L-proline-containing glutamic acid-urea dimer derivative and application thereof

Abstract

The invention relates to the technical field of radiopharmaceutical chemistry and clinical nuclear medicine, in particular to a glutamic acid-urea dimer derivative containing L-proline and application of the glutamic acid-urea dimer derivative. A radioactive preparation obtained by labeling the L-proline-containing glutamic acid-urea dimer derivative with radionuclide has high uptake in tumors, is good in tumor / non-target ratio, can be specifically combined with a prostate specific membrane antigen, and can be used as a novel tumor radioactive drug which has popularization and application values and is used for diagnosing prostate cancer.

Description

Technical Field

[0001] The invention relates to the technical field of radiopharmaceutical chemistry and clinical nuclear medicine, and in particular to a glutamic acid-urea dimer derivative containing L-proline and application thereof. Background Art

[0002] Prostate cancer (PCa) is the most common malignancy of the male reproductive system and is considered the second leading cause of death in men after heart disease, making it an important global public health issue. Therefore, effective diagnosis of PCa is crucial for the treatment and prognosis of patients.

[0003] Small molecule inhibitors containing glutamic acid-urea units can specifically bind to prostate-specific membrane antigen (PSMA), and radionuclide labeling has become a hot topic in international radiopharmaceutical research. 99m Tc is the most common single photon emission computed tomography (SPECT) imaging radionuclide. 99 Mo / 99m Tc generator, suitable half-life (T 1 / 2 =6.02h), 140kev gamma single photon emission energy, cheap and easily available nuclide sources, rich coordination valence states, drug-boxable, reliable quality and other advantages make it an ideal nuclide in the development of SPECT molecular probes. Therefore, the development of new PSMA-targeted 99m Tc tumor radiopharmaceuticals have important clinical application value.

[0004] Increasing the number of targeting groups in the radiolabeled molecule is a feasible strategy to further improve the accumulation of the probe in the tumor. 68 Ga]Ga-PSMA-D5 ([EuK]2-DOTA), compared with the monomer, effectively increased the absolute tumor uptake value, and its tumor to non-target ratio was significantly improved (Chen Y, Zhang X, Ni M, et al. Synthesis, Preclinical Evaluation, and First-in-Human PET Study of [ 68Ga]-Labeled Biphenyl-Containing PSMA Tracers. J Med Chem 2023, 66 (18), 13332-13345.). In addition, the linker connects the targeting group and the chelating group connected to the radionuclide, which plays an important role in regulating the efficacy and pharmacokinetics of radiopharmaceuticals. Proline as a linker has obvious positive significance in optimizing the pharmacokinetics of radioactive probes, especially in reducing the uptake of non-target organs (Ruan Q, Ding D, Diao L, et al. Synthesis and Preclinical Evaluation of Novel 99m Tc-Labeled FAPI-46 Derivatives with Significant Tumor Uptake and Improved Tumor-to-Nontarget Ratios. J Med Chem 2024, 67(4), 3190-3202.). Based on the above background, the present invention uses L-proline as a linker to synthesize derivatives containing two glutamic acid-urea targeting groups, and with the participation of other co-ligands, 99m The exploration of new tumor radioactive drugs that specifically target PSMA by Tc labeling has important scientific significance and broad clinical application prospects. Summary of the invention

[0005] The present invention provides a glutamic acid-urea dimer derivative containing L-proline and application thereof. The derivative has good stability and is easy to prepare. After being radioactively labeled, it can be used for tumor diagnosis and treatment. It has high tumor uptake and good target / non-target ratio, and has important scientific significance and application prospects in the field of tumor diagnosis and treatment.

[0006] Specifically, the present invention provides the following technical solutions:

[0007] A glutamic acid-urea dimer derivative containing L-proline and its application, wherein the structural formula is (I):

[0008]

[0009] In the formula, n represents an integer of 0 or greater.

[0010] Preferably, in the above-mentioned L-proline-containing glutamic acid-urea dimer derivative, when n=1, the structural formula of the L-proline-containing glutamic acid-urea dimer derivative is the following one (II), and the corresponding derivative prepared from the derivative is 99mTc complexes specifically bind to PSMA. The uptake in non-target organs is low, and the tumor uptake value and tumor-to-non-target ratio are high, which can achieve good results in the diagnosis and treatment of prostate tumors.

[0011]

[0012] The present invention also provides a radioactive preparation, which comprises the above-mentioned L-proline-containing glutamic acid-urea dimer derivative labeled with a radioactive nuclide and application thereof.

[0013] Preferably, in the above radioactive preparation, the radioactive nuclide portion is a metal radioactive nuclide.

[0014] Preferably, in the above radioactive preparation, the metal radionuclide is 99m Tc, 99 Tc, 94m Tc, 94 Tc, 52 Mn, 186 Re or 188 Re.

[0015] Most preferably, in the above radioactive preparation, the radionuclide is 99m Tc, the structural formula of the radioactive agent is (III):

[0016]

[0017] In the formula, n represents an integer of 0 or greater.

[0018] The present invention also provides the use of the radioactive preparation in preparing tumor radioactive medicine.

[0019] The beneficial effects of the present invention are as follows: the present invention provides a glutamic acid-urea dimer derivative containing L-proline and its application, and the radioactive preparation obtained by labeling the derivative with a radioactive nuclide has high uptake in tumors and a good tumor / non-target ratio, and is a new tumor radioactive drug with promotion significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Attached Figure 1 : 99m SPECT imaging of the control group 2 hours after injection of Tc-DELH-EDDA in Balb / c model mice bearing 22Rv1 tumors.

[0021] Attached Figure 2 : After the PSMA inhibitor 2-PMPA was injected 30 minutes in advance, 99m SPECT imaging of the inhibition group 2h after injection of Tc-DELH-EDDA in Balb / c model mice bearing 22Rv1 tumors. DETAILED DESCRIPTION

[0022] The present invention provides a glutamic acid-urea dimer derivative containing L-proline and its application. In a preferred embodiment, the present invention provides a general structural formula: 99m Radioactive preparation of Tc-DELH-EDDA:

[0023]

[0024] Where n=1.

[0025] The preparation steps are as follows:

[0026] a: Synthesis of ligand DELH:

[0027] 6-Chloronicotinic acid (Compound 1) was dissolved in ethanol (EtOH), 80% hydrazine hydrate was added, refluxed and stirred for 4 hours, cooled to room temperature, the precipitate was filtered, the filter cake was washed, and vacuum dried to obtain Compound 2; Compound 2 and di-tert-butyl dicarbonate (Di-tert-butyl dicarbonate) was dissolved in N,N-dimethylformamide (DMF), stirred at room temperature for 12 h, and purified by column chromatography to obtain compound 3; compound 3, L-proline (L-Pro), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), and triethylamine (TEA) were dissolved in DMF, stirred at room temperature for 12 h, and purified by column chromatography to obtain compound 4; an appropriate amount of L-glutamic acid di-tert-butyl ester hydrochloride (compound 5) was weighed into a round-bottom flask, an appropriate amount of dichloromethane (DCM) was added to dissolve, and then triphosgene (Triphosgene), N-E-benzyloxycarbonyl-L-lysine tert-butyl ester hydrochloride (H-Lys(Z)-OtBu.HCl), T EA, react at room temperature for 4 hours, and separate and purify by column chromatography to obtain compound 6; compound 6 was dissolved in methanol (MeOH), and reduced with palladium carbon (Pd / C) and hydrogen (H2) to obtain compound 7; compound 7, (benzyloxycarbonyl)-L-aspartic acid (Asp-Cbz), HATU, and TEA were dissolved in DMF, stirred at room temperature for 12 hours, and purified by column chromatography to obtain compound 8; compound 8 was dissolved in methanol, and reduced with Pd / C and H2 to obtain compound 9; compound 4 and compound 9, HATU, and TEA were dissolved in DMF, stirred at room temperature for 12 hours, and purified by column chromatography to obtain compound 10; compound 10 was dissolved in DCM, an equal volume of trifluoroacetic acid (TFA) was added, and the reaction was carried out at room temperature for 3 hours, and purified by column chromatography to obtain the final product DELH.

[0028] The specific synthetic route is:

[0029]

[0030] b: 99m Preparation of Tc-DELH-EDDA complex:

[0031] Weigh N-tris(hydroxymethyl)methylglycine (Tricine) and ethylenediamine-N,N'-diacetic acid (EDDA) and dissolve them in physiological saline, add succinate buffer with a pH of 7.0, adjust the solution pH to 7.0-8.0 with NaOH, and add ligand DELH, SnCl2﹒2H2O and freshly washed Na 99m TcO4, react at 100°C for 20-30 minutes to obtain the 99m Tc-DELH-EDDA complex.

[0032] Prepared by the above method 99m The radiochemical purity of the Tc-DELH-EDDA complex is greater than 90%, and it is a hydrophilic substance with good in vitro stability. The imaging results show that it has high uptake and good retention in the tumor site of tumor-bearing mice, low uptake in non-target tissues, and after injection of PSMA inhibitors for inhibition, tumor uptake is significantly reduced, indicating that it exhibits PSMA-specific uptake in tumors and is a new type of SPECT molecular probe with excellent performance that can be used for tumor imaging.

[0033] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention. If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the art or the product instructions are used.

[0034] The present invention is described in detail below by way of embodiments: 99m Tc-labeled glutamic acid-urea dimer derivative containing L-proline can be used for SPECT / CT imaging targeting PSMA. Its general structural formula is 99m Tc-DELH-EDDA.

[0035]

[0036] Where n=1.

[0037] The preparation method is as follows, but is not limited to the complexes illustrated:

[0038] 1. 99m Preparation of Tc-DELH-EDDA

[0039] a. Synthesis of DELH

[0040] Synthesis of compound 2. Compound 1 (2.0 g, 12.7 mmol) was dissolved in 20 mL of ethanol, and hydrazine hydrate (1.48 mL, 31.7 mmol) was added. The mixture was refluxed overnight and then cooled to room temperature to obtain a solid, which was collected by filtration and washed with petroleum ether / ethyl acetate (2:1) to obtain a yellow solid, namely compound 2 (1.60 g, 81%). 1 H NMR (400MHz, DMSO-d6): δ 8.52 (d, J = 2.3 Hz, 1H), 7.88 (dd, J = 8.9, 2.3 Hz, 1H), 6.63 (d, J = 9.0 Hz, 1H).

[0041] Synthesis of compound 3. Compound 2 (2.0 g, 13.2 mmol) and di-tert-butyl dicarbonate (3.18 g, 14.59 mmol) were dissolved in DMF (10 mL), 2.76 mL of TEA was added, and the mixture was stirred at room temperature for 12 h. The reaction progress was monitored by TLC, and the filtrate was concentrated. Column chromatography purification, [DCM / MeOH=50 / 1 (v / v)], finally gave a white solid, namely compound 3 (2.5 g, 74.5%). 1 H NMR (600MHz, Methanol-d4) δ8.63 (d, J = 1.0 Hz, 1H), 8.04 (s, 1H), 6.68 (s, 1H), 1.96 (s, 1H), 1.46 (s, 9H), 1.27 (s, 6H).

[0042] Synthesis of compound 4. Compound 3 (0.5 g, 1.97 mmol), L-proline (0.25 g, 2.17 mmol) and HATU (0.83 g, 2.17 mmol) were dissolved in DMF (5 mL), TEA (0.41 mL, 2.96 mmol) was added, and stirred at room temperature for 12 h. The reaction progress was monitored by TLC, and the filtrate was concentrated. Column chromatography purification, [DCM / MeOH=20 / 1 (v / v)], finally gave a light yellow solid, namely compound 4 (0.42 g, 60.7%). 1 HNMR(600MHz,Methanol-d4)δ8.37(s,1H),7.86(s,1H),6.72(s,1H),3.73(d,J= 2.4Hz,2H),2.66(s,1H),2.45–2.11(m,1H),1.99(s,3H),1.43(d,J=77.3Hz,9H).

[0043] Synthesis of compound 6. Weigh triphosgene (2.0 g, 6.74 mmol) in a round-bottom flask, add 20 mL of DCM to dissolve, then add compound 5 (5.98 g, 20.22 mmol), TEA (9.37 mL, 67.4 mmol), stir at room temperature for 1 h, then add N-E-benzyloxycarbonyl-L-lysine tert-butyl ester hydrochloride (7.54 g, 20.22 mmol) and TEA (2.81 mL, 20.22 mmol), and react at room temperature for 2 h. After the reaction, remove the solvent by distillation under reduced pressure, and purify by column chromatography [DCM / MeOH=100 / 1 (v / v)] to obtain an oily substance, which is compound 6 (8.0 g, 64%). 1 H NMR (600MHz, DMSO-d6) δ7.52–7.14(m,5H),6.27(d,J=23.8Hz,2H),5.00(s,1H),4.07–3.88(m,2H),2.98(d,J=6.3Hz, 2H), 2.22(d,J=16.8Hz,2H),1.87(d,J=6.8Hz,2H),1.67(s,2H),1.45–1.35(m,27H),1.30–1.15(m,3H),0.86(s,1H).

[0044] Synthesis of compound 7. Weigh compound 6 (3.0 g, 4.82 mmol) in a round-bottom flask, add 5 mL of methanol to dissolve, then add palladium carbon (340 mg, 1.74 mmol), react at room temperature under hydrogen pressure for 12 h, and monitor the reaction progress by TLC. After the reaction, filter with diatomaceous earth, remove the solvent by vacuum distillation, and purify with column chromatography [DCM / MeOH=30 / 1 (v / v)] to obtain an oily substance, namely compound 7 (2.0 g, 85%). 1 H NMR(600MHz,Chloroform-d)δ5.20(s,1H),4.34(d,J=5.0Hz,2H),4.12(d,J=7.2Hz,1H),2.68(d,J=1.3Hz,1H), 2.33(d,J=9.7Hz,2H),2.05(s,2H),1.81(d,J=58.4Hz,2H),1.60(s,2H),1.45(d,J=16.6Hz,27H),1.26(s,2H).

[0045] Synthesis of compound 8. Weigh (benzyloxycarbonyl)-L-aspartic acid (1.0 g, 3.74 mmol), HATU (3.56 g, 9.35 mmol), and compound 7 (4.56 g, 9.35 mmol) in a round-bottom flask, add 15 mL of DMF to dissolve, then add TEA (1.3 mL, 9.35 mmol), react at room temperature for 12 h, and monitor the reaction progress by TLC. Remove the solvent under reduced pressure, purify by column chromatography, [DCM / MeOH=80 / 1 (v / v)], and obtain a colorless oil, which is compound 8 (2.9 g, 64%). 1 H NMR(400MHz,Methanol-d4)δ7.41–7.22(m,5H),5.10(s,2H),4.52(m,1H),4.29–4.08(m,3H ),3.72(s,1H),3.26–2.93(m,4H),2.81(s,7H),2.31(d,J=7.4Hz,13H),1.56–0.88(m,56H).

[0046] Synthesis of compound 9. Weigh compound 8 (2.0 g, 1.65 mmol) in a round-bottom flask, add 5 mL of methanol to dissolve, then add palladium carbon (219 mg, 1.12 mmol), react at room temperature under hydrogen pressure for 12 h, and monitor the reaction progress by TLC. After the reaction, filter with diatomaceous earth, remove the solvent by vacuum distillation, and purify with column chromatography [DCM / MeOH=30 / 1 (v / v)] to obtain a white powder, namely compound 9 (1.5 g, 88%). 1 H NMR(600MHz,Chloroform-d)δ4.31–4.09(m,6H),3.81(d,J=6.3Hz,1H),3.10(m,4 H),2.65–2.26(m,6H),2.12–1.98(m,4H),1.81–1.65(m,4H),1.41-0.95(m,62H).

[0047] Synthesis of compound 10. Weigh compound 4 (50 mg, 0.14 mmol), HATU (60.84 mg, 0.16 mmol), and compound 9 (168.3 mg, 0.16 mmol) in a round-bottom flask, add 5 mL of DMF to dissolve, then add TEA (29.19 uL, 0.21 mmol), react at room temperature for 12 h, and monitor the reaction progress by TLC. Remove the solvent under reduced pressure, purify by column chromatography [DCM / MeOH=30 / 1 (v / v)], and obtain a colorless oil, which is compound 10 (85.0 mg, 42%). 1H NMR (600MHz, Methanol-d4) δ7.90(d,J=9.3Hz,1H),7.65(s,1H),6.69(d,J=8.8Hz,1H),4.52(s,1H),4.14(d,J =48.4Hz,3H),3.86(d,J=0.9Hz,1H),3.37–2.66(m,12H),2.29(s,4H),2.11–1.66(m,8H),1.64–0.80(m,72H).

[0048] Synthesis of compound DELH. Weigh compound 10 (50 mg, 0.04 mmol) and dissolve it in 2 mL DCM, then add 2 mL TFA and react at room temperature for 3 h. Monitor the reaction progress by TLC. Remove the solvent under reduced pressure and purify by column chromatography [DCM / MeOH=5 / 1 (v / v)] to obtain a colorless oil, which is compound DELH (25.0 mg, 73%). 1 H NMR(600MHz,DMSO-d6)δ8.14(d,J=8.1Hz,1H),7.79(s,2H),4.48(s,1H),4.26–3.79(m,4H) ,3.60(dd,J=2.1Hz,1H),3.21–2.60(m,5H),2.24(s,5H),2.04–0.81(m,22H).MS-ESI:calcd for[MH] - :966(M=C 39 H 57 N 11 O 18 ),found:966.

[0049] The synthetic route is:

[0050]

[0051] b. 99m Preparation of Tc-DELH-EDDA complex

[0052] Weigh 20 mg of Tricine and 10 mg of EDDA and dissolve them in 0.5 mL of normal saline. Add succinate buffer with a pH of 7.0. Use NaOH (1 mol / L) to adjust the solution pH to 7.0-8.0. Then add 20 μg of ligand DELH, 100 μg of SnCl2﹒2H2O and 0.5 mL of freshly washed Na 99m TcO4 (about 370MBq), react at 100℃ for 20min to obtain the 99m Tc-DELH-EDDA complex.

[0053]

[0054] The present invention 99m Performance determination of Tc-DELH-EDDA complex:

[0055] 1. Identification of complexes

[0056] a. High performance liquid chromatography (HPLC) identification:

[0057] A C18 reverse phase column and SCL-10AVP high pressure liquid chromatograph were used. Phase A was water (containing 0.1% trifluoroacetic acid), phase B was acetonitrile (containing 0.1% trifluoroacetic acid), and the gradient was 0-2min phase B was 10%, 2-10min phase B changed from 10% to 90%, 10-20min phase B was 90%, and 20-25min phase B changed from 90% to 10%. The injection volume was 10 μL and the flow rate was 1 mL / min. The retention time (R t )for: 99m Tc-DELH-EDDA: 13.34min.

[0058] b. Thin layer chromatography (TLC) identification:

[0059] The development system is: polyamide film as support, ammonium acetate (1 mol / L) / methanol = 2:1 (V / V) as developing agent. Under this system, the R f The values ​​are shown in Table 1 below

[0060] Table 1 Chromatographic results of each component of the complex (R f value)

[0061]

[0062] The radiochemical purity of the markers determined by the above two methods is greater than 90%.

[0063] 2. Determination of lipid-water partition coefficient of complex

[0064] Take 0.9 mL of pH 7.4 phosphate buffer (0.025 mol / L) in a 5 mL centrifuge tube, add 1 mL of n-octanol and 0.1 mL of 99m The Tc-DELH-EDDA solution was covered with a stopper, vortexed, and centrifuged for 5 min (5000 r / min). Then 3×0.1 mL was taken from the organic phase and the aqueous phase respectively, and the radioactivity counts of the two phases were measured, and the distribution coefficient D (D = radioactivity of the organic phase / radioactivity of the aqueous phase) was calculated. This was repeated three times. 99mThe lipid-water partition coefficient (log D) of the Tc-DELH-EDDA complex is -1.59±0.05, indicating that it is a hydrophilic substance.

[0065] 3. Determination of the stability of the complex

[0066] Will 99m The radiochemical purity of the Tc-DELH-EDDA complex was measured after it was placed in mouse whole blood at room temperature and at 37°C for 6 hours. The results showed that the radiochemical purity was greater than 90% after it was placed in mouse whole blood at room temperature and at 37°C for 6 hours, indicating that it has good in vitro stability.

[0067] 4. Biodistribution of the complex in 22Rv1 mice

[0068] 0.10 mL was injected into the tail vein of 22Rv1 mice 99m Tc-DELH-EDDA labeling solution (about 3.7×10 5 Bq), and the mice were anesthetized with isoflurane gas 2h after injection and then killed. In addition, PSMA inhibitor (2-PMPA) was used to 99m Tc-DELH-EDDA was used for the in vivo inhibition experiment in mice. The method was as follows: 0.20 mL of saline containing 500 μg of 2-PMPA was injected into the tail vein, and 0.10 mL was injected 30 minutes later. 99m Tc-DELH-EDDA labeling solution (about 3.7×10 5 Bq), and 2h later, the mice were anesthetized with isoflurane gas and then killed. The heart, liver, spleen, lung, kidney, muscle, bone, stomach, large intestine, small intestine, tumor, blood and other related tissues and organs were taken, wiped clean and weighed, and the radioactivity count was measured on a γ-Counter to calculate the percentage of injected dose per gram (%ID / g) of each tissue. The number of mice in each group was 3. The results are shown in Table 2.

[0069] Table 2 99m Biodistribution of Tc-DELH-EDDA in 22Rv1 tumor-bearing mice 2h after injection (%ID / g)

[0070]

[0071] From Table 2, we can see that 99m Tc-DELH-EDDA can effectively inhibit both tumors and kidneys (high expression of PSMA), with blocking rates of 95% and 73% in kidneys and tumors, respectively, indicating its good targeting of PSMA.

[0072] 5. SPECT imaging of the complex in tumor-bearing mice

[0073] Injection of 22Rv1 tumor-bearing Balb / c mice into the tail vein 99m Tc-DELH-EDDA solution 0.5 mL (about 3.7 × 10 7 Bq), and 2 hours later, isoflurane gas was used for anesthesia. The mice were fixed in prone position and SPECT / CT imaging of the control group was performed. First, 0.20 mL of saline containing 500 μg of 2-PMPA was injected into the tail vein of Balb / c mice bearing 22Rv1 tumors, and 0.50 mL was injected 30 minutes later. 99m Tc-DELH-EDDA labeling solution (about 3.7×10 7 Bq), and 2h later, isoflurane gas anesthesia was used. The mice were fixed in prone position, and SPECT / CT imaging of the inhibition group was performed. SPECT imaging results showed that in the control group (such as the attached Figure 1 (shown) 99m Tc-DELH-EDDA accumulated significantly in the tumor and had a good tumor stasis effect, and the uptake in other non-target tissues was very low. Figure 2 The uptake of the PSMA-targeting SPECT molecular probe was significantly inhibited, indicating that its uptake in the tumor was specific and that it could be used as a novel PSMA-targeting SPECT molecular probe with excellent performance.

[0074] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention, changing different linkers, such as D-proline and other amino acids, peptide chains, polyethylene glycol (PEG) chains, fatty chains, etc., or using Tricine and triphenylphosphine tris-sulfonate sodium (TPPTS), Tricine and diphenylphosphine benzene-3-sulfonate sodium (TPPMS), Tricine and 3,3'-(phenylphosphine diyl) di(benzene-1-sulfonic acid) disodium (TPPDS), Tricine and nicotinic acid (NIC), Tricine and isonicotinic acid (ISONIC), Tricine and 3,5-pyridinedicarboxylic acid (PDA), Tricine and 3-pyridinesulfonic acid (PSA), Tricine and glucoheptonate, Tricine and glucosamine, Tricine and mannitol, Tricine and diphenylphosphine benzoic acid and other co-ligands to obtain radioactive preparations after labeling with radioactive nuclides all fall within the scope of protection claimed by the present invention.

Claims

1. A glutamic acid-urea dimer derivative containing L-proline, characterized in that: The structural formula of the L-proline-containing glutamic acid-urea dimer derivative is (I): In the formula, n represents an integer of 0 or greater.

2. A radioactive preparation, characterized in that: The radioactive agent comprises the L-proline-containing glutamic acid-urea dimer derivative according to any one of claims 1 labeled with a radionuclide.

3. The radioactive preparation according to claim 2, characterized in that The radionuclide is 99m Tc, 99 Tc, 94m Tc, 94 Tc, 52 Mn, 186 Re or 188 Re.

4. The radioactive preparation according to claim 3, characterized in that The structural formula of the radioactive agent is (II): In the formula, n represents an integer of 0 or greater.

5. Use of the radioactive preparation according to any one of claims 2 to 4 in the preparation of a tumor imaging agent.

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