Radioactive metal complex

Abstract

To obtain a radioactive metal complex using Py-macrodipa as a chelating agent.SOLUTION: The radioactive metal complex includes a chelating agent having a structure represented by the general formula (1) and a radioactive metal having an atomic number of 22 or more and falling within period 4 or period 5. The radioactive metal is a 3-valent metal element or a 4-valent metal element, and specifically, radioactive zirconium is preferable.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] The present invention relates to a radioactive metal complex, and in particular to a radioactive metal complex having Py-macropa and a radioactive metal. [Background technology]

[0002] Alpha particles (α-particles) have a short range but impart a great deal of energy to objects they collide with. By utilizing this property, highly selective cancer treatments can be achieved. Targeted isotope therapy, in which such cancer treatments are injected into the body to directly irradiate cancer cells from within, is being developed. Targeted isotope therapy is a type of radioisotope therapy / nuclear medicine therapy (hereinafter referred to as nuclear medicine therapy), in which radioactive materials are delivered to specific cancer cells using antibodies or peptides. Nuclear medicine therapy refers to treatments in which radioactive materials are administered to patients, but also includes treatments in which radioactive materials are distributed throughout the patient's body without the use of antibodies or peptides.

[0003] In targeted isotope therapy, when alpha-emitting nuclides are accumulated in cancer cells, the cancer cells are highly exposed to radiation and die, but the alpha rays do not reach surrounding normal cells, resulting in fewer side effects. To deliver alpha-emitting nuclides to cancer tissue, molecularly targeted drugs such as antibodies and peptides are labeled with the nuclides via an appropriate chelating agent. The delivery of alpha-emitting nuclides to the desired tissue is called drug delivery.

[0004] When labeling a medium-sized compound such as a peptide or a high-molecular compound such as a protein with a metal radionuclide, this is achieved by introducing an appropriate chelating agent into the compound and forming a complex between the chelating agent and the metal radionuclide.

[0005] The radioisotope that is practically used in the above-mentioned targeted isotope therapy is yttrium-90 ( 90 Y) and lutetium-177( 177These radionuclides, such as Lu, are all beta-ray (β-ray)-emitting nuclides, and are elements belonging to the 6th period or lower, with relatively small atomic radii. When labeling antibodies or peptides with these radionuclides, DOTA is practically used as a chelating agent, whereas many α-ray-emitting nuclides are elements belonging to the 7th period, particularly actinides, with relatively large atomic radii. To form a complex with actinide ions, DOTA must be reacted at a high concentration, otherwise the complex formation reaction will not proceed, and high reaction temperatures are required (see Non-Patent Document 1). N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown6 (Macropa) (hereinafter referred to as Macropa) has been proposed as a chelating agent suitable for actinide ions used in labeling with actinides with large atomic radii (see Non-Patent Documents 1 and 2, and Patent Document 1).

[0006] Macropa has good reactivity with actinide ions, and complexes can be formed by reacting low concentrations of macropa with actinide ions at room temperature. Actinides emit alpha particles, so they can be used in targeted isotope therapy. Specifically, by labeling molecular targeted drugs such as antibodies and peptides with actinides, it may be possible to create targeted isotope therapeutic drugs. For this reason, labeling techniques for actinide elements using macropa are being actively researched.

[0007] On the other hand, in nuclear medicine therapy, companion diagnostic agents are also required to evaluate the effectiveness of therapeutic drugs. In companion diagnostics, in order to minimize patient exposure, it is desirable to use nuclides that emit positrons without emitting alpha or beta particles, and to perform diagnosis using positron emission tomography (PET). 225Actinides such as Ac emit alpha particles but do not emit positrons, so a positron-emitting nuclide must be used as a companion diagnostic agent for diagnosis.

[0008] As described above, when an actinide element is selected as a therapeutic nuclide, the use of macropa enables efficient labeling of drugs such as peptides and antibodies. However, there is a problem in that diagnostic positron-emitting nuclides and macropa do not necessarily form stable complexes. Therefore, there is a need for a technology that avoids the complexity of using separate chelating agents for therapeutic and diagnostic purposes. Therefore, the present applicant has proposed the technology described in Patent Document 2. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] US Patent Application Publication No. 2020 / 0353105 [Patent Document 2] Japanese Patent Publication No. 2023-135733 [Patent Document 3] Patent No. 7315004 [Non-patent literature]

[0010] [Non-Patent Document 1] “Evaluation of polydentate picolinic acid chelating ligands and an α-melanocyte-stimulating hormone derivative for targeted alpha therapy using ISOL-produced 225Ac”, EJNMMI RADIOPHARMACY AND CHEMISTRY, 2019,4,21. [Non-patent document 2] “Macrocyclic Receptor Exhibiting Unprecedented Selectivity for Light Lanthanides”, JACS,2009,131,9,3331-3341. [Non-patent document 3] “Py-Macrodipa: A Janus Chelator Capable of Binding Medicinally Relevant Rare-Earth Radiometals of Disparate Sizes”, Aohan Hu et al.,doi:10.1021 / jacs.1c05339 Summary of the Invention [Problem to be solved by the invention]

[0011] When using positron emission tomography (PET) as a companion diagnostic for a targeted isotope therapeutic drug, it is necessary to separately synthesize a drug labeled with a PET nuclide. For companion diagnostic drugs, it is desirable to use a drug that is the same molecular target as the therapeutic drug and uses the same chelating agent, with only the nuclide replaced. Therefore, a method using Py-macrodipa, a derivative of macropa, as a chelating agent is being considered.

[0012] However, when Py-macrodipa is used as a chelating agent, the radioactive scandium ( 44 No studies have been conducted on methods for reacting with radioactive metal ions other than Sc. 44 The half-life of Sc is about 4 hours. On the other hand, the half-life of the nuclides used in targeted isotope therapy is about several days. 44 Many of them have a longer half-life than Sc. For example, yttrium 90 ( 90 Y) is 2.7 days, and lutetium 177 ( 177 Lu) for 6.6 days, and actinium-225 ( 225Ac) is 10.0 days. To accurately predict the therapeutic effect of targeted isotope therapy using PET, it is desirable to track the biodistribution of labeled agents, such as labeled antibodies and labeled peptides, over several days or more. In other words, it is desirable to enhance the usefulness of companion PET diagnostic agents by labeling them with PET nuclides with longer half-lives. Therefore, complexes of radioactive metal ions with half-lives longer than 4 hours and Py-macrodipa as a chelating agent were desired.

[0013] The present invention has been made in view of the above, and an object of the present invention is to provide a radioactive metal complex synthesized from Py-macrodipa as a chelating agent and a radioactive metal. [Means for solving the problem]

[0014] In order to solve the above-mentioned problems and achieve the object, a radioactive metal complex according to one embodiment of the present invention comprises a chelating agent having a structure represented by general formula (1) and a radioactive metal having an atomic number of 22 or more and being included in the fourth or fifth period. [ka]

[0015] In one aspect of the present invention, in the radioactive metal complex of the above invention, the radioactive metal is a trivalent metal element or a tetravalent metal element.

[0016] A radioactive metal complex according to one aspect of the present invention is the radioactive metal complex of the above invention, wherein the radioactive metal is radioactive zirconium ( 89 Zr). [Effects of the Invention]

[0017] According to the radioactive metal complex of the present invention, it is possible to obtain a radioactive metal complex in which Py-macrodipa as a chelating agent and a radioactive metal are synthesized. [Brief explanation of the drawings]

[0018] [Figure 1] FIG. 1 is a diagram illustrating an example of a synthesis method for synthesizing a radioactive metal complex by reacting a radioactive metal with Py-macrodipa according to one embodiment of the present invention. [Figure 2] FIG. 2 is a diagram illustrating an example of a synthesis method for synthesizing a non-radioactive metal complex by reacting a non-radioactive metal with Py-macrodipa according to a modified embodiment of the present invention. [Figure 3] FIG. 3 is a chromatogram showing the results of liquid chromatography analysis of Py-macrodipa, natZr-Py-macrodipa, and 89Zr-Py-macrodipa complexes according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0019] An embodiment of the present invention will be described below with reference to the drawings. The present invention is not limited to the embodiment described below. First, in describing the embodiment of the present invention, in order to facilitate understanding of the present invention, the inventor will first describe the experiments and intensive studies he conducted to solve the above-mentioned problems.

[0020] That is, according to the findings of the present inventors, targeted isotope therapy is being considered, in which drugs that accumulate in cancer tissue, such as antibodies, are labeled with a radioactive substance and then administered to cancer patients to treat cancer and other diseases through internal radiation irradiation. In targeted isotope therapy, the use of so-called alpha-particle (α-particle) emitters, such as actinide elements, has attracted particular attention. Although α-particles have a short range, they have the property of imparting a large amount of energy to objects they collide with, making it possible to develop highly selective cancer therapeutic drugs. To transport α-particle-emitting nuclides to cancer tissue, the nuclides are labeled via a chelating agent appropriate for the molecular targeted drug.

[0021] A chelating agent called N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown6 (Macropa) (hereinafter referred to as Macropa) has been proposed as a chelating agent used to label actinide elements with large atomic radii as α-particle-emitting nuclides (Non-Patent Documents 1 and 2, Patent Document 2).

[0022] On the other hand, as mentioned above, nuclear medicine treatment also requires companion diagnostic agents for diagnosis. However, because actinide ions (actinide ions) do not emit radiation suitable for diagnosis, it is necessary to synthesize PET (Positron Emission Tomography) nuclide-labeled agents (hereinafter referred to as PET agents) as companion diagnostic agents.

[0023] Chelating agents used in labeling with radioactive metal ions for diagnostic PET drugs can easily bind to various radioisotopes (RI), and examples thereof include 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), as well as analogous compounds thereof, as described in Patent Document 3. DOTA and NOTA are highly versatile chelating agents that form complexes with many metal nuclides, including radioactive copper (Cu), gallium (Ga), yttrium (Y), indium (In), lutetium (Lu), and actinium (Ac).

[0024] However, the chelating agents DOTA and NOTA have the problem that the metal ions they can capture have a relatively small ionic radius, and the yield of their binding reaction with actinide elements, which have a relatively large ionic radius, is low.

[0025] On the other hand, the above-mentioned macropa, for example, actinium 225 ( 225 It only forms complexes with ions with relatively large ionic radii, such as the actinide series (Ac). Furthermore, all actinide ions in the actinide series are therapeutic nuclides. Therefore, it was necessary to prepare separate PET agents, such as DOTA and NOTA, labeled with diagnostic radioactive metal ions, as companion diagnostic agents.

[0026] In this regard, considering the properties of the drug administered to a living organism such as the human body, it is preferable to use the same molecular targeted drug or chelating agent as the therapeutic drug in the companion diagnostic drug, if possible. This is because using different chelating agents for the therapeutic nuclide (actinide element) and the diagnostic nuclide results in differences in the properties of the drug in the body. Therefore, if it becomes possible to use the same molecular targeted drug or chelating agent as the therapeutic drug, changes in the properties of the drug in the body can be minimized. Furthermore, it becomes possible to avoid the cumbersome task of using different chelating agents for the therapeutic and diagnostic radioactive materials used in nuclear medicine therapy.

[0027] Regarding the above-mentioned problems, the present inventors have conducted various intensive studies and have investigated a method of using the same chelating agent for the companion diagnostic drug and the therapeutic drug. In order to use macropa as a chelating agent for PET nuclides, it is possible to use a chelating agent for radioactive metal nuclides such as 89 Zr was used to evaluate the binding ability with macropa. As a result of various evaluations, the present inventors have synthesized Py-macrodipa (Py-macrodipa) represented by the following general formula (1), which is one of the derivative compounds of macropa, and Zr, which is an example of a radioactive metal ion, by a predetermined synthesis method. 89 It was found that it was possible to stably bond with Zr.

[0028] [ka]

[0029] According to the findings of the present inventors, the chelating agent Py-macrodipa can chelate not only actinide ions with a large ionic radius but also therapeutic nuclides with a relatively small ionic radius. 135 La and scandium ( 44 It has been reported that it forms a complex with Sc (Non-Patent Document 3). However, 44 As for Sc, its half-life is short, about 4.0 hours. In this case, 44 When a complex of Sc and Py-macrodipa is used for PET diagnosis, there is a problem that PET diagnosis can only be performed within about half a day after administration of the diagnostic agent. Therefore, the inventors further investigated a technology that can stably synthesize complexes even for diagnostic nuclides with radioactive metal ions having a relatively long half-life and a relatively small ionic radius.

[0030] The present inventors have found that radioactive metal ions with relatively long half-lives, such as zirconium ( 89 We investigated a method for synthesizing a complex of zirconium and Py-macrodipa using Zr. In this regard, conventionally, Py-macrodipa was used to synthesize a complex of zirconium with a metal element in the fourth period or a metal element in the fifth period whose atomic number is 22 or more, such as 89 As a result of extensive research and various experiments by the present inventors, it has been found that complexes of Py-macrodipa with radioactive metal ions of trivalent or tetravalent metal elements, such as Zr, can be produced by a predetermined method. 4+ It was found that Py-macrodipa and metal ions form a complex. The specific method is a method of reacting them by heating in an organic solvent at a temperature of 60°C to 100°C. In contrast, in the prior art, a method of reacting Py-macrodipa and metal ions in water at room temperature has been used.

[0031] The present inventors have discovered the following complexes of radioactive metal ions and Py-macrodipa: 89The synthesis of a Zr-Py-macrodipa complex confirmed that PET diagnosis could be performed for more than a week. Specifically, the inventors discovered that it is possible to synthesize a complex as shown in the following general formula (2) by combining trivalent or tetravalent radioactive metal ions, which have relatively small ionic radii and cannot be reacted with Py-macrodipa, a chelating agent for actinide elements, which have relatively large ionic radii. R represents a trivalent or tetravalent radioactive metal ion.

[0032] [ka]

[0033] Based on the above, antibodies and peptides carrying Py-macrodipa are not only therapeutic agents, 89 By labeling with a metal ion having a relatively small ionic radius, such as Zr, it becomes possible to use it as a companion diagnostic agent without changing its chemical structure. The present invention and one embodiment described below were devised by the inventors through the above-mentioned intensive studies.

[0034] (Method for synthesizing radioactive metal complexes) Next, a method for synthesizing a zirconium complex will be described as an example of a method for synthesizing a radioactive metal complex according to one embodiment of the present invention. Figure 1 is a diagram showing a specific method for synthesizing a radioactive metal complex according to this embodiment.

[0035] As shown in Figure 1, first, a Py-macrodipa solution containing a compound containing Py-macrodipa dissolved therein is introduced into a microtube, which is a reaction vessel, as a chelating agent solution of a predetermined concentration. The compound is dissolved in, for example, ultrapure water or an organic solvent. Here, Py-macrodipa as a chelating agent is a compound represented by the above-mentioned general formula (1). The concentration of the Py-macrodipa solution is 10 -7 mol / L or more 10 -1 mol / L, and in this embodiment, for example, 10 -2mol / L (10 mmol / L). The amount of Py-macrodipa solution introduced into the microtube is, for example, 10 -2 The chelating agent can be used as a solution by dissolving it in water or an organic solvent beforehand, or it can be added in powder form, mixed with the radioactive metal, and then dissolved in water or an organic solvent.

[0036] Next, a substantially neutral buffer solution is introduced into the microtube. For example, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) with a concentration of about 1 mol / L and a pH of 7.0 is used as the buffer solution. The amount introduced is, for example, 19 μL for a solution with a concentration of 1.0 mol / L. The buffer solution used in this embodiment is, 89 It is preferable to use a buffer solution from which metal ions other than Zr, which are impurities, have been removed in advance. This allows the Fe ions to be removed from the final reaction solution. 3+ , Ti 4+ , Y 3+ This reduces the possibility of metal ions such as these being mixed in.

[0037] Next, an organic solvent is introduced into the microtube. The concentration of the organic solvent is preferably 1% by volume or more, more preferably 10% by volume or more, to improve the radiochemical yield. Because the reaction rate decreases when the organic solvent concentration exceeds 95% by volume, the concentration is preferably 95% by volume or less. Therefore, the concentration of the organic solvent is preferably 1% by volume or more and 95% by volume or less, more preferably 10% by volume or more and 95% by volume or less. The amount of organic solvent introduced is, for example, 60 μL for an organic solvent with a final concentration of 60% by volume. Specifically, in this embodiment, an organic solvent containing dimethyl sulfoxide (DMSO) with a dipole moment of 3.7D is used as the organic solvent, and the final concentration is, for example, 60% by volume. The order in which the Py-macrodipa solution, buffer solution, and organic solvent are introduced into the microtube is not limited to the above order, and various orders are possible.

[0038] After the Py-macrodipa solution, buffer solution, and organic solvent were introduced into the microtube, the reaction solution in the microtube was added with radioactive zirconium ( 89 Zr) containing purified solution ( 89 A Zr-containing purified solution is introduced. The solvent of the purified solution is, for example, hydrochloric acid, and the concentration range is 0.01 mol / L or more and 6 mol / L or less. This produces a mixed solution in the microtube. 89 The amount of the Zr-containing purified solution introduced is determined based on the amount and concentration of the Py-macrodipa solution introduced, and in this embodiment, it is, for example, 20 μL.

[0039] In a microtube, Py-macrodipa solution, buffer solution, organic solvent, and 89 After mixing the Zr-containing purified solution, it is heated to a predetermined temperature and maintained for a predetermined time. 89 In this embodiment, 89 The Zr-containing purified solution is preferably introduced into the microtube just before heating the mixed solution. This is because, even in the presence of an organic solvent such as DMSO, 89 This is because when Zr is left under neutral conditions and at room temperature, it becomes hydroxided and becomes inactive in the reaction with Py-macrodipa. 89 The reaction between Zr and Py-macrodipa does not proceed. This is presumably because the reaction with Py-macrodipa requires a relatively high activation energy, while the activation energy for hydroxide formation is low. 89 After adding Zr, it is preferable to quickly heat the mixture to a predetermined temperature to react with Py-macrodipa quickly. 89 After Zr is complexed with Py-macrodipa, 89 Zr does not become hydroxide. 89 Since Zr and Py-macrodipa react without being affected by impurities, the reaction can be carried out efficiently.

[0040] In this embodiment, the predetermined temperature is preferably 60°C or higher, and if the substance bound to Py-macrodipa is a substance that can withstand high temperatures, it may be, for example, 90°C or higher, specifically, 95°C. The predetermined time is, for example, about 30 minutes, between 15 minutes and 2 hours. 89 The reaction between Zr and Py-macrodipa is completed. 89 Zirconium complex with Py-macrodipa bonded to Zr ( 89 Zr-Py-macrodipa complex) is obtained.

[0041] (Method for synthesizing non-radioactive metal complexes) FIG. 2 is a diagram showing a specific method for synthesizing a non-radioactive metal complex according to this embodiment. 89 To confirm that the Zr-Py-macrodipa complex was formed, non-radioactive zirconium ( nat Zr) and Py-macrodipa complex ( nat We will explain how to synthesize Zr-Py-macrodipa complexes.

[0042] First, Py-macrodipa powder (Py-macrodipa powder) is introduced into a microtube, which is a reaction vessel, as shown in Figure 2. Here, the mass of the Py-macrodipa powder is set to, for example, 1.13 mg, which corresponds to 2 μmol.

[0043] Next, an organic solvent, such as DMSO, is introduced into the microtube. This dissolves the Py-macrodipa powder in the organic solvent. The amount of DSMO introduced is, for example, 200 μL. Then, a non-radioactive metal compound solution ( nat Zr compound solution) are mixed. nat The concentration of zirconium chloride in the Zr compound solution is, for example, 10 -2mol / L (10 mmol / L). Next, triethylamine (TEA: C3H9N) is further introduced into the microtube. The amount of TEA introduced is, for example, 2 μL, which is equivalent to 14 μmol. This creates a mixed solution in the microtube.

[0044] In a microtube, Py-macrodipa powder, organic solvent, and nat After mixing the Zr compound solution, the mixture is heated to a predetermined temperature, for example, 80°C, and maintained for a predetermined time, for example, about 2 hours. nat React with Zr.

[0045] After the reaction, the mixture in the microtube was diluted 20 times with ultrapure water and subjected to HPLC separation, and the fractions from 20 to 22 minutes were collected. The collected fractions were freeze-dried to remove the solvent. nat A white powder of Zr-py-macrodipa complex was obtained.

[0046] ( nat Method for growing Zr-Py-macrodipa complex single crystals Next, the above obtained nat Approximately 0.5 mg of the white powder of the Zr-Py-macrodipa complex is taken out and dissolved in N,N-dimethylformamide (DMF). Next, a DMF solution of ammonium hexafluorophosphate (F6H4NP) with a concentration of, for example, 500 mmol / L (0.5 mol / L) is introduced in an amount of, for example, 4 μL, equivalent to 2 μmol. Then, diethyl ether (C4H4) is added as a poor solvent. 10 Single crystals were grown by the vapor diffusion method using HCl (CH3CH2)2O. The process took approximately two months to grow single crystals by the vapor diffusion method.

[0047] The present inventor, 89 The radioactivity of the Zr-Py-macrodipa complex was measured. 89It was confirmed that Zr and Py-macrodipa bound at a rate of 95%. The formation of the complex was confirmed by high performance liquid chromatography (HPLC) and single crystal X-ray crystal structure analysis.

[0048] Furthermore, through various experiments conducted by the present inventors, it has been found that Zr 4+ It was confirmed that complexes can be formed between Py-macrodipa and tetravalent or trivalent metal ions such as zirconium. Furthermore, for metal elements such as zirconium, a hydroxyl group (OH) is added to Py-macrodipa to neutralize the charge. - ) was also confirmed to be coordinated.

[0049] FIG. 3 shows the Py-macrodipa according to this embodiment. nat Zr-Py-macrodipa, and 89 1 is a chromatogram showing the results of liquid chromatography analysis of the Zr-Py-macrodipa complex. nat Zr indicates the natural isotope of Zr.

[0050] From Figure 3, the retention time of Py-macrodipa (dashed line) and nat The retention time of Zr-Py-macrodipa (solid line) is different from that of Py-macrodipa alone. nat It is clear that Zr-Py-macrodipa exists. nat The retention time of Zr-Py-macrodipa (solid line) and 89 The retention time of the Zr-Py-macrodipa complex (dotted line) is almost the same as that of the non-radioactive Zr complex. 89 It can be seen that the Zr complex is the same substance. nat The retention time of Zr-Py-macrodipa, 89 The slight time difference between the retention time of the Zr-Py-macrodipa complex is due to the radiation sensor being placed after the ultraviolet light absorption spectrometer.

[0051] As explained above, according to this embodiment, it was found that Py-macrodipa and zirconium (natZr, 89Zr) are bonded by heating in an organic solvent at a predetermined temperature for a predetermined time, and it was found that a Zr-Py-macrodipa complex can be synthesized as a substance. In addition, it is possible to identify the complex structure by X-ray single crystal structure analysis, and the Py-macrodipa confirmed by single crystal X-ray structure analysis 89 The structural formula with Zr was confirmed to be expressed by the following chemical formula (3).

[0052] [ka]

[0053] Although one embodiment of the present invention has been specifically described above, the present invention is not limited to the above-described embodiment, and various modifications based on the technical concept of the present invention are possible. For example, the numerical values ​​and materials given in the above-described embodiment are merely examples, and different numerical values ​​and materials may be used as necessary. The present invention is not limited by the descriptions and drawings that form part of the disclosure of the present invention according to this embodiment.

[0054] For example, in the above-described embodiment, the buffer may be an MES buffer, a HEPES buffer, an acetate buffer, or an aqueous ammonium acetate solution.

[0055] For example, in the above-described embodiment, DMSO is used as the organic solvent, but the organic solvent is not necessarily limited to DMSO, and at least one solvent selected from the group consisting of DMF, N-methylformamide (NMF), N-methylpyrrolidone (NMP), and urea can be used.

[0056] The radioactive metal complex according to the present invention can be suitably used as a companion diagnostic agent for targeted isotope therapy for cancer.

Claims

1. A chelating agent having a structure represented by general formula (1); a radioactive metal having an atomic number of 22 or greater and included in Period 4 or Period 5; Radioactive metal complexes. 【Chemistry 1】

2. The radioactive metal is a trivalent metal element or a tetravalent metal element. The radioactive metal complex of claim 1.

3. The radioactive metal is radioactive zirconium The radioactive metal complex of claim 1.

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