Glutamate-urea dimer derivatives containing l-aspartate linkers and uses thereof

Abstract

This invention relates to the fields of radiopharmaceutical chemistry and clinical nuclear medicine, specifically to a glutamate-urea dimer derivative containing an L-aspartic acid linker and its applications. The glutamate-urea dimer derivative containing the L-aspartic acid linker is used... 99m The radioactive agents obtained by Tc labeling exhibit high uptake in tumors and low uptake in non-target tissues, resulting in a good tumor / non-target ratio. They also specifically bind to prostate-specific membrane antigens and can be used as novel radiopharmaceuticals for the diagnosis of prostate cancer with significant potential for widespread application.

Description

Technical Field

[0001] This invention relates to the fields of radiopharmaceutical chemistry and clinical nuclear medicine, specifically to a glutamic acid-urea dimer derivative containing an L-aspartic acid linker and its applications. Background Technology

[0002] Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein located on the cell membrane that is specifically and highly expressed in prostate cancer (PCa). Furthermore, its expression level is associated with tumor invasiveness, making it an important target for PCa detection and treatment.

[0003] Small molecule inhibitors containing glutamate-urea units specifically bind to PSMA on the surface of prostate cancer cells. Radiolabeling of PSMA-targeting inhibitors containing glutamate-urea units has become a hot topic in international radiopharmaceutical research. 99m Tc, as the most common radionuclide used in single-photon emission computed tomography (SPECT) imaging, can be obtained from... 99 Mo / 99m Tc generator obtains, and 99m Tc-labeled drugs can be prepared in kits, making them easy to use in clinical practice. Therefore, the development of novel drugs targeting PSMA is crucial. 99m Tc-based radiopharmaceuticals for tumors have significant clinical application value.

[0004] In radiopharmaceutical research, increasing the number of targeting groups in radiolabeled molecules is a feasible strategy to further enhance probe accumulation within tumors. In 2023, a literature report... 68 Biodistribution of Ga-PSMA-D5 (containing two glutamic acid-urea pharmacophore groups) in tumor-bearing mice showed that, compared to 68 Ga-PSMA-617, 68 Ga-PSMA-D5 showed higher tumor uptake and a higher tumor / kidney ratio (Chen Y, Zhang X, Ni M, et al. Synthesis, Preclinical Evaluation, and First-in-Human PET Study of […]). 68[Ga]-Labeled Biphenyl-Containing PSMA Tracers. J Med Chem. 2023; 66(18):13332-13345.). Furthermore, the linker connects the targeting group and the chelating group linked to the radionuclide, playing a crucial role in regulating the efficacy and pharmacokinetics of radiopharmaceuticals. Based on this background, this invention uses L-aspartic acid as a linker to synthesize derivatives containing two glutamate-urea targeting groups, and with the participation of other co-ligands, it is further processed... 99m Using Tc labeling to explore novel, specific, PSMA-targeting radiopharmaceuticals for tumors has significant scientific implications and broad clinical application prospects. Summary of the Invention

[0005] This invention provides a glutamic acid-urea dimer derivative containing an L-aspartic acid linker and its application. The derivative has good stability, is easy to prepare, and can be used for tumor diagnosis and treatment after radiolabeling. It exhibits high tumor uptake and a good target / non-target ratio, which 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 an L-aspartic acid linker and its application, wherein the structural formula is (I):

[0008]

[0009] The corresponding derivative prepared from this derivative 99m Tc complexes specifically bind to PSMA, exhibiting very low uptake in non-target organs, high tumor uptake values, and tumor / non-target ratios, thus achieving excellent results in tumor diagnosis and treatment.

[0010] The present invention also provides a radioactive preparation comprising the above-mentioned glutamic acid-urea dimer derivative containing an L-aspartic acid linker labeled with a radionuclide and its application.

[0011] Preferably, in the above-mentioned radioactive preparation, the radionuclide portion is a metallic radionuclide.

[0012] Preferably, in the above-mentioned radioactive agents, the metallic radionuclide is... 99m Tc, 99 Tc, 94m Tc, 94 Tc, 52 Mn, 186 Re or 188 Re.

[0013] Most preferably, in the above-mentioned radioactive preparation, the radionuclide is... 99m Tc, the structural formula of the radioactive agent is (II):

[0014]

[0015] The present invention also provides the application of the above-mentioned radioactive agents in the preparation of tumor radiopharmaceuticals.

[0016] The beneficial effects of this invention are as follows: This invention provides a glutamic acid-urea dimer derivative containing an L-aspartic acid linker and its application. The radioactive preparation obtained by labeling it with a radionuclide exhibits high uptake in tumors and a good tumor / non-target ratio, making it a novel radiopharmaceutical with promotional significance. Attached Figure Description

[0017] Appendix Figure 1 : 99m SPECT imaging of the control group 2 hours after injection of Tc-DGAH-EDDA into Balb / c model mice bearing 22RV1 tumors.

[0018] Appendix Figure 2 : After injecting the PSMA inhibitor 2-PMAP 30 minutes in advance, 99m SPECT imaging of the inhibition group 2 hours after injection of Tc-DGAH-EDDA into Balb / c model mice bearing 22RV1 tumors. Detailed Implementation

[0019] This invention provides a glutamic acid-urea dimer derivative containing an L-aspartic acid linker and its applications. In a preferred embodiment, this invention provides a derivative with the following general structural formula: 99m Radioactive preparations of Tc-DGAH-EDDA:

[0020]

[0021] The preparation steps are as follows:

[0022] a: Synthesis of ligand DGAH:

[0023] 6-Chloronicotinic acid (compound 1) was dissolved in 80% hydrazine hydrate, 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 were then reacted... L-glutamic acid di-tert-butyl ester hydrochloride (compound 4) was dissolved in N,N-dimethylformamide (DMF) and stirred at room temperature for 12 h. The mixture was then purified by column chromatography to obtain compound 3. An appropriate amount of L-glutamic acid di-tert-butyl ester hydrochloride (compound 4) was weighed into a round-bottom flask, dissolved in dichloromethane (DCM), and then triphosgene, N-E-benzyloxycarbonyl-L-lysine tert-butyl ester hydrochloride (H-Lys(Z)-OtBu.HCl), and triethylamine (TEA) were added sequentially. The mixture was reacted at room temperature for 4 h, and purified by column chromatography to obtain compound 5. Compound 5 was dissolved in methanol and reduced with palladium on carbon (Pd / C) and hydrogen (H2) to obtain compound 6. L-aspartic acid di-tert-butyl ester hydrochloride (compound 7) was purified by NaOH water... Compound 8 was obtained; Compound 8 and benzyl chloroformate (Cbz-Cl) were reacted at low temperature for 6 h to obtain Compound 9; Compound 6, Compound 9, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) and TEA were dissolved in DMF, stirred at room temperature for 12 h, and purified by column chromatography to obtain Compound 10; Compound 10 was dissolved in methanol and reduced by Pd / C and H2 to obtain Compound 11; Compound 3, Compound 11, HATU and TEA were dissolved in DMF, stirred at room temperature for 12 h, and purified by column chromatography to obtain Compound 12; Compound 12 was dissolved in DCM, an equal volume of trifluoroacetic acid (TFA) was added, reacted at room temperature for 3 h, and purified by column chromatography to obtain the final product DGAH.

[0024] The specific synthesis route is as follows:

[0025]

[0026] b: 99m Preparation of Tc-DGAH-EDDA complex:

[0027] Weigh out N-tris(hydroxymethyl)methylglycine (Tricine) and ethylenediamine-N,N'-diacetic acid (EDDA) and dissolve them in physiological saline. Add succinate buffer solution with a pH of 7.0, adjust the pH of the solution to 7.0-8.0 with NaOH, and then add the ligand DGAH, SnCl2·2H2O and freshly rinsed NaOH in sequence. 99m TcO4 was reacted at 100℃ for 20-30 minutes to obtain the aforementioned product. 99m Tc-DGAH-EDDA complex.

[0028] Prepared by the above method99m The Tc-DGAH-EDDA complex has a radiochemical purity greater than 90%, is hydrophilic, and exhibits good in vitro stability. Imaging results show that it has high uptake and good retention at the tumor site in tumor-bearing mice, with low uptake in non-target tissues. After injection of a PSMA inhibitor, tumor uptake is significantly reduced, indicating that it exhibits PSMA-specific uptake in tumors. It is a novel SPECT molecular probe with excellent performance for tumor imaging.

[0029] The following embodiments are used to illustrate the present invention, but are not intended to limit the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they should be performed in accordance with the techniques or conditions described in the literature in the field, or in accordance with the product manual.

[0030] The present invention is described in detail below through embodiments: a 99m Tc-labeled glutamate-urea dimer derivatives containing L-aspartate linkers can be used for SPECT / CT imaging targeting PSMA, and their general structural formula is: 99m Tc-DGAH-EDDA.

[0031]

[0032] The preparation methods are as follows, but are not limited to the exemplified complexes:

[0033] 1. 99m Preparation of Tc-DGAH-EDDA

[0034] a. Synthesis of DGAH

[0035] 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, then cooled to room temperature to give a solid. The solid was collected by filtration and washed with petroleum ether / ethyl acetate (2:1) to give a yellow solid, which was Compound 2 (1.60 g, 81.0%). 1 H NMR (400MHz, DMSO-d6): δ 8.520 (d, J = 2.3 Hz, 1H), 7.88 (dd, J = 8.9, 2.3 Hz, 1H), 6.63 (d, J = 9.0 Hz, 1H).

[0036] 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), and 2.76 mL of TEA was added. The mixture was stirred at room temperature for 12 h, and the reaction progress was monitored by TLC. The filtrate was concentrated and purified by column chromatography [DCM / MeOH = 50 / 1 (v / v)], finally yielding a white solid, which was 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).

[0037] Synthesis of Compound 5. Triphosgene (2.0 g, 6.74 mmol) was weighed into a round-bottom flask, dissolved in 20 mL of DCM, followed by the addition of Compound 4 (5.98 g, 20.22 mmol) and TEA (9.37 mL, 67.4 mmol). The mixture was stirred at room temperature for 1 h, then N-E-benzyloxycarbonyl-L-lysine tert-butyl hydrochloride (7.54 g, 20.22 mmol) and TEA (2.81 mL, 20.22 mmol) were added, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the solvent was removed by vacuum distillation, and the mixture was purified by column chromatography [DCM / MeOH = 100 / 1 (v / v)] to obtain an oily substance, which was Compound 5 (8.0 g, 64.0%). 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).

[0038] Synthesis of Compound 6. Compound 5 (3.0 g, 4.82 mmol) was weighed into a round-bottom flask, dissolved in 5 mL of methanol, and then palladium on carbon (340 mg, 1.74 mmol) was added. The reaction was carried out under hydrogen pressure at room temperature for 12 h, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered through diatomaceous earth, the solvent was removed by vacuum distillation, and the mixture was purified by column chromatography [DCM / MeOH = 30 / 1 (v / v)] to obtain an oily substance, which was Compound 6 (2.0 g, 85%). 1H 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).

[0039] Synthesis of Compound 8. Compound 7 (2.0 g, 7.10 mmol) was weighed into a round-bottom flask, dissolved in 5 mL of dioxane, followed by 5 mL of NaOH (1 mol / L). The reaction was carried out at room temperature for 12 h, and the reaction progress was monitored by TLC. After the reaction was completed, the pH was adjusted to weakly acidic, the solvent was removed by vacuum distillation, and the mixture was washed several times with diethyl ether and petroleum ether to obtain a white powder, which was crude compound 8 (0.86 g, 91%). 1 H NMR (600MHz, Methanol-d4) δ4.18-3.92(m,1H),2.86-2.57(m,2H).

[0040] Synthesis of Compound 9. Compound 8 (2.5 g, 18.78 mmol) was dissolved in 25 mL of aqueous solution, and K₂CO₃ (5.2 g, 37.6 mmol) was added. The mixture was then cooled in an ice bath. Benzyl chloroformate (3.9 mL, 26.3 mmol) was then added dropwise to the mixture, and the mixture was stirred at room temperature for 18 h. The reaction was monitored by TLC. The mixture was extracted with diethyl ether, the pH was adjusted to 1 with hydrochloric acid, and the acidified solution was extracted with ethyl acetate. The solution was dried over anhydrous MgSO₄ and concentrated to give Compound 9 (3.5 g, 87%). 1 H NMR (600MHz, Methanol-d4) δ7.52-7.16 (m, 5H), 5.08 (d, J = 0.8Hz, 2H), 4.62 (d, J = 9.1Hz, 1H), 2.79-2.48 (m, 2H).

[0041] Synthesis of Compound 10. Compound 9 (1.0 g, 3.74 mmol), HATU (3.56 g, 9.35 mmol), and Compound 6 (4.56 g, 9.35 mmol) were weighed into a round-bottom flask, dissolved in 15 mL of DMF, and then TEA (1.3 mL, 9.35 mmol) was added. The reaction was carried out at room temperature for 12 h, and the reaction progress was monitored by TLC. After cooling to room temperature, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography [DCM / MeOH = 80 / 1 (v / v)] to obtain a colorless oily substance, which was Compound 10 (2.9 g, 64%). 1H 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).

[0042] Synthesis of Compound 11. Compound 10 (2.0 g, 1.65 mmol) was weighed into a round-bottom flask, dissolved in 5 mL of methanol, and then palladium on carbon (219 mg, 1.12 mmol) was added. The reaction was carried out under hydrogen pressure at room temperature for 12 h, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered through diatomaceous earth, the solvent was removed by vacuum distillation, and the mixture was purified by column chromatography [DCM / MeOH = 30 / 1 (v / v)] to obtain a white powder, which was compound 11 (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).

[0043] Synthesis of Compound 12. Compound 3 (100 mg, 0.40 mmol), HATU (165.40 mg, 0.44 mmol), and Compound 11 (635.90 mg, 0.60 mmol) were weighed into a round-bottom flask, dissolved in 5 mL of DMF, and then TEA (82.49 μL, 0.60 mmol) was added. The reaction was carried out at room temperature for 12 h, and the reaction progress was monitored by TLC. After cooling to room temperature, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography [DCM / MeOH = 40 / 1 (v / v)] to obtain a colorless oily substance, which was Compound 12 (0.30 g, 58.1%). 1 H NMR(400MHz, Methanol-d4)δ8.56(d,J=2.4Hz,1H),8.01(d,J=7.0Hz,1H),7.70(s,1H),5.47(s,1H),4.31- 3.98(m,4H),3.06(d,J=80.8Hz,5H),2.79(s,3H),2.38-2.20(m,4H),1.94(d,J=36.8Hz,3H),1.43(m,74H).

[0044] Synthesis of compound DGAH. Compound 12 (200 mg, 0.15 mmol) was weighed and dissolved in 2 mL of DCM, then 2 mL of TFA was added. The reaction was carried out at room temperature for 3 h, and the reaction progress was monitored by TLC. After cooling to room temperature, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography [DCM / MeOH = 5 / 1 (v / v)], yielding a colorless oily substance, which was compound DGAH (110 mg, 84.6%). 1 H NMR (600MHz, Methanol-d4) δ8.44(s,1H),8.12(d,J=1.8Hz,1H),6.88(s,1H),4.64(s,1H),4.23(d,J=7.2Hz,3 H), 3.63 (d, J = 30.3Hz, 4H), 3.30-3.07 (m, 3H), 2.95-2.51 (m, 3H), 2.37 (s, 3H), 1.95 (s, 6H), 1.67-0.77 (m, 8H). MS-ESI:calcd for[M+H] + :871(M=C 34 H 50 N 10 O 17 ),found:871.

[0045] The synthetic route is as follows:

[0046]

[0047] b. 99m Preparation of Tc-DGAH-EDDA complex

[0048] Weigh 20 mg Tricine and 10 mg EDDA and dissolve them in 0.5 mL of physiological saline. Add succinate buffer (pH 7.0), and adjust the pH of the solution to 7.0-8.0 with NaOH (1 mol / L). Then, add 20 μg of ligand DGAH, 100 μg of SnCl2·2H2O, and 0.5 mL of freshly rinsed NaOH solution sequentially. 99m The above-mentioned product can be obtained by reacting TcO4 (approximately 370 MBq) at 100°C for 20 minutes. 99m Tc-DGAH-EDDA complex.

[0049]

[0050] This invention 99m Performance determination of Tc-DGAH-EDDA complex:

[0051] 1. Identification of coordination compounds

[0052] a. Identification by high performance liquid chromatography (HPLC):

[0053] A C18 reverse-flow column and an SCL-10AVP high-performance liquid chromatograph were used. Phase A was water (containing 0.1% trifluoroacetic acid), and phase B was acetonitrile (containing 0.1% trifluoroacetic acid). The gradient was as follows: 0-2 min, phase B 10%; 2-10 min, phase B changed from 10% to 90%; 10-20 min, phase B 90%; 20-25 min, phase B changed from 90% to 10%. The injection volume was 10 μL, and the flow rate was 1 mL / min. Retention time (R0) was determined. t )for: 99m Tc-DGAH-EDDA: 13.11 min.

[0054] b. Identification by thin-layer chromatography (TLC)

[0055] The development system is as follows: polyamide film as support, ammonium acetate (1 mol / L) / methanol = 2:1 (V / V) as developing solvent. Under this system, the R of each radioactive component... f The values ​​are shown in Table 1 below.

[0056] Table 1 Chromatographic results of each component of the complex (R f value)

[0057]

[0058] The radiochemical purity of the markers identified by both methods was greater than 90%.

[0059] 2. Determination of the lipid-water partition coefficient of the complex

[0060] Take 0.9 mL of pH 7.4 phosphate buffer (0.025 mol / L) into a 5 mL centrifuge tube, add 1 mL of n-octanol and 0.1 mL of [unclear - possibly a specific compound or solution] to the centrifuge tube. 99m Tc-DGAH-EDDA solution, capped, vortexed, and centrifuged for 5 min (5000 r / min). Then, 3 × 0.1 mL were taken from the organic phase and the aqueous phase respectively, and the radioactivity counts of the two phases were measured. The partition coefficient D (D = radioactivity of organic phase / radioactivity of aqueous phase) was calculated. This was repeated for three sets. The measured values ​​were... 99m The lipid-water partition coefficient (logD) of the Tc-DGAH-EDDA complex is -2.72±0.13, indicating that it is a hydrophilic substance.

[0061] 3. Stability determination of complexes

[0062] Will 99mThe radiochemical purity of the Tc-DGAH-EDDA complex was determined after being placed in mouse whole blood at room temperature and at 37°C for 8 hours. The results showed that the radiochemical purity was greater than 90% after being placed in mouse whole blood at room temperature and at 37°C for 8 hours, indicating that it has good in vitro stability.

[0063] 4. Biodistribution experiment of the complex in normal Kunming mice

[0064] 0.10 mL was injected into the tail vein of normal Kunming mice. 99m Tc-DGAH-EDDA labeled solution (approximately 3.7 × 10⁻⁶) 5 Bq), mice were anesthetized with isoflurane gas 2 hours after injection and then sacrificed. In addition, the PSMA inhibitor (2-PMPA) was used to... 99m The Tc-DGAH-EDDA inhibition experiment in mice was conducted as follows: 0.20 mL of physiological saline containing 500 μg 2-PMAP was injected via the tail vein, followed by an injection of 0.10 mL of the saline solution 30 min later. 99m Tc-DGAH-EDDA labeled solution (approximately 3.7 × 10⁻⁶) 5 Two hours after administration of Bq, mice were anesthetized with isoflurane gas and then euthanized. Relevant tissues and organs, including the heart, liver, spleen, lungs, kidneys, muscles, bones, stomach, large intestine, small intestine, and blood, were collected, cleaned, weighed, and their radioactivity counts were measured using a γ-counter. The percentage injection dose per gram (%ID / g) for each tissue was calculated. Five mice were included in each group. The results are shown in Table 2.

[0065] Table 2 99m Biodistribution (%ID / g) of Tc-DGAH-EDDA in normal Kunming mice 2 hours after injection.

[0066]

[0067] As can be seen from Table 2, the kidney is an organ with high PSMA expression. 99m Aside from a certain basal uptake in the kidneys, Tc-DGAH-EDDA is uptaken in very low amounts in other non-target organs.

[0068] 5. SPECT imaging of the complex in tumor-bearing mice

[0069] Tail vein injection from Balb / c mice bearing 22RV1 tumors 99m0.5 mL (approximately 37 MBq) of Tc-DGAH-EDDA solution was administered, followed by isoflurane gas anesthesia 2 hours later. Mice were then fixed in a prone position for SPECT / CT imaging of the control group. 0.20 mL of physiological saline containing 500 μg 2-PMAP was first injected via the tail vein into Balb / c mice bearing 22RV1 tumors, followed by a second injection of 0.50 mL 30 minutes later. 99m Tc-DGAH-EDDA labeled solution (approximately 3.7 × 10⁻⁶) 7 Two hours later, mice were anesthetized with isoflurane gas. The mice were then fixed in a prone position, and SPECT / CT imaging was performed on the inhibition group. SPECT imaging results showed that in the control group (see attached...) Figure 1 (As shown) 99m Tc-DGAH-EDDA showed significant uptake in tumors but very low uptake in other non-target tissues. In contrast, in the inhibition group (as shown in the appendix...) Figure 2 As shown, tumor uptake was significantly inhibited, indicating that its uptake in tumors is specific, suggesting that it can serve as a high-performance novel SPECT molecular probe targeting PSMA.

[0070] Although the present invention has been described in detail above with general description and specific embodiments, some modifications or improvements can be made to it based on the present invention, which will be obvious to those skilled in the art. Therefore, any modifications or improvements made without departing from the spirit of this invention, such as changing different linkers, like D-aspartic acid and other amino acids, peptide chains, polyethylene glycol (PEG) chains, aliphatic chains, etc., or radioactive preparations obtained by radiolabeling with coligands such as Tricine and sodium triphenylphosphine tris(m-sulfonate) (TPPTS), Tricine and sodium diphenylphosphine-3-sulfonate (TPPMS), Tricine and disodium 3,3'-(phenylphosphinediyl)bis(phenyl-1-sulfonic acid) (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 glucohepanoate, Tricine and glucosamine, Tricine and mannitol, Tricine and diphenylphosphine benzoic acid, etc., are all within the scope of protection claimed by this invention.

Claims

1. A glutamic acid-urea dimer derivative containing an L-aspartic acid linker, characterized in that, The structural formula of the glutamic acid-urea dimer derivative containing the L-aspartic acid linker is (I): (I)。 2. A radioactive preparation, characterized in that, The radioactive agent is used 99m Tc, 99 Tc, 94m Tc, 94 Tc, 52 Mn, 186 Re or 188 The glutamic acid-urea dimer derivative containing an L-aspartic acid linker as described in claim 1, labeled with a Re radionuclide.

3. The radioactive agent according to claim 2, characterized in that, The structural formula of the radioactive agent is (II): (II).

4. The use of the radioactive agent according to any one of claims 2-3 in the preparation of a prostate cancer imaging agent.