH, where R 1 is C.-C 5 alkyl, and n is 1 ; or in two R terms T is P(0)R-OH, where R 1 is OH, in the third R term T is P(0)R'OH, where R 1 is -O-^-C.. alkyl), and n is 1; or (B) an overall charge of -1 - when in one R term T is P(0)R'OH, where R 1 is OH, and in the other two R terms T is P(0)R'OH, where R 1 is -0-(C.-C 5 alkyl), and n is 1 ; or in one R term T is P(0)R-OH, where R 1 is OH, and in the other two R terms T is P(0)R 1 OH, where R 1 is C.-C 5 alkyl, and n is 1 ; or in one R term T is P(0)R 1 OH, where R 1 is OH, and in the other two R terms T is COOH, and n is 1 ; or (C) an overall neutral charge - when in the three R terms T is P(0)R'OH, where R 1 is -0-(C C 5 alkyl), and n is 1 ; or in the three R terms T is P(0)R'OH, where R 1 is C^C,. alkyl, and n is 1 ; or (D) an overall charge of + 1 - when one of A, Q or Z is N + -R 5 X , where R 5 and X ' are defined as above; and in one R term, the T moiety is P(0)R 1 OH, where R 1 is C.-C 3 alkyl or -0-(C.-C 5 alkyl); and in the other two R terms, the T moiety is COOH or P(0)R'OH, where R 1 is C--C 5 alkyl or -0-(C.-C 5 alkyl); and all X and Y terms are H. Both the complexes and conjugates may be formulated to be in a pharmaceutically acceptable form for administration to an animal. Use of the complexes and conjugates of this invention with other metal ions for use as contrast agents, such as for magnetic resonance imaging, is also possible. The use of those complexes and conjugates is discussed in another copending application. The complexes of this invention contain a ligand of Formula (I) which is numbered for nomenclature purposes as follows: 13 R 10 The present invention concerns development of radiopharmaceutical agents having synthetic modifications to the chelate enabling site specific delivery ofthe radiopharmaceutical agentto a desired tissue. The advantage being an increased delivery of the radiopharmaceutical agent in the areas of interest based upon tissue affinity. The -. ς specificity ofthe complex of Formula (I) may be controlled by adjusting the total charge and lipophilic character of the complex. The overall range ofthe charge ofthe complex isfrom -3 to + 1. For example, for a complex having 2 or more P0 3 H 2 groups, the overall charge is highly negative and bone uptake is expected; whereas when the overall charge ofthe complex is 0 (thus neutral), the complex may have the ability to cross the blood brain barrier and normal 20 brain uptake may be possible. Tissue specificity may also be realized by ionic or covalent attachment ofthe chelate to a naturally occurring or synthetic molecule having specificity for a desired target tissue. One possible application of this approach is through the use of chelate conjugated monoclonal antibodies which would transport the radioactive chelate to diseased tissue 25 enabling diagnosis and therapy. Additionally, the present radiopharmaceutical agents of Formula (I) which are neutral in charge are particularly preferred for forming the conjugates of this invention since undesirable ionic interactions between the chelate and protein are minimized which preserves the antibody immunoreactivity. 2 Q While not wishing to be bound by theory, it is believed that when a charged complex ofthe invention is made (e.g. possibl -2 or -3 for bone, -1 for liver, or + 1 for heart), the variations in that chelate ionic charge can influence biolocalization. Thus, if the antibody . or other directing moiety is also specificfor the same site, then the conjugate displaystwo portions to aid in site specific delivery. g 5 The terms used in Formula (I) and forthis invention are further defined as follows. "C.-C 3 alkyl", "C.-C,- alkyl", "C C ]8 alkyl", include both straight and branched chain alkyl groups. An "animaf" includes a warm-blooded mammal, preferably a human being. "Biologically active material" refers to, for example, a dextran, peptide, or molecules that have specific affinity for a receptor, or preferably antibodies or antibody fragments. "Antibody" refers to any polyclonal, monoclonal, chimeric antibody or 5 heteroantibody, preferably a monoclonal antibody; "antibody fragment" includes Fab fragments and F(ab') 2 fragments, and any portion of an antibody having specificity toward a desired epitope or epitopes. When using the term "radioactive metal chelate/antibody conjugate" or "conjugate", the "antibody" is meant to include whole antibodies and/or antibody fragments, including semisynthetic or genetically engineered variants thereof. 10 Preferred antibodies are 1 1 16-NS-19-9 (anti-colorectal carcinoma), 1116-NS-3d (anti-CEA), 703D4 (anti-human lung cancer), 704A1 (anti-human lung cancer), CC49 (anti-TAG-72), CC83 (anti-TAG-72) and B72.3. The hybridoma cell lines 1 1 16-NS-19-9, 1 1 16-NS-3d, 703D4, 704A1 , CC49, CC83 and B72.3 are deposited with the American Type Culture Collection, having the accession numbers ATCC HB 8059, ATCC CRL 8019, ATCC HB 8301 , ATCC HB 8302, ATCC HB 15 9459, ATCC HB 9453 and ATCC HB 8108, respectively. As used herein, "complex" refers to a complex of the compound of the invention, e.g. Formula (I), complexed with a metal ion, where at least one metal atom is chelated or sequestered; "conjugate" refers to a metal ion conjugate that is covalently attached to an antibody or antibody fragment. The terms "bifunctional coordinator", "bifunctional chelating 0 agent" and "functionalized chelant" are used interchangeably and referto compounds that have a chelant moiety capable of chelating a metal ion and a moiety covalently bonded to the chelant moiety that is capable of serving as a means to covalently attach to an antibody or antibody fragment. The bifunctional chelating agents described herein (represented by Formula I) can 5 be used to chelate or sequester the metal ions so as to form metal ion chelates (also referred to herein as "complexes"). The complexes, because of the presence of the functionalizing moiety (represented by R 4 or R8 in Formula I), can be covalently attached to biologically active materials, such as dextran, molecules that have specific affinity for a receptor, or preferably covalently attached to antibodies or antibody fragments. Thus the complexes described herein 0 may be covalently attached to an antibody or antibody fragment or have specific affinity for a receptor and are referred to herein as "conjugates". As used herein, "pharmaceutically-acceptable salt" means any salt or mixtures of salts of a complex or conjugate of formula (I) which is sufficiently non-toxic to be useful in therapy or diagnosis of animals, preferably mammals. Thus, the salts are useful in accordance 5 with this invention. Representative of those salts formed by standard reactions from both organic and inorganic sources include, for example, sulfuric, hydrochloric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, palmoic, mucic, glutamic, gluconic, d- camphoric, glutaπc, glycolic, phthalic, tartaric, formic, lauric, steric, salicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoicand cinnamic acids and other suitable acids. Also included are salts formed by standard reactions from both organic and inorganic sources such as ammonium, alkali metal ions, alkaline earth metal ions, and other similar ions- Particularly preferred are the salts ofthe complexes or conjugates of formula (I) where the salt is potassium, sodium or ammonium. Also included are mixtures ofthe above salts. The ligands for use in the complex or conjugate of Formula (I) are prepared by various processes. Typical general synthetic approaches to such processes are provided by the reaction schemes given below. in Scheme 1, the ligands of Formula (I) are prepared wherein X and Y = H, n = 1 (butwould also apply if n = 2 or 3 with the corresponding change in the reagent), RhasT = P0 3 H 2 , and Q, A and Z = CH. Scheme 1 (4) (5) compound of Formula (I) Scheme 2 preparesthe compounds of Formula (I) wherein Xand Y = H, n = 1 (butwould also apply if n = 2 or 3 with the corresponding change in the reagent), and hasT where R 1 = -0-(C.-C 5 alkyl); and Q, Aand Z = CH- Scheme 2 Scheme 3 prepares the compounds of Formula (I) wherein X and Y = H, n = 1 (butwould also apply if n = 2 or 3 with the corresponding change in the reagent), R hasT = where R 1 = C^C.. alkyl; and Q, Aand Z = CH- Scheme 3 of Formula (I) Scheme 4 prepares the compounds of Formula (I) wherein Xand Y = H, n = 1 (butwould also apply if n = 2 or 3 with the corresponding change in the reagent), R hasT = where R 1 = -0-(C f C s alkyl) or C.-C 3 alkyl; A = C-Br; and Q and Z = CH. Scheme 4 Scheme 4 Cont'd Scheme 5 prepares the compounds of Formula (I) wherein X and Y = H, n = 1 (butwould also apply if n = 2 or 3 with the corresponding change in the reagent), R has T = where R 1 = -0-(C.-C 5 alkyl) or C,-C 5 alkyl; A = where R 4 = H, N0 2 , NH 2 or SCN; and Q and Z = CH. Scheme 5 (22) (23) Scheme 5 Cont'd Scheme 5 Cont'd Scheme 6 prepares the compounds of Formula (I) wherein X and Y = H, n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), R has T = where R 1 = -0-(C.-C 5 alkyl) or C.-C 5 alkyl; A = C-OR 8 , where R 8 = C.-C 5 alkylamino; and Qand Z = CH. Scheme 6 Cont ' d CH 3 CN Scheme 6 Cont'd a compound of Formula (I) Scheme 6 Cont ' d (37) (1) H 3 CP(OC 2 H 5 ) 2 CH 2 0, THF Scheme 7 prepares the compounds of Formula (I) wherein Xand Y = H, n = 1 (butwould also apply if n = 2 or 3 with the corresponding change in the reagent), R hasT = 0 II -P-OH ; R 1 where R 1 = -OH, -0-(C.-C 3 alkyl) or C,-C 3 alkyl; Z = C-C(0)-R 6 , where Rδ = OH; and Aand Q = CH. Scheme 7 Cont'd a compound of Formula (I) a compound of Formula (I) a compound of Formula (I) Scheme 8 prepares the compounds of Formula (I) wherein Xand Y = H, n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), RhasT = O II -P-OH ; R - i 1 where R 1 = -OH, -0-(C.-C 5 alkyl) or C--C 5 alkyl; Z = C-CH 2 -OR 3 , where R 3 = benzyl; and QandA = CH. Scheme 8 a compound of Formula (I) Scheme 8 Cont'd Pd/H 2 compound of Formula (I) a compound of Formula (I) Scheme 8 Cont'd a compound of Formula (I) a compound of Formula (I) Scheme 8 Cont'd 0 II HP(OEt)2 a compound of Formula (I) Scheme 9 prepares the compounds of Formula (I) wherein Xand Y = H, n = 1 (butwould also apply if n = 2 or 3 with the corresponding change in the reagent), RhasT = O II -P-OH ; R 1 where R- = -0 H, -0-(C.-C 3 alkyl) or C.-C 5 alkyl; A = N or N * -R s X " , where R 5 = C--C 16 alkyl and X " is defined as before; and Qand Z = CH. Scheme 9 Scheme 9 Cont'd a compound of Formula (I) a compound of Formula (I) a compound of Formula (I) Scheme 9 Cont'd Scheme 10 prepares the compounds of Formula (I) wherein Xand Y = H, n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), R has T = O II -P-OH ; R - i 1 where R 1 = -OH, -0-(C.-C 3 alkyl) or C t -C 3 alkyl; Q = -\T-R S X " , where R 5 = C t -C 16 alkyl and X " is defined as before; and Aand Z = CH- Scheme 10 Scheme 10 Cont'd Scheme 11 preparesthecompoundsof Formula (I) whereinXand Y = H, n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), RhasT = 0 II -P-OH ; R ' l 1 where R 1 = -OH, -0-(C.-C 5 alkyl) or C.-C 5 alkyl; Q = N or l\T-R 5 X " , where R 5 = C.-C 16 alkyl and X " is c led as before; and AandZ = CH. Scheme 11 a compound of Formula (I) Scheme 11 Cont'd Scheme 12 prepares the compounds of Formula (I) wherein Xand Y = H, n = 1 (butwould also apply if n = 2 or 3 with the corresponding change in the reagent), R atthe 3 position has T = - °P-OH ; where R 1 = -OH or -0-(C t -C 3 alkyl); and the other Rterms haveT = COOH; and A, Q andZ = CH. Scheme 12 (102) a compound of Formula (I) Scheme 13 prepares the compounds of Formula (I) wherein Xand Y = H, n = 1 (butwould also apply if n = 2 or 3 with the corresponding change in the reagent), R atthe 3 and 6 positions have T = O - "P-OH ; where R 1 = -OH or -O-^-C.. alkyl); and the R atthe 9 position has T = COOH; and A, Qand Z = CH. Scheme 13 Scheme 14 prepares the compounds of Formula (I) wherein Xand Y = H, n = 1 (butwould also apply if n = 2 or 3 with the corresponding change in the reagent), terms at the 3 and 9 positions have T = 0 - "P-OH ; where R 1 = -OH or-0-(C.-C 5 alkyl); and the Rterm atthe 6 position has T = COOH; and A, Q and Z = CH- Scheme 14 (108) compound of Formula (I) Scheme 15 preparesthe compounds of Formula (I) wherein n = 1 (butwould also apply if n = 2 or 3 with the corresponding change in the reagent), Rterms at the 3 and 9 20 25 σ. © Scheme 15 Cont'd (HI) (112) a compound of Formula (I) Scheme 15 Cont'd (110) Scheme 16 prepares the compounds of Formula (I) wherein n = 1 (but would also apply if n = 2 or 3 with the corresponding change in the reagent), Rterms atthe 3 and 6 positions have T = O - "P-OH ; where R * = -OH or -0-(C.-C 5 alkyl); and Xand Y = H; the Rterm atthe 9 position has T = where R 4 = N0 2 or NH 2 ; and one of X or Y = H and the other = COOH, A, Q and Z = CH. Scheme 16 (109) (115) (116) compound of Formula (I) compound of Formula (I) Scheme 16 Cont'd (118) (117) compound of Formula (I) compound of Formula (I) In the above Schemes, the general process description illustrates specific steps that may be used to accomplish a desired reaction step. The general description of these process steps follows. The synthetic Scheme 1 begins with a halogenation of commercially available bis- pyridyl alcohol (1) using thionyl chloride. Similar procedures for converting an alcohol to an electrophilic substrate, such as treatment with toluenesulfonyl chloride, HBr or HCl, should also result in a similarly reactive product which would work well in subsequent ring closure reactions. Macrocyclization procedures are numerous in the literature and the desired 1Ω tetraazamacrocyde (3) was prepared according to the method of Stetter et al., Tetrahedron 37, 767-772 (1981). More general procedures have since been published which give good yields of similar macrocycles using milder conditions [A. D. Sherry et al., J. Org. Chem. 54, 2990-2992 (1989)]. Detosylation of the intermediate macrocycle [(3) to yield (4)] was accomplished under acidic conditions in good yield. Reductive detosylation procedures are also well known in the . _ literature and can be adapted to the present reaction sequence. Phosphonomethylation to obtain the tris-aminophosphonic acid derivative (5; PCTMP) was conducted under typical Mannich base conditions using phosphorous acid and formaldehyde. In addition to phosphonic acid derivatives, phosphonate esters [e.g. of formula (6)] can also be prepared under organic conditions in alcohols or aprotic solvents (e.g. _ n acetonitrile, benzene, toluene, tetrahydrofuran) and using the desired dialkylphosphite as the nucleophilic species (see Scheme 2). Depending upon the reactivity of the amine, these reactions may be conducted at a temperature between about -10 to about 100 C C. In addition, trialkyi phosphites can be employed under similar Mannich conditions to give the phosphonate ester via oxidation of phosphorous (III) to phosphorous (V) with simultaneous expulsion of one _ ς mole of alcohol (Arbuzov reaction). These reactions can be conducted with or without the presence of a solvent. When alcohols are employed as the solvent for either dialkyl or trialkyi phosphite reactions, it is beneficial to use the alcohol from which the corresponding phosphonate ester is derived in order to avoid alternative products arising from transesterification. Esters of this type are also prepared via N-alkylation of α-halo- _ n dialkylphosphonates in solvents such as acetonitrile, chloroform, dimethylformamide, tetrahydrofuran or 1,4-dioxane with or without the addition of a non-nucleophilic base such as potassium carbonate at room temperature or above. The resulting perester intermediate is then readily hydrolyzed under basic conditions (-aqueous hydroxide, pH = 8-14, 30-1 10°C) to give the corresponding half-acid derivative. __ In Scheme 3, macrocydic methylphosphinic acids (10 and 1 1) are prepared under conditions similar to those described in Scheme 2. Using diethoxymethylphosphine as the nucleophilic species and paraformaldehyde, condensation can be conducted in solvents such as tetrahydrofuran, dimethylformamide, dioxane, acetonitrile or alcholic media The resulting phosphinate ester is then hydrolyzed under acid (6N HCl, 80-100°C) or basic (stoichiometric quantities of base, 40-100 C C) conditions to give the corresponding methylphosphonic acid. Alternatively, the method devised by A. D. Sherry etal. (Inorg. Chem., submitted 1991) using ethylphosphonicacid generated in situ can be used to obtain phosphinate derivatives having increased lipophilic character- Scheme 4 illustrates an approach to incorporate additional functionality into the pyridine unit of the 12-membered tetraazamacrocyde- Thus, chelidamic acid (Sigma Chemical Company; 12) can be converted to the bϊs-halomethyl derivative (13) having appropriate substitution atthe pyridyl 4-position. Transformations leading to this intermediate are general in nature and its preparation is described by Takalo et al. [Acta Chemica Scandinavica B 42, 373- 377(1988)]. Subsequent macrocyciization using this intermediate (15) can be accomplished by the standard DMF reaction at 100°C with the sodiotritosylated triamine, or at room temperature with the trϊtosylated free base and potassium carbonate, sodium carbonate, or cesium carbonate as base to give products similar to those previously described- Subsequent reactions leading to phosphonate half-acids and phosphinate functionality are identical to those transformations and conditions described in the preceding Schemes. In Scheme 4, 4-halopyridyl substituted macrocycles (16) are described which can undergo substitution atthe 4-position ofthe pyridyl moiety as described in Scheme 5. Thus, organometallic Pd(ll) complexes can be employed to facilitate the coupling reaction between phenylacetylene and phenylacetylene derivatives and the pyridyl macrocycle. Typical reaction conditions for this transformation utilize anhydrous conditions with triethylamine as solvent and at reaction temperature between about 10 to about 30°C for optimum yields. The identical product can also be obtained using Cu(l) phenylacetylide in anhydrous pyridine at a temperature between about 80 to about 110°C. In addition, standard anionic alkylatϊon procedures can be employed to affect substitution on the pyridine nucleus with, for example, sodioalkoxides in DMF or dioxane at from about 80 to about 100°C using bases such as potassium carbonate or sodium hydroxide. Macrocydic tetraazamacrocycles (24, 25, 26, 27, 28) derivatized in this manner are compatible with transformations described in previous Schemes resulting in analogous phosphonate chelants. A variation of 4-pyridyl substitution is described in Scheme 6 whereby the 4-hydroxypyridyl moiety (29) is alkylated with a bromoalkylnitrile yielding an intermediate ether linked nitrile (31) which is subsequently incorporated into the macrocydic structure. This type of alkylation procedure-is best accomplished under anhydrous conditions in an aprotic solvent such as tetrahydrofuran (THF) and using a non-nucleophilic base such as sodium hydride or butyllithium at temperatures between from about -30 to about 80°C. The generality of this approach has been described by Chaubet et al., for acyclic analogs [Tetrahedron Letters 31 (40), 5729-5732 (1990)]. The macrocydic nitrile prepared in this manner can be reduced to the primary amine (36) by standard procedures foil owed by protection of the primary amine with 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON; 37) . Subsequent functionalization ofthe macrocydic secondary amines (38, 39, 40, 41, 42, 43) can then be accomplished by the procedures discussed with the additional requirement that the BOC protecting group be removed using trifluoroacetic acid as described in Scheme 6. Functionalization can also be carried out on the 3-position of the pyridine ring within the macrocydic structure as illustrated in Scheme 7. Newkome et al. [Tetrahedron 39(12), 2001-2008 (1983)] has previously described the synthesis of ethyl 2,6- halomethylnicotinate (45) which serves as the initial starting material in this synthetic route. Thus, the tris-tosylated macrocycle intermediate (46) can be detosylated under acidic conditions (HBr/AcOH, 25-115°C) with simultaneous hydrolysis to yield the nicotinic acid derivative (48), or reduction of the ester in refluxing ethanol prior to detosylation will result in the 3-hydroxymethyl intermediate (47). The nicotinic acid macrocycle can then be substituted into the general scheme for secondary amine functionalization to yield the various types of phosphonate chelants of Formula (I) (49, 50, 51 , 52, 53). In contrast, the 3-hydroxymethyl analog is advantageously protected prior to functionalization ofthe macrocydic amines. The benzyl (Bz) protecting group is shown in Scheme 8 since it must be resistant to the severe acid conditions encountered in the detosylation step. After appropriate functionalization of the secondary amines has been accomplished as described in previous Schemes, the benzyl group is removed under mild catalytic hydrogenation conditions (58). Macrocy ic derivatives can also be prepared as in Schemes 12-14 where both carboxylate and phosphonate chelating fuctionalities are present in the same molecule. Thus, varying degrees of carboxylate functionality can be introduced under typical aqueous alkylation procedures using bromoacetic acid. Following this step, the remaining amines can be phosphonomethylated by procedures discussed in previous Schemes using formaldehyde and phosphorous acid, dialkyl phosphonates or trialkyi phosphites. Schemes 15 and 16 delineate a synthetic approach which introduces an aromatic nitrobenzyl substituent at one of the macrocydic nitrogen positions. Typically, the macrocydic amine is mono-N-functionalized in an organic solvent such as acetonitrile or DMF at room temperature using a non-nucleophilic base such as potassium carbonate. Additional functionalization of the remaining nitrogen positions is then preformed by methods and conditions described in previous Schemes. After the introduction of the desired chelating moieties, the nitro group is reduced using platinum oxide and hydrogen in water. In this form, the chelating agent is compatible with conjugation techniques which will enable attachment to larger synthetic or natural molecules. The metal ions used to form the complexes of this invention are 153 Sm, 177 Lu, ,59 Gd, ,49 Pm, 140 La, ,75 Yb, 166 Ho, 90 Y, 7 Sc, 186 Re, lβ8 Re, ,42 Pr, 99m Tc, 67 Ga, 68 Ga, 10b Rh, 97 Ru, , ln, ' 13m ln or 115m ln. The anion present is halide, preferably chloride, or salt free (metal oxide) The complexes are prepared by methods well known in the art. Thus, for example, see Chelating Agents and Metal Chelates, Dwyer & Mellor, Academic Press (1964), Chapter 7. See also methods for making amino acids in Synthetic Production and Utilization of Amino Acids, (edited by Kameko, et al-) John Wiley & Sons (1974). An example ofthe preparation of a complex involves reacting a bicyclopolyazamacrocyclophosphoπic acid with the metal ion under aqueous conditions at a pH from 5 to 7. The complex formed is by a chemical bond and results in a stable radionuclide composition, e.g. stable to the disassociation ofthe radionuclide from the ligand. The complexes ofthe present invention are administered at a ligand to metal molar ratio of at least about 1 :1, preferably from 1 : 1 to 3: 1, more preferably from 1 : 1 to 1.5: 1. A large excess of ligand is undesirable since uncomplexed ligand may be toxic to the animal or may result in cardiac arrest or hypocalcemic convulsions. The antibodies or antibody fragments which may be used in the conjugates described herein can be prepared by techniques well known in the art. Highly specific monoclonal antibodies can be produced by hybridization techniques well known in the art, see for example, Kohlerand Milstein [Nature, 256, 495-497 (1975); and Eur.J. Immunol., 6, 511-519 (1976)]. Such antibodies normally have a highly specific reactivity. In the antibody targeted conjugates, antibodies directed against any desired antigen or hapten may be used. Preferably the antibodies which are used in the conjugates are monoclonal antibodies, or fragments thereof having high specificity for a desired epitope(s). Antibodies used in the present invention may be directed against, for example, tumors, bacteria, fungi, viruses, parasites, mycoplasma, differentiation and other cell membrane antigens, pathogen surface antigens, toxins, enzymes, allergens, drugs and any biologically active molecules. Some examples of antibodies or antibody fragments are 1116-NS-19-9, 1116-NS-3d, 703D4, 704A1 an B72.3 All of these antibodies have been deposited in ATCC. A more complete list of antigens can be found in U.S Patent 4,193,983, which is incorporated herein by reference. The conjugates of the present invention are particularly preferred for the diagnosis of various cancers. This invention is used with a physiologically acceptable carrier, excipient or vehicle therefore. The methods for preparing such formulations are well known. The formulations may be in the form of a suspension, injectable solution or other suitable formulations- Physiologically acceptable suspending media, with or without adjuvants, may be used. An "effective amount" ofthe formulation is used for diagnosis and therapy. The dose will vary depending on the disease and physical parameters of the animal, such as weight. In vivo diagnostics are also contemplated using formulations of this invention. The invention will be further clarified by a consideration ofthe following examples, which are intended to be purelyexemplar of the present invention. Some terms used in the following examples are defined as follows: LC = liquid chromatrography, purifications were carrier out at low pressure using Dionex 201 Oi system fitted with a hand-packed Q-Sepharose'" anion exchange column (23 x2 cm). DMF = dimethylformamide. AcOH = acetic acid. ICP = inductively coupled plasma. g = gram(s). mg = milligrams. kg = kilogram(s). mL = milliliter(s). μL = microliter(s). pH Stability General Procedure A stock 1S3 SmCI 3 solution was prepared by adding 2 μL of 3x1 O^M 153 SmCI 3 in 0.1 HCl to 2 mL of a 3x10""M SmCI 3 carrier solution. Appropriate ligand solutions were then prepared in deionized water. The 1 : 1 iigand/metal complexes were then prepared by combining the ligands (dissolved in 100-500 μL of deionized water) with 2 mL of the stock 153 SmCI 3 solution, followed by through mixing to give an acidic solution (pH = 2). The pH of the solution was then raised to 7.0 using 0.1 N NaOH. The percent metal as a complex was then determined by passing a sample of the complex solution through a Sephadex"" G-50 column, eluting with 4: 1 saline (85% NaCI/NH 4 OH) and collecting 2 x 3 mL fractions. The amount of radioactivity in the combined elutions wasthen compared with that left on the resin (non- complexed metal is retained on the resin). The pH stability profile was generated by adjusting the pH of an aliquot of the complex solution using 1M NaOH or 1M HCl and determining the percent of the metal existing as a complex using the ion exchange method described above. STARTING MATERIALS Example A Preparation of 2,6-bis(chloromethyl)pyridine. To 100 mL of thionyl chloride that was cooled (ice bath) was added 24 g (0.17 mol) of 2,6-bis(hydroxymethyl)pyridine. After 30 min, the reaction mixture was warmed to room temperature, then refluxed for 1.5 hrs. After cooling the reaction mixture to room temperature, the solid which formed was filtered, washed with benzene and dried in vacuo The solid was then neutralized with saturated NaHC0 3 , filtered and dried to yield 23.1 g (71.5%) of the titled product as an off-white crystalline solid, mp 74.5-75.5°C, and further characterized by: ■ H MR (CDCI 3 ) δ 4.88 (s, 4H), 7.25-7.95 (m, 3H). Example B Preparation of 3,6,9-tris(p-tolylsulfonyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15), 11,13- triene A DMF solution (92 mL) of 6.9 g (11.4 mmol) of 1,4,7-tris(p- tolylsulfonyljdiethylenetriamine disodium saltwas stirred and heated to 100°C under nitrogen. To the solution was added dropwise over 45 min 2 g (1 T.4mmo!) of 2,6- bis(chloromethyl)pyridine (prepared by the procedure of Example A) in 37 mLof DMF. When the addition was completed the reaction mixture was stirred at 40°C for 12 hrs. To the reaction mixture was then added 50-75 mLof water, resulting in immediate dissolution of NaCI, followed by precipitation ofthe title product. The resulting slurry wasthen filtered and the solid washed with water and dried in vacuo. The title product was obtained as a light-tan powder, 6.5 g (86%), mp 168-170°Cdec. and further characterized by: Η MR(CDCI 3 ) δ 2.40 (s, 3H), 2.44 (s, 6H), 2.75 (m, 4H), 3.30 (m, 4H), 4.28 (s, 4H), 7.27 (d, 2H), 7.34 (d, 4H), 7.43 (d, 2H), 7-65 (d, 4H), 7-75 (t, 1 H); and 3 C MR 621-48, 47.29, 50.37, 54-86, 124.19, 127.00, 127.11, 129.73, 135.04, 135-74, 138.95, 143-42, 143.73, 155-15. Example C Preparation of 3,6,9,15-tetraazabicydo[9.3.1]pentadeca-1(15),11,13-triene. A solution of HBr and AcOH was prepared by mixing 48% HBr and glacial AcOH in a 64:35 ratio- To 112 mLof the HBr/AcOH mixture was added 5.5 g (8.2 mmol) of 3,6,9-trϊs(p- tolylsulfonyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),11,13-triene (prepared by the procedure of Example B) and the reaction mixture was heated at mild reflux with constant stirring for 72 hrs. The reaction mixture was then cooled to room temperature and concentrated to approximately 1/10 of the original volume. The remaining solution was stirred vigorously and 15-20 mL of diethyl ether was added. An off-white solid formed which was filtered, washed with diethyl ether, and dried in vacuo. The dry tetrahydrobromide salt was then dissolved in 10 mLof water, adjusted to pH 9.5 with NaOH (50% w/w) and continuously extracted with chloroform for 4 hrs. After drying over anhydrous sodium sulfate, the chloroform was evaporated to give a light-tan oil which gradually crystallized upon standing at room temperature to yield 1.2 g (71 %) ofthe title product, mp 86-88°C and further characterized by: % H NMR (CDCl 3 ) δ 2.21 (m, 4H). 2.59 (m, 4H), 3.06 (s, 3H), 3.85 (s, 4H), 6.89 (d, 2H), 7.44 (t, 1 H); and C MR 648-73, 49.01, 53.63, 119.67, 136.29, 159.54. FINAL PRODUCTS Example 1 Preparation of 3,6,9, 15-tetraazabicyclo[9.3.1 Jpentadeca- 1 ( 15), 1 1 , 13-triene-3,6,9- trimethylenephosphonic acid (PCTMP). A mixture of 2.06 g (10 mmol) of 3,6,9, 15-tetraazabicyclo[9.3.1 Jpentadeca- 5 1(15),1 1,13-triene (prepared by the procedure of Example C), 1 1.3 g (138 mmol) of phosphoric acid and 15 g (152 mmol) of concentrated HCl was heated to gentle reflux (103 °C) with constant stirring followed by the dropwise addition (2 mL/min) of 12.2 g (150 mmol, 15 mL) of aqueous formaldehyde (37%). After complete addition, the reaction mixture was stirred at reflux for 16 hrs, cooled to room temperature and concentrated to a thick, viscous oil. The 10 product was then purified by LC anion exchange chromatography (0-30% formic acid, 3 mL/min, retention time = 32 min). The combined fractions were freeze-dried to give 4.8 g (99%) of the title product as a white solid, mp 275-280°C and further characterized by: • H NMR (D 2 0) δ 2.83 (m, 6H), 3.46 (m, 10H), 7.28 (d, 2H), 7.78 (t, 1 H); and 15 13 C NMR 8 53.61, 53.81, 55.27, 57.93, 62.20, 125.48, 143.08, 152.31 ; and 31 P NMR δ 8.12 (2P), 19.81 (1P). Example 2 0 Preparation of the complex of 153 Sm-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1 (15),1 1 ,13- triene-3,6,9-trimethylenephosphonic acid ( *S3 Sm-PCTMP) A solution of the ligand of Example 1 was prepared by dissolving 3.8 mg of ligand/0.517 mL of deionized water (pH = 2). A 1 : 1 ligand/metal complex was then prepared by combining 40 μl of the ligand solution with 2 mL of aqueous SmCI 3 -H 2 0 (3x10^ in 0.1 N HCl) 5 containing tracer 153 SmCI 3 . After thorough mixing, the percent metal as a complex was determined by passing a sample of the complex solution through a Sephadex™ column, eluting with 4: 1 saline (0.85% NaCI/NH 4 0H), and collecting 2 x 3 mL fractions. The amount of radioactivity in the combined elutions was then compared with that left on the resin. Under these conditions, complex was removed with the eluent and non-complexed metal is retained 0 on the resin. Bythis method complexation was determined to be 98%. A sample of the solution that was passed through the resin was used for pH studies. The pH stability was then determined using the General Procedure above. Example 3 Preparation of the complex of 166 Ho-3,6,9, 15-tetraazabicydo[9.3.1 ]pentadeca-1 ( 15), 1 1 , 13- 5 triene-3,6,9-trimethylenephosphonic acid ( 166 Ho-PCTMP) When the procedure of Example 2 was repeated using 166 HoCI in place of 153, SmCI 3 , the title product was obtained. Example 4 Preparation ofthe complex of 9D Y-3,6,9,15-tetraazabicyclo[9.3-1]pentadeca-1(15),11,13-triene- 3,6,9-trimethylenephosphonicacid ( S0 Y-PCTMP) When the procedure of Example 2 was repeated using 90 YCI 3 in place of 153 SmCI 3 , the title product was obtained- BIODISTRIBUTION General Procedure Sprague Dawley rats were allowed to acclimate for five days then injected with 100 μL ofthe complex solution via a tail vein. The rats weighed between 150 and 200 g atthe time of injection. After 30 min-the rats were killed by cervical dislocation and dissected- The amount of radioactivity in each tissue was determined by counting in a Nal scintillation counter coupled to a multichannel analyzer- The counts were compared to the counts in 100 μL standards in order to determine the percentage ofthe dose in each tissue or organ. The percent dose in blood was estimated assuming blood to be 7% ofthe body weight. The percent dose in bone was estimated by multiplying the percent dose in the femur by 25- The percent dose in muscle was estimated assuming muscle to be 43% of the body weight. EXAMPLE I The percent ofthe injected dose of complex of of Example 2 ( 153 Sm-PCTMP) in several tissues are given in Table I- The numbers representthe average of 5 rats per data point. TABLE I % INJECTED DOSE IN SEVERAL TISSUES FOR i53Sm-PCTMP EXAMPLE ll The percent ofthe injected dose ofthe complex of 16e Ho with the ligand of Example 1 (PCTMP), prepared in Example 3, in several tissues are given in Table II- The numbers representthe average of 3 rats per data point- TABLE II % INJECTED DOSE IN SEVERAL TISSUES FOR I66H0-PCTMP EXAMPLE III The percent of the injected dose of complex of 90 Y with the ligand of Example 1 (PCTMP), prepared in Example 4, in several tissues are given in Table III. The numbers represent the average of 3 rats per data point. TABLE III % INJECTED DOSE IN SEVERAL TISSUES FOR 90Y-PCTMP The bone to blood ratio (% dose/G) was 140. The bone to liver ratio was 76. The bone to muscle ratio was 400. EXAMPLE IV The complex of ,53 Sm with the ligand of Example 1 (PCTMP) had a bone localization of about 60% at a 5: 1 ligand to metal ratio. This result suggests that the reduced charge chelate could deliver specifically to bone. Other embodiments of the invention will be apparent to those skilled in the art from a consideration of this specification or practice ofthe invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following claims.

Claims: WHAT IS CLAIMED IS: 1. A complex which comprises a bicydopolyazamacrocyclophosphonic acid compound of the formula R-N N-R wherein: f R = - ( C ) n -T ; I Y where: X and Y are independently H, OH, C.-C 3 alkyl or COOH; n is an integer of 1 , 2 or 3; with the proviso that: when n is 2, then the sum of X and Y must equal two or more H; and when n is 3, then the sum of X and Y must equal three or more H; T is H, C,-C lg alkyl, COOH, OH, S0 3 H, where: R 1 is OH, C.-C 3 alkyl or -0-(C.-C 5 alkyl); R 4 is H, N0 2 , NH 2 , isothiocyanato, semicarbazido,thiosemicarbazido, maleimido, bromoacetamϊdo orcarboxyl; R 2 is H or OH; with the proviso that when R 2 is OH, then the Rterm containing the R 2 must have all X and Y equal to H; with the proviso that at least one T must be P(0)R * OH and with the proviso that when one T is then oneXorY of that Rterm may be COOH and all other X and Y terms of that Rterm must be H; A is CH, N, C-Br, C-CI, C-OR 3 , C-OR 8 , N ÷ -R s X " , R 3 is H, C -C arkyl, benzyl, or benzyl substituted with at least one R 4 ; R 4 is defined as above; R 5 is C t -C ]6 alkyl, benzyl, or benzyl substituted with at least one R"; R 8 is C.-C ι6 alkyiamino; χ- is CI , Br, l orH 3 CC0 2 -; Q and Z independently are CH, N, N * -R s X " , C-CH 2 -OR 3 or C-C(0)-R 6 , R 3 and R 5 are defined as above; R 6 is -0-(C,-C 3 alkyl), OH or NHR 7 ; R 7 is C j -C.. alkyl or a biologically active material; X ' is defined as above; or pharmaceutically-acceptable salts thereof ; with the proviso that: a) when Q, A or Z is N or N + -R 5 X " , then the other two groups must be CH; b) when A is C-Br, C-CI, C-OR 3 or C-OR 8 , then both Q and Z must be CH; c) the sum of the R 4 , R 7 and R 8 terms, when present, may not exceed one, and d) only one of Q or Z can be C-C(0)-R 6 and when one of Q or Z is C-C(0)-R 6 , then A must be CH; complexed with a metal ion of 153 Sm, 177 Lu, 159 Gd, 149 Pm, 140 La, 175 Yb, 166 Ho, 90 Y, 7 Sc, ,86 Re, 188 Re, 142 Pr, 99m Tc, 67 Ga, ω Ga, 05 Rh, 97 Ru, * * 'In, 113m ln or 115m ln. 2. A complex of Claim 1 wherein the metal is 153 Sm. ,77 Lu, 159 Gd, 149 Pm, 1 0 La, ' 75 Yb, ,66 Ho, 90 Y, 7 Sc, 1 2 Pr, "-"Tc, 67 Ga, 68 Ga, 11l ln, 113m ln or 115m ln. 3. A complex of Claim 2 wherein the metal ion is 1s3 Sm, 177 Lu, ,66 Ho, 90 Y, 99m Tc, 67 Ga, 68 Ga, 1,, ln, 113m ln or 115m ln. 4. A complex of Claim 3 wherein the metal ion is 153 Sm, 177 Lu or 166 Ho. 5. A complex of Claim 1 wherein at least two R terms have T equal to P(0)R'OH, where R1 is OH, and in the third R term T is H, COOH or C.-C lg alkyl; A, Q and Z are CH; n is 1 , and X and Y independently are H or C.-C alkyl. 6. A complex of Claim 1 wherein three R terms haveT equal to P(0)R'OH where R 1 is OH; and X and Y are H, and named as 3,6,9, 15-tetraazabicyclo[9.3.1]pentadeca- 1 (15), 1 1 ,13-triene-3,6,9-trimethylenephosphonic acid. 7. A complex of Claim 6 wherein the metal ion is ,53 Sm, 177 Lu, 166 Ho, 90 Y, 99m Tc, 67 Ga, 68 Ga, 111 ln, 1,3m ln or 1lSm ln. 8. A complex of Claim 5 wherein in two R terms T is P(0)R'OH, where R' is OH, and in the third R term T is COOH, and n is 1. 9. A complex of Claim 5 wherein in two R terms T is P(0)R-OH, where R 1 is OH, in the third R term T is P(0)R 1 OH, where R 1 is C.-C 5 alkyl, and n is 1. 10. A complex of Claim 5 wherein in two R terms T is P(0)R'OH, where R 1 is OH, in the third Rterm T is P^R'OH, where R 1 is -0-(C.-C 5 alkyl), and n is 1. 1 1. A complex of Claim 1 wherein in the R term at least one T equal PfOJR'OH, where R 1 is OH, and in the other two R terms, T is COOH or P(0)R'OH, X and y are H; A, Q and Z are CH; and n and R 1 are defined as in Claim 1. 12- A complex of Claim 11 wherein in one Rterm T is P(0)ROH, where R * is OH, and in the othertwo Rterms T is P(0)R * OH, where R' is -0-{C.-C 3 alkyl), and n is 1. 13. A complex of Claim 11 wherein in one Rterm T is P(0)R'OH, where R' is O OHH, a annrdl i inn t thhe other two Rterms T is P(0)R 1 OH, where R * is C.-C 3 alkyl, and n is 1. 14. A complex of Claim 1 1 wherein in one Rterm T is P(0)R * OH, where R 1 is OH, and in the othertwo Rterms T is COOH, and n is 1- 15. A complex of Claim 1 wherein in the Rterm three T equal P(0)R'OH, where R 1 is C r C s alkyl or -0-(C t -C 3 alkyl); n is 1 ; X and Y are H; and A, Q and Z are CH. 16. A complex of Claim 15 wherein in the three RtermsT is P(0)R * OH, where R 1 is -0-(C.-C 3 alkyl), and n is 1. 17. Acomplex of Claim 15 wherein in the three Rterms Tis PtOjR'OH, where R l is C J -C J alkyl, and n is 1. 18- A complex of Claim 1 wherein X and Y are H. 19. A complex of Claim 1 wherein n is 1. 20. A complex of Claim 1 wherein A, Q and Zare CH. 21. A complex of Claim 1 wherein Q, A and Z are CH; and in the three Rterms X,Y and n are defined as in Claim 1, and one Tterm is where R 2 and R 4 are defined as in Claim 1, and the othertwo Tterms are defined as in Claim 1. 22. A complex of Claim 21 wherein n is 1. 23. Acomplex of Claim 22 wherein in the Rterm that contains a T moiety which has the R 4 group present, also has one of X or Y of that R term equal to COOH 24. A complex of Claim 23 wherein in the two terms not containing an R 4 term, all remaining X and Y terms are H. 25. A complex of Claim 24 wherein in the two R terms not containing an R 4 term, both Tterms are P(0)R 1 OH, where R 1 is defined as in Claim 1 and is the same moiety 26. A complex of Claim 24 wherein in the two R terms not containing an R 4 term, one T term is a COOH and the other T term is P(0)R'OH, where R 1 is defi ned as i n Claim 1. 27. Acomplex of Claim 1 wherein X and Y are H; T is COOH where: R 1 is -OH, C.-C 5 alkyl or -0-(C.-C 5 alkyl). 28. A complex of Claim 27 wherein Q and Z are CH. 29. A complex of Claim 28 wherein A is C-OR 3 , C-OR 8 or where R 3 , R 4 and R8 are defined as in Claim 1. 30. A complex of Claim 27 wherein A is CH, and one of Q or Z is CH and the other is C-C(0)-R 6 , where R 6 is defined as in Claim 1. 31. A complex of Claim 28 wherein R 6 is NHR 7 , where R 7 is a biologically active material. 32. Acomplex of Claim 19 wherein one of A, Q or Z is N + -R 5 X ' , where R 5 and X " are defined as in Claim 31 ; and in one R term, the T moiety is P(0)R'OH, where R 1 is C 1 -C 5 alkyl or -O-tC.-C.. alkyl); and in the othertwo R terms, the T moiety is PfO^OH, where R 1 is C.-C 5 alkyl, -0-(C,-C 5 alkyl) or COOH; and all X and Y terms are H. 33. A complex of Claim 32 wherein in all three Rterms, the T moiety is PtOjR'OH, where R 1 is C,-C 5 alkyl or -0-(C.-C 5 alkyl). 34. A complex of Claim 32 wherein in all three R terms, the T moiety is p(0)R * OH, where R 1 is -0-(C,-C alkyl). 35- A conjugate comprising a bicyclopolyazamacrocyclophosphonic acid compound ofthe formula R-N N-R wherein: R = -(C) n -T; I Y where: X and Y are independently H, OH, C.-C 3 alkyl or COOH; 20 π is an integer of 1,2 or 3; with the proviso that: when n is 2, then the sum of Xand Y must equal two or more H; and when n is 3, then the sum of X and Y must equal three or more H; T is H, C C 18 alkyl, COOH, OH, S0 3 H, ? ** - where: R τ is OH, C.-C 3 alkyl or -0-(C C 5 alkyl); 30 R 4 is H, N0 2 , NH 2 , isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or carboxyl; R 2 is H or OH; with the proviso that when R 2 is OH, then the R term containing the R 2 must have all Xand Y equal to H; with the proviso that at least one T must be P(0)ROH and that when one T is then one X or Y of that R term may be COOH and all other X and Y terms of that R term must be H; A is CH, N, C-Br, C-CI, C-OR 3 , C-OR 8 , N *-R 5 X, R 3 is H, C.-C 5 alkyl, benzyl, or benzyl substituted with at least one R 4 ; R 4 is defined as above; R 5 is C.-C 16 alkyl, benzyl, or benzyl substituted with at least one R 4 ; R 8 is C l -C 16 alkylamino; X is C|-, Br, l or H 3 CC0 2 -; Q and Z independently are CH, N, N + -R 5 X " , C-CH 2 -OR 3 or C-C(0)-R 6 ; R 3 and R 5 are defined as above; R 6 is -0-(C 1 -C 3 alkyl), OH or NHR 7 ; R 7 is C^C.. alkyl or a biologically active material; X ' is defined as above; or pharmaceutically-acceptable salts thereof; with the proviso that: a) when Q, A or Z is N or N + -R 5 X " , then the othertwo groups must be CH; b) when A is C-Br, C-CI, C-OR 3 or C-OR 8 , then both Q and Z must be CH; c) the sum ofthe R 4 , R 7 and R 8 terms, when present, may not exceed one; and d) only one of Q or Z can be C-C(0)-R 6 and when one of Q or Z is C-C(0)-R 6 , then A must be CH; complexed with a metal ion of 53 Sm, 177 Lu, 159 Gd, 149 Pm, 140 La, ,75 Yb, 166 Ho, 90 Y, 47 Sc, 186 Re, ,88 Re, ' 42 Pr, 99m Tc, 67 Ga, 68 Ga, 105 Rh, 97 Ru, "'In, ,13m ln or 115πι ln; and covalently attached to.a biologically active material. 36. A conjugate of Claim 35 wherein the metal ion is ,53 Sm, 177 Lu, 159 Gd, 1 9 Pm, 1 4 0 L3( 1 75 γb( 166 Hθ 90γ ( 47 $Cj ,ι 3 m | n or H5m |n 37- A conjugate of Claim 35 wherein the biologically active material is a dextran, a polypeptide, a molecule that has specific affinity for a receptor, an antibody or antibody fragment, ora monoclonal antibody or fragment thereof. 38. A conjugate of Claim 37 wherein the antibody or antibody fragment is B72.3- 39. A conjugate of Claim 36 or 37 wherein the metal ion is 1S3 Sm, 177 Lu, 166 Ho, 90 Y, 99m Tc, "Ga, ∞Ga, " Mn, ,,3m ln or * 15m ln. 40. A conjugate of Claim 39 wherein the metal ion is 153 Sm, 177 Lu or 166 Ho. 41 - A conjugate of Claim 35 wherein X and Y are H. 42- A conjugate of Claim 35 wherein n is 1 - 43- A conjugate of Claim 35 wherein A, Q and Z are CH. 44- Aconjugateof Claim 35 wherein Q, A and Zare CH; and in the three R terms X, Y and n are defined as in Claim 35, and one Tterm is where R 2 and R 4 are defined as in Claim 35, and the other two Tterms are defi ned as in Claim 35. 45. Aconjugate of Claim 44 wherein n is 1- 46- A conjugate of Claim 45 wherein in the R term that contains a T moiety which has the R 4 group present, also has one of XorY of that Rterm equal to COOH. 47. A conjugate of Claim 46 wherein in the two Rterms not containing an R 4 term, all remaining X and Yterms are H. 48- Aconjugate of Claim 47 wherein in the two Rterms not containing an R 4 term, both Tterms are P(0)R T OH, where R 1 is defined as in Claim 35 and isthe same moiety. 49. A conjugate of Claim 47 wherein in the two R terms not containing an R 4 term, one Tterm is a COOH and the other Tterm is P(0)R'OH, where R " ' is defined as in Claim 34. 50. A conjugate of Claim 42 wherein X and Y are H; T is COOH where: R 1 is OH, C,-C 3 alkyl or -0-(C.-C 5 alkyl). 51. A conjugate of Claim 50 wherein Q and Z are CH. !0 52. A conjugate of Claim 50 wherein A is C-OR 3 , C-OR 8 , where R 3 and R8 are defined as in Claim 35, or where R 4 is defined as in Claim 35. 53. A conjugate of Claim 50 wherein A is CH, and one of Q or Z is CH and the other is C-C(0)-R 6 , where R 6 is defined as in Claim 35. 0 54. A conjugate of Claim 53 wherein R 6 is NHR 7 , where R 7 is a biologically active material. 55. A pharmaceutical formulation comprising a complex of any one of Claims 1-34 with a pharmaceutically-acceptable carrier. 5 56. The pharmaceutical formulation of Claim 55 comprising a complex of Claim 6 with a pharmaceutically-acceptable carrier. 57. A pharmaceutical formulation comprising a conjugate of any one of Claims 35-54 with a pharmaceutically-acceptable carrier. 0 58. A method forthe diagnosis of a disease state in an animal which comprises administering to said animal an effective amount of the formulation of Claim 55 wherein the • metal ion is "t-Tc, ∞Ga; 67 Ga, "Mn, 113m ln or 97 Ru. 59. A method forthe diagnosis of a disease state in an animal which comprises 5 administering to said animal an effective amount of the formulation of Claim 56 wherein the metal ion is 99m Tc, ∞Ga, 67 Ga, "Mn, 1,3m ln or 97 Ru. 60. A method forthe diagnosis of a disease state in an animal which comprises administering to said animal an effective amount of the formulation of Claim 57 wherein the metal ion is 99m Tc, 68 Ga, "Ga, "Mn, " 3m in or 97 Ru. 61. A method forthe diagnosis and therapy of a disease state in an animal which comprises administering to said animal an effective amount ofthe formulation of Claim 55 wherein the metal ion is *53 Sm, 177 Lu, ,59 Gd, 140 La, ,66 Ho, 47 Sc, 186 Re, ,88 Re, '^Rh, or " Sm ln. 62. A method forthe diagnosis and therapy of a disease state in an animal which comprises administering to said animal an effective amount ofthe formulation of Claim 56 wherein the metal ion is ,53 Sm, 177 Lu, 159 Gd, , 0 La, t66 Ho, 47 Sc, 186 Re, 188 Re, 105 Rh, or " Sm ln. 63- A method forthe diagnosis and therapy of a disease state in an animal which comprises administering to said animal an effective amount of the formulation of Claim 57 wherein the metal ion is 1S3 Sm, t77 Lu, ,59 Gd, 140 La, 166 Ho, 47 Sc, ,86 Re, 188 Re, ,05 Rh, or " Sm ln. 15 64. A method forthe therapy of a disease state in an animal which comprises administering to said animal an effective amount of the formulation of Claim 55 wherein the metal ion is , 9 Pm, ,42 Pr, 90 Y or ,75 Yb. 65. A method forthe therapy of a disease state in an animal which comprises 20 administering to said animal an effective amount ofthe formulation of Claim 56 wherein the metal ion is 1 9 Pm, 142 Pr, 90 Y or 175 Yb. 66. A method forthe therapy of a disease state in an animal which comprises administeringto said animal an effective amount of the formulation of Claim 57 wherein the 25 metal ion is 149 Pm, 142 Pr, 90 Y or 175 Yb- 67- The complex as claimed in any one of Claims 1-34for use as a pharmaceutical- 68- The conjugate as claimed in any one of Claims 35-54 for use as a 30 pharmaceutical. 69. A kit for use as a therapeutic agenthaving as an ingredent a Jigand of Formula (I) as daimed in Claim 1. __ 70. A process for preparing the complex as claimed in any one of Claims 1 -34, which comprises reacting a bicyclopolyazamacrocyclophosphonicacid compound as claimed in Claim 1 with a metal ion of 1S3 Sm, 177 Lu, 159 Gd, 149 Pm, 140 La, 175 Yb, 166 Ho, 90 Y, 47 Sc, 186 Re, 188 Re, , 2 Pr, 99m TC( Gaι 6 β Gaι ιos Rh( 97 RU( ni |n _ ιi3m |n or ιi5 , n under aqueous conditions at a pH from 5 to 7. 71. The process of Claim 70 wherein the bicyclopolyazamacrocyclophosphonic acid compoun ιdd iiss 33,,66,,99,,1155--tt(etraazabicyclo[9.3.1]pentadeca-1(15),1 1 ,13-triene-3,6,9-tri- methylenephosphonic acid.

Inventors: KIEFER GARRY E, SIMON JAIME, KIEFER, GARRY, E., SIMON, JAIME
Applicants: DOW CHEMICAL CO, THE DOW CHEMICAL COMPANY
Application year: 1992
Main classification: A61K43
IPC codes: A61K51, C07B59, C07F5, C07F9, C07F13