IN SITU SYNTHESIS OF RADIOPHARMACEUTICALS

Abstract: The present invention relates to a process of making radiopharmaceuticals in situ, i.e. wherein a radionuclide and an acyclic ligand react with constituents of the complex forming reaction solution to produce an administratable radiopharmaceutical agent. By forming radiopharmarceuticals according to the present invention, it is possible to obtain radiopharmaceuticals previously unattainable because of problems associated with the ligand synthesis or with the complex forming reaction.

Description: IN SITU SYNTHESIS OF RADIOPHARMACEUTICALS Background of the Invention The present invention relates to novel in situ synthesis methods of forming radiopharmaceuticals. The use of radiopharmaceuticals for diagnostic and therapeutic purposes is well known in the area of biological and medical research. In particular, radiopharmaceuticals are used as radiographic imaging agents for visualizing skeletal structures, organs, or tissues. Such imaging is accomplished by preparation of radioactive agents, which when introduced into the body of a patient, are localized in the specific structure which is to be studied. The localized agents may then be traced, plotted or scintiphotographed by radiation detectors, such as, traversing scanners or scintillation cameras. The distribution and relative intensity of the detected radioactive agents indicates the position of the structure in which the agent is localized, and also shows the presence of aberrations in structure or function, pathological conditions or the like. In a similar manner, radiopharmaceuticals may be used as therapeutic agents, for providing radiation to a particular pathological condition which is to be treated. Such treatment may be accomplished by preparation of radioactive therapeutic agents which again are designed to localize in a particular structure, organ or tissue. When such an agent is localized, radiation may be delivered directly to the pathological condition requiring radiation treatment. In general, both diagnostic and therapeutic radiopharmaceuticals are comprised of a radionuclide- labelled compound. In the case of metal-based radionuclides the metal can exist in it's free state, as an ion, or in the form of a metal complex with a ligand or group of ligands. Examples of metal radionuclides that form complexes are Tc-99m and Re-186. The former is used in diagnostic work and the latter is used for therapy. The resultant radiopharmaceuticals further include appropriate carriers and auxiliary agents, such as delivery vehicles suitable for injection, aspiration or inges ion by the patient, as well as physiological buffers and salts, and the like. Prior art methods of forming radiopharmaceuticals generally require initial synthesis of the ligand, followed by a separate synthesis of the radionuclide complex (i.e. a labelling procedure) . In particular, radiopharmaceuticals of the prior art are formed by first synthesizing the desired structure specific ligand, according to known methods for such a ligand. The prepared ligand, generally in a lyophilized kit also containing one or more excipients is then reacted with a radionuclide- containing solution under radionuclide complex-forming reaction conditions. For example, when it is desired to form a technetium-99m radiopharmaceutical, the prepared ligand may be reacted along with a reducing agent with a pertechnetate solution under technetium-99m complex-forming reaction conditions. The complexes are then administered to the patient via injection, inhalation or ingestion. The radionuclide-containing solutions can be obtained from a generator, as in the case of Tc-99m, or can be supplied in saline or water by a manufacturer, as with Re- 186. With Tc-99m the radionuclide solution is eluted from a Mo-99/Tc-99m generator system. The complex-forming reaction is carried out at complex-forming temperatures (e.g. 20°C to 100° C) for a few minutes to several hours when forming technetium complexes. A large excess (e.g. greater than one hundred fold excess to metal radionuclide) of the prepared ligand is used and a sufficient amount of reducing agent is present, if needed, to insure reduction of the radionuclide to facilitate complexation by the ligand. Radiopharmaceutical agents are then prepared by combining the radionuclide complex, in an amount sufficient for the desired diagnostic or therapeutic purpose, with a pharmaceutically acceptable radiological vehicle. The radiological vehicle should be acceptable for injection, aspiration or ingestion. Examples of such vehicles are human serum albumin; aqueous buffer solutions, e.g. tris(hydromethyl)aminomethane (and its salts), phosphate, citrate, bicarbonate, etc.; sterile water; physiological saline; and balanced ionic solutions containing chloride and or dicarbonate salts or normal plasma cations such as Ca +2 , Na + , K + , and Mg +2 . Also, agents known as "stabilizers" can be included. These hold the radionuclide in a stable form until it can be reacted with the ligand. These stabilizers can include agents known as "transfer ligands" which are particularly useful in holding the metal stable in a reduced oxidation state until the ligand can capture it. Examples of transfer ligands include salts of glucoheptonic acid, tartaric acid, and citric acid, or other suitable ligands as will be discussed in more detail below. As the above would indicate, in a standard metal radionuclide radiopharmaceutical the ligand must be completely presynthesized and reacted with the metal radionuclide to give a complex in which the ligand is essentially unchanged after complex formation with the exception of removal of hydrogen ions or protecting groups. Removal of these groups facilitates coordination of the ligand to the metal radionuclide. In situ reaction of ligands facilitated by metals or metal complexes is know in the prior art. There are numerous examples of this type in inorganic literature references. Some of the most well known work describes the following reaction type: In this work, the ligand cyclization reaction was facilitated by the presence of the nickel, which held the ends of the acyclic ligand in place and allowed the formation, in good yield, of the product ligand through closure of the ring. The metal provided a "template" for the ring closure of the reaction and from this effect the term "template syntheses" has been coined for this process. This has also been found in syntheses involving cyclic tetrapeptides as described in a number of references. In these cases the ligand was the desired product with the metal being removed at the end by standard means. In some cases the ultimate ligand- etal complex is the target. Such is the case in the work of Sargeson and coworkers in which the template reaction yields a metal complex that has unique physicochemical properties because the metal is "locked in" and is not easily removed from the ligand. An example of such a reaction is shown below: w h e n N N H rt C H j C H j N H j An example also exists in the field of radiopharmaceutical chemistry in which a metal complex of a ligand is formed in situ by reaction of the ligand and a constituent of the reaction solution with the metal radionuclide. It should be noted that in this example, the constituent of the solution does not end up being bound either directly to the metal radionuclide nor to an atom of the ligand that does bond to the radionuclide. Objects of the Invention It is one object of the present invention to provide a process of making radiopharmaceuticals in situ, i.e. wherein a radionuclide and an acyclic ligand complex react with constituents of a complex forming reaction solution to produce an administratable radiopharmaceutical agent. It is a further object of the present invention to provide a process of making radiopharmaceuticals previously unattainable because of problems associated with the ligand synthesis or with the complex forming reaction. Detailed Description of the Invention The present invention relates to a novel process of forming radiopharmaceuticals, in situ. In particular, radiopharmaceuticals may be produced in situ by reacting a non-radioactive acyclic ligand with a radionuclide, wherein the acyclic ligand is capable of forming a cyclic ligand upon simple chemical conversion. The acyclic ligand first binds to the radionuclide, and then undergoes conversion to the cyclic ligand by reaction with itself, reaction with components in the reaction solution, or by simple rearrangement of the manner in which it bonds to the radionuclide, to form the final radiopharmaceutical. Any suitable radionuclide may be used, including a metal radionuclide, selected from the group consisting of Tc, Re, Co, Cu, Ni, Ru, Cr, W, Rh, Zn, In, Ga, Mo, Mn, Pt, Pd, Os, Ir and Sm. Preferably the radionuclide is Tc-99m, Re-186 or Re-188. Acyclic ligands which may be used in the process according the present invention include any known ligands which are suitable for the formation of radionuclide complexes. For example, ligands such as, acyclic tetra- and penta- peptides and, also, tri- and di- peptides that have auxiliary groups attached so that they can undergo ring closure reactions may be used. In particular, the acyclic ligand may be any ligand having the general formula: W ^A'"~ "' ^B ( I ) D ^^-Z ^C - -Υ wherein W, X, Y, and Z are the same or different and are chosen from the group consisting of S, 0, PR, NR, or AsR; wherein R is hydrogen or any straight or branched chain radical of up to 12 carbon atoms, preferable 1-8 carbon atoms, where one or two of the carbon atoms may be substituted with an 0, and the carbon radicals contain hydrogens, or optionally, substituent groups such as =0, F, Cl, Br, I, OR', C0 2 R', S0 3 R'; wherein R' is hydrogen or any straight or branched chain radical of 1-4 carbon atoms in which one of the carbon atoms may be substituted by an 0 or S; if W, X, Y, or Z is NR, then R may also be NR or OR; A, B, and C are the same or different straight chain carbon radicals of 2-5 carbon atoms in which 1-4 of the carbon atoms have been substituted in some or all locations with R or with a substituent group such as =0, F, Cl, Br, I, OR', C0 2 R', S0 3 R'; wherein R' is hydrogen or any straight or branched chain radical of 1-4 carbon atoms in which one of the carbon atoms may be substituted by an O or S; and D contains 1-8 carbon atoms, including a 2-6 carbon atom chain terminating in a group which allows it to form a bond to W following reaction with a radionuclide, and further optionally contains substituent groups such as =0, F, Cl, Br, I, OR', C0 2 R', S0 3 R'; wherein R' is hydrogen or any straight or branched chain radical of 1-4 carbon atoms in which one of the carbon atoms may be substituted by an 0 or S. In one preferred embodiment of the present invention. the acyclic ligand includes at least three and at most ive amino acid groups and has the formula: wherein R t to Rg are the same or different and are selected from the group consisting of hydrogen or substituents of any natural or synthetic amino acid; X is OH or HH—-c-—cooH . wherein Rg and R j0 have the same meanings as R t to R 8 above. The radiopharmaceutical forming reaction will take place in situ over a period of time by reaction of the radionuclide and ligand complex with constituents already present from the complex formation. In particular, constituents such as water, H + , OH " , chloride, or ethanol may be available to yield the radiopharmaceutical agent in final administratable form. In addition, the complex may simply react with itself to yield the radiopharmaceutical agent. In particular, the reaction according to the present invention may follow the general reaction: ( N ) wherein M represents a metal radionuclide optionally having one or more additional ligands attached to the metal, and wherein A, B, C, D, W, X, Y, and Z have the same definitions as given above in formula (I) . According to this general reaction, it is possible to react a ligand with a radionuclide to form a radionuclide complex, which changes over a period of time to a radiopharmaceutical agent having desirable biodistribution properties, by further reaction of constituents present at the time the ligand reacts with the radionuclide. Therefore, it becomes unnecessary to carry out all of the separate reactions which are required in the prior art. Rather, the entire process of forming the radiopharmaceutical agent may be performed in a single reaction stage, by providing the constituents necessary for such formation. The process according to the present invention further provides a means for forming radiopharmaceuticals which were previously unobtainable because of problems associated with synthesis of the ligand, or with formation of the radionuclide complex. In particular, such previously unobtainable radiopharmaceuticals may now be formed because the ligand does not have to be presynthesized nor does the metal have to be complexed with the final form of the ligand, both of which may be chemically and radiopharmaceutically unfavorable processes. A radiopharmaceutical agent according to the present invention is generally used in the form of a composition which is suitable for diagnostic or therapeutic functions. In addition to the radioactive agent, such a radiopharmaceutical composition will usually comprise a liquid, pharmaceutically acceptable carrier material, preferably a physiological saline solution. A radiodiagnostic examination can be performed with such a composition by administering the composition to the patient and then recording the radioactive radiation emitted from the patient by means of, for example, a gamma camera. The present invention further relates to a method of preparing a radiopharmaceutical agent according to the present invention by reacting a radionuclide in the form of a radionuclide solution in the presence of a reducing agent and optionally a suitable chelator with an appropriate compound. The reducing agent serves to reduce the metal radionuclide in the solution which is obtained from a generator or supplied from a manufacturer. Suitable reducing agents are, for example, dithionite, formamidine sulphinic acid, diaminomethane disulphinate or suitable metallic reducing agents, for example, reducing metals such as tin metal, or reducing ions such as Sn(II) , Fe(II), Cu(I), Ti(III) or Sb(III) ; wherein Sn(II) has proved to be particularly suitable. For the above-mentioned complex-forming reaction, the radionuclide solution is reacted with a ligand having the general formula (I) above directly, or in a two step reaction in which the metal is first bound to a transfer ligand and then displaced by the ligand of choice. Examples of suitable transfer ligands for the radionuclide are dicarboxylic acids, polycarboxylic acids or hydroxy car oxylie acids, such as oxalic acid, malonic acid, succinic acid, aleic acid, orthophthalic acid, malic acid, lactic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid or derivatives of these acids; phosphorus compounds such as pyrophosphates; or enolates. Citric acid, tartaric acid, ascorbic acid, glucoheptonic acid or a derivative thereof are particularly suitable transfer ligands when the radionuclide is technetium-99m. The present invention also relates to a kit, comprising: (1) A ligand according to the general formula (I) ; the ligand preferably being in a dry condition, and also preferably having an inert, pharmaceutically acceptable carrier and/or auxiliary substances added thereto; and (2) a reducing agent and optionally a chelator; wherein ingredients (1) and (2) may optionally be combined; and further wherein instructions for use with a prescription for carrying out the above-described method by reacting ingredients (1) and (2) with a radionuclide solution may be optionally included. Examples of suitable reducing agents and chelators for the above kit have been listed above. The radionuclide solution can be obtained simply by the user himself from a generator which is available to him, or as the solution is supplied from a manufacturer. As noted above the ingredients (1) and (2) may be combined, provided they are compatible. Such a monocomponent kit, in which the combined ingredients are preferably lyophilized, is excellently suitable to be reacted by the user with the radionuclide solution in a simple manner. The ingredient (1) of the above kits may be delivered as a solution, for example, in the form of a physiological saline solution, or in some buffer solution, but is preferably present in a dry condition, for example in a lyophilized condition. When used as a component for an injection liquid, it should be sterile, and, if the ingredient (1) is present in a dry condition, the user should use a sterile physiological saline solution as a solvent. If desired, ingredient (1) may be stabilized in a usual manner with suitable stabilizers such as ascorbic acid, gentisic acid or salts of these acids, or it may be provided with other auxiliary means such as fillers, e.g. glucose, lactose, mannitol, inositol, and the like. The following example set forth below describes one embodiment according to the present invention. EXAMPLE 1 Synthesis of a radiopharmaceutical aαent b direct labelling In a reaction vial are added 1 mg tetra-L-alanine, 0.2 ml phosphate buffer 0.5M pH 12, 100 μm SnCl 2 .H 2 0 dissolved in 25 * μl HCl 0.05N, and 2 ml generator eluate containing 370 MBq 99mTc as pertechnetate. After inculbation for 10 minutes at roon temperature the reaction mixture is analyzed by RP-HPLC on a 250 mm X 4.6 mm (I.D.) Hypersil ODS column eluted at a rate of 1 ml/min in an isocratic way with a mixture of ethanol - 0.025M phosphate buffer pH 5.85 (30:70) . Radioactivity in the effluent is monitored with a 2 inch Nal (tl) scintillation detector coupled to a single channel analyzer and integrator. The HPLC-chromatogram shows the presence of mainly one radioactive species (peak A) and a small amount of another compound (peak B) . Electrophoresis experiments with isolated peak A and peak B show that peak A has a free corboxyl group (migration distance is larger at higher pH) whereas the migration distance of peak B doew not increase with increasing pH, indicating the absence of a free carboxyl group. Coinjection of peak B with 99Tc-cyclo- tetra-L-alanine (structure confirmed by FAB-mass spectro etry and single crystal X-ray analysis) shows that peak B is 99mTc-cyclotetra-alanine as indicated in Scheme I. Peak A is assumed to be non-cyclisized 99mTc-tetra-L- alanine as represented in Scheme I. Incubation of isolated peak A at pH 5.85 (phosphate buffer) results in the gradual conversion to peak B, whereas peak B remains stable in the same conditions. L- t • i ro-o I on i n« + Sn 2+ + TcO., " Scheme I . Preparation of TCO-A 4 and Tc0-cycl-A 4 A 4 = tetra-alanine EXAMPLE 2 Synthesis of a radiopharmaceutical agent bv exchange labelling In a reaction vial are added 1 mg tetra-L-alanine, 4.5 mg sodium tartrate dissolved om 0.3 ml water, 0.2 ml phosphate buffer 0.5M pH 4, 100 μm SnCl 2 .H 2 0 dissolved in 25 μl HCl 0.05N, and 2 ml generator eluate containing 370 MBq 99mTc as pertechnetate. The solution is heated for 10 minutes on a boiling water-bath. Analysis of the cooled reaction mixture by HPLC indicated the presence of a species corresponding to peak B of example 1 (cyclic 99mTc- A4) , a small amount of a species corresponding to peak A of example 1 and a small amount of 99mTc-tartrate. The relative amount of peak B decreases if labelling is performed at higher pH values. k, + Sn 2 * + f αrtrotβ + TcO, " The forgoing has been a discussion of the preferred embodiments of the present invention, but is not intended to limit the invention in any way. Rather, many modifications, variations, and changes in detail may be made within the scope of the present invention.

Claims: What is claimed is: 1. A method of making a radiopharmaceutical agent comprising: reacting a non-radioactive acyclic ligand, that is capable of forming a cyclic ligand upon simple chemical conversion; with a radionuclide; wherein said acyclic ligand binds to said radionuclide and then converts to said cyclic ligand, in situ, to form said radiopharmaceutical agent. 2. A method of making a radiopharmaceutical agent according to claim 1, wherein said acyclic ligand converts to said cyclic ligand by reaction with itself, reaction with components in the reaction solution, or by simple rearrangement of the manner in which it binds to the radionuclide. 3. A method of making a radiopharmaceutical agent according to claim 1, wherein said radionuclide is a metal radionuclide, selected from the group consisting of Tc, Re, Co, Cu, Ni, Ru, Cr, W, Rh, Zn, In, Ga, Mo, Mn, Pt, Pd, Os, Ir and Sm. 4. A method of making a radiopharmaceutical agent according to claim 3, wherein said metal radionuclide is Tc-99m, Re-186, or Re-188. 5. A method of making a radiopharmaceutical agent according to claim 1, wherein said acyclic ligand has the general formula: wherein W, X, Y, and Z are the same or different and are chosen from the group consisting of S, 0, PR, NR, or AsR; wherein R is hydrogen or any straight or branched chain radical of up to 12 carbon atoms, preferable 1-8 carbon atoms, where one or two of the carbon atoms may be substituted with an 0, and the carbon radicals contain hydrogens, or optionally, substituent groups such as =0, F, Cl, Br, I, OR', C0 2 R', S0 3 R'; wherein R' is hydrogen or any straight or branched chain radical of 1-4 carbon atoms in which one of the carbon atoms may be substituted by an o or S; if W, X, Y, or Z is NR, then R may be NR or OR; A, B, and C are the same or different straight chain carbon radicals of 2-5 carbon atoms in which 1-4 of the carbon atoms have been substituted in some or all locations with R or with one of said substituent groups; and D contains 1-8 carbon atoms, including a 2-6 carbon atom chain terminating in a group which allows it to form a bond to W following reaction with a radionuclide, and further optionally containing at least one of said substituent groups. 6. A method of making a radiopharmaceutical agent according to claim 1, wherein said method follows the general reaction: wherein M represents a metal radionuclide with or without one or more additional ligands attached to the metal; and wherein W, X, Y, and Z are the same or different and are chosen from the group consisting of S, 0, PR, NR, or AsR; wherein R is hydrogen or any straight or branched chain radical of up to 12 carbon atoms, preferable 1-8 carbon atoms, where one or two of the carbon atoms may be substituted with an 0, and the carbon radicals contain hydrogens, or optionally, substituent groups such as =0, F, Cl, Br, I, OR', C0 2 R', S0 3 R'; wherein R' is hydrogen or any straight or branched chain radical of 1-4 carbon atoms in which one of the carbon atoms may be substituted by an 0 or S; if W, X, Y, or Z is NR, then R may be NR or OR; A, B, and C are the same or different straight chain carbon radicals of 2-5 carbon atoms in which 1-4 of the carbon atoms have been substituted in some or all locations with R or with one of said substituent groups; and D contains 1-4 carbon atoms, including a 2-6 carbon atom chain terminating in a group which allows it to form a bond to W following reaction with a radionuclide and further optionally containing at least one of said substituent groups. 7. A method of making a radiopharmaceutical agent comprising: providing an acyclic ligand containing at least three and at most five amino acid groups, and having the general formula: wherein R x to R are the same or different and are selected from the group consisting of hydrogen or substituents of any natural or synthetic amino acid; and X is OH or MH —-c-—cooH . wherein Rg and R w have the same meanings as R x to R 8 above; reacting said acyclic ligand with a radionuclide; wherein said acyclic ligand coordinates with said radionuclide, and then undergoes internal reaction to generate a second ligand which stays wholly or partially coordinated to said radionuclide. 8. A method of making a radiopharmaceutical agent according to claim 7, wherein said acyclic ligand generates said second ligand by reaction with itself, reaction with components in the reaction solution, or by simple rearrangement of the manner in which it binds to the radionuclide. 9. A method of making a radiopharmaceutical agent according to claim 7, wherein said radionuclide is a metal radionuclide, selected from the group consisting of Tc, Re, Co, Cu, Ni, Ru, Cr, W, Rh, Zn, In, Ga, Mo, Mn, Pt, Pd, Os, Ir and Sm. 10. A method of making a radiopharmaceutical agent according to claim 9, wherein said metal radionuclide is Tc-99m, Re-186, or Re-188. 11. A kit for forming a radiopharmaceutical agent comprising: a ligand having the general formula: wherein W, X, Y, and Z are the same or different and are chosen from the group consisting of S, O, PR, NR, or AsR; wherein R is hydrogen or any straight or branched chain radical of up to 12 carbon atoms, preferable 1-8 carbon atoms, where one or two of the carbon atoms may be substituted with an 0, and the carbon radicals contain hydrogens, or optionally, substituent groups such as =0, F, Cl, Br, I, OR', C0 2 R', S0 3 R'; wherein R' is hydrogen or any straight or branched chain radical of 1-4 carbon atoms in which one of the carbon atoms may be substituted by an 0 or S; if W, X, Y, or Z is NR, then R may be NR or OR; A, B, and C are the same or different straight chain carbon radicals of 2-5 carbon atoms in which 1-4 of the carbon atoms have been substituted in some or all locations with R or with one of said substituent groups; and D contains 1-8 carbon atoms, including a 2-6 carbon atom chain terminating in a group which allows it to form a bond to W following reaction with a radionuclide and further optionally containing at least one of said substituent groups; and further comprising a reducing agent. 12. A kit according to claim 11, wherein said reducing agent is selected from the group consisting of dithionite, formamidine sulphinic acid, diaminomethane disulphinate or suitable metallic reducing agents such as Sn(II), Fe(II), Cu(I), Ti(III) or Sb(III) . 13. A kit according to claim 11, further including a pharmaceutically acceptable carrier. 14. A kit according to claim 13, wherein said carrier is a sterile physiological saline solution. 15. A kit according to claim 11, further including stabilizers and fillers. 16. A kit according to claim 15, wherein said stabilizers are ascorbic acid, gentisic acid or salts of these acids. 17. A kit according to claim 15, wherein said fillers are glucose, lactose, mannitol, inositol, and the like. 18. A kit according to claim 11, further including a transfer ligand. 19. A kit according to claim 18, wherein said transfer ligand is selected from the group consisting of dicarboxylic acids, polycarboxylic acids or hydroxy carboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, orthophthalic acid, malic acid, lactic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid, glucoheptonic acid or derivatives of these acids; phosphorus compounds such as pyrophosphates; or enolates. 20. A kit according to claim 11, further including instructions for use with a prescription for reacting the components of said kit with a radionuclide solution. 21. A kit according to claim 11, wherein said ligand and said reducing agent are combined, and are provided in a lyophilized condition. 22. A method of making a radiopharmaceutical agent from a kit, said method comprising: providing a kit including: an acyclic ligand having the general formula: wherein W, X, Y, and Z are the same or different and are chosen from the group consisting of S, 0, PR, NR, or AsR; wherein R is hydrogen or any straight or branched chain radical of up to 12 carbon atoms, preferable 1-8 carbon atoms, where one or two of the carbon atoms may be substituted with an 0, and the carbon radicals contain hydrogens, or optionally, substituent groups such as =0, F, Cl, Br, I, OR', C0 2 R', S0 3 R'; wherein R' is hydrogen or any straight or branched chain radical of 1-4 carbon atoms in which one of the carbon atoms may be substituted by an 0 or S; if W, X, Y, or Z is NR, then R may be NR or OR; A, B, and C are the same or different straight chain carbon radicals of 2-5 carbon atoms in which 1-4 of the carbon atoms have been substituted in some or all locations with R or with one of said substituent groups; and D contains 1-8 carbon atoms, including a 2-6 carbon atom chain terminating in a group which allows it to form a bond to W following reaction with a radionuclide and further optionally containing at least one of said substituent groups; and further including a reducing agent; and combining said kit with a radionuclide solution; wherein said acyclic ligand binds to said radionuclide and then converts to a cyclic ligand, in situ, to form said radiopharmaceutical agent. 23. A method of imaging using a radiopharmaceutical agent comprising: forming said radiopharmaceutical agent by reacting a non-radioactive acyclic ligand, that is capable of forming a cyclic ligand upon simple chemical conversion; with a radionuclide; wherein said acyclic ligand binds to said radionuclide and then converts to said cyclic ligand, in situ, to form said radiopharmaceutical agent; administering said radiopharmaceutical agent to a living being; and scanning said living being with detection means to detect said administered radiopharmaceutical agent.

Inventors: VERBRUGGEN ALFONS M, VERBRUGGEN, ALFONS, M.
Applicants: MALLINCKRODT MEDICAL INC, MALLINCKRODT MEDICAL, INC.
Application year: 1992
Main classification: C07F13
IPC codes: A61K51, C07B59, C07F13