L-proline-containing glutamate-urea dimer derivative and use thereof

Abstract

The present application relates to the field of radiopharmaceutical chemistry and clinical nuclear medicine technology, and particularly relates to a glutamic acid-urea dimer derivative containing L-proline and application thereof. A radioactive preparation obtained by labeling the glutamic acid-urea dimer derivative containing L-proline with a radionuclide has high uptake in tumors, has a good tumor / non-target ratio, specifically binds with prostate specific membrane antigen, and can be used as a new tumor radioactive drug with popularization and application value for prostate cancer diagnosis.

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 L-proline and its applications. Background Technology

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

[0003] Small molecule inhibitors containing glutamate-urea units can specifically bind to prostate-specific membrane antigen (PSMA), and radiolabeling them has become a research hotspot in international radiopharmaceuticals. 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 a suitable half-life (Tc). 1 / 2 The advantages of gamma single-photon emission energy (γ = 6.02h), inexpensive and readily available nuclide sources, abundant coordination valence states, kiteability, and reliable quality make it an ideal nuclide for the development of SPECT molecular probes. Therefore, the development of novel nuclides targeting PSMA is crucial. 99m Tc-based radiopharmaceuticals for tumors have significant clinical application value.

[0004] Increasing the number of targeting groups in radiolabeled molecules is a feasible strategy to further enhance probe accumulation within tumors. For example, […]. 68 [Ga]Ga-PSMA-D5([EuK]2-DOTA), compared with the monomer, effectively increased the absolute tumor uptake value and significantly improved the tumor-to-non-target 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 target group and the chelating group linked to the radionuclide, playing a crucial role in regulating the efficacy and pharmacokinetics of radiopharmaceuticals. Proline, as a linker, has significant positive implications for optimizing the pharmacokinetics of radiopharmaceutical probes, especially in reducing uptake by 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 MedChem 2024, 67(4), 3190-3202.). Based on the above background, this invention uses L-proline as a linker to synthesize derivatives containing two glutamate-urea targeting groups, and with the participation of other co-ligands, performs... 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 L-proline 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 L-proline and its applications, wherein the structural formula is (I):

[0008]

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

[0010] Preferably, among the above-mentioned L-proline-containing glutamic acid-urea dimer derivatives, when n=1, the structural formula of the L-proline-containing glutamic acid-urea dimer derivative is one of the following (II), and the corresponding derivative prepared from this derivative... 99mTc complexes specifically bind to PSMA. They exhibit low uptake in non-target organs, but high tumor uptake and tumor-to-non-target ratios, demonstrating excellent efficacy in the diagnosis and treatment of prostate cancer.

[0011]

[0012] The present invention also provides a radioactive preparation comprising the above-mentioned L-proline-containing glutamic acid-urea dimer derivative labeled with a radionuclide and its application.

[0013] Preferably, in the above-mentioned radioactive preparation, the radionuclide portion is a metallic radionuclide.

[0014] 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.

[0015] Most preferably, in the above-mentioned radioactive agent, 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 higher.

[0018] The present invention also provides the use of the above-mentioned radioactive agents in the preparation of radiopharmaceuticals for tumors.

[0019] The beneficial effects of this invention are as follows: This invention provides a glutamic acid-urea dimer derivative containing L-proline 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

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

[0021] Appendix Figure 2 : After injecting the PSMA inhibitor 2-PMPA 30 minutes in advance, 99m SPECT imaging of the inhibition group of Tc-DELH-EDDA injected into Balb / c model mice bearing 22Rv1 tumors 2 h later. Detailed Implementation

[0022] This invention provides an L-proline-containing glutamic acid-urea dimer derivative and its applications. In a preferred embodiment, this invention provides a general structural formula of [structure not specified]. 99m Radioactive preparations of Tc-DELH-EDDA:

[0023]

[0024] In the formula, 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), and 80% hydrazine hydrate was added. The mixture was refluxed and stirred for 4 hours, cooled to room temperature, and the precipitate was filtered. The filter cake was washed and dried under vacuum to obtain compound 2. Compound 2 and di-tert-butyl dicarbonate were then reacted... Compound 3 was obtained by dissolving dicarbonate in N,N-dimethylformamide (DMF) and stirring at room temperature for 12 h, followed by column chromatography purification. Compound 3, L-proline (L-Pro), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), and triethylamine (TEA) were dissolved in DMF and stirred at room temperature for 12 h, followed by column chromatography purification to obtain compound 4. An appropriate amount of L-glutamic acid di-tert-butyl hydrochloride (compound 5) was weighed into a round-bottom flask, dissolved in dichloromethane (DCM), and then triphosgene, N-E-benzyloxycarbonyl-L-lysine tert-butyl hydrochloride (H-Lys(Z)-OtBu.HCl), and T... Compound 6 was obtained by reacting EA at room temperature for 4 h and then purified by column chromatography. Compound 6 was dissolved in methanol (MeOH) and reduced with palladium on 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 and stirred at room temperature for 12 h, then 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, compound 9, HATU, and TEA were dissolved in DMF and stirred at room temperature for 12 h, then purified by column chromatography to obtain compound 10. Compound 10 was dissolved in DCM, and an equal volume of trifluoroacetic acid (TFA) was added. The mixture was reacted at room temperature for 3 h and purified by column chromatography to obtain the final product DELH.

[0028] The specific synthesis route is as follows:

[0029]

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

[0031] Weigh out N-tris(hydroxymethyl)methylglycine (Tricine) and ethylenediamine-N,N'-diacetic acid (EDDA) and dissolve them in physiological saline. Add succinate buffer (pH 7.0), adjust the pH of the solution to 7.0-8.0 with NaOH, and then add the ligand DELH, SnCl2·2H2O, and freshly rinsed NaOH sequentially. 99m TcO4 was reacted at 100℃ for 20-30 minutes to obtain the aforementioned product. 99m Tc-DELH-EDDA complex.

[0032] Prepared by the above method 99m The Tc-DELH-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.

[0033] 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.

[0034] The present invention is described in detail below through embodiments: a 99m Tc-labeled L-proline-containing glutamate-urea dimer derivatives can be used for SPECT / CT imaging targeting PSMA, and their general structural formula is: 99m Tc-DELH-EDDA.

[0035]

[0036] In the formula, n = 1.

[0037] The preparation methods are as follows, but are not limited to the exemplified complexes:

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

[0039] Synthesis of a.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, 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%). 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), 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).

[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), and TEA (0.41 mL, 2.96 mmol) 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 = 20 / 1 (v / v)], finally yielding a pale yellow solid, which was 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. Triphosgene (2.0 g, 6.74 mmol) was weighed into a round-bottom flask, dissolved in 20 mL of DCM, followed by Compound 5 (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)], yielding an oily substance, which was 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. Compound 6 (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 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. (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) were weighed into a round-bottom flask, dissolved in 15 mL of DMF, followed by the addition of TEA (1.3 mL, 9.35 mmol). The reaction was carried out at room temperature for 12 h, and the reaction progress was monitored by TLC. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography [DCM / MeOH = 80 / 1 (v / v)], yielding a colorless oily substance, which was 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. Compound 8 (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 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. Compound 4 (50 mg, 0.14 mmol), HATU (60.84 mg, 0.16 mmol), and Compound 9 (168.3 mg, 0.16 mmol) were weighed into a round-bottom flask, dissolved in 5 mL of DMF, and then TEA (29.19 μL, 0.21 mmol) was added. The reaction was carried out at room temperature for 12 h, and the reaction progress was monitored by TLC. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography [DCM / MeOH = 30 / 1 (v / v)] to give a colorless oily substance, which was 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. Compound 10 (50 mg, 0.04 mmol) was weighed and dissolved in 2 mL of DCM, then 2 mL of LTFA was added. The reaction was carried out at room temperature for 3 h, and the reaction progress was monitored by TLC. 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 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 as follows:

[0050]

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

[0052] 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 DELH, 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-DELH-EDDA complex.

[0053]

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

[0055] 1. Identification of coordination compounds

[0056] a. Identification by high performance liquid chromatography (HPLC):

[0057] 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-DELH-EDDA: 13.34 min.

[0058] b. Identification by thin-layer chromatography (TLC):

[0059] 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.

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

[0061]

[0062] The radiochemical purity of the markers identified by both methods is greater than 90%.

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

[0064] 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-DELH-EDDA solution, capped, vortexed, and centrifuged for 5 min (5000 r / min). Then, 3 × 0.1 mL were taken from both the organic and aqueous phases, 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. 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. Stability determination of complexes

[0066] Will 99m The radiochemical purity of the Tc-DELH-EDDA complex was determined after being 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 being 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 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-DELH-EDDA inhibition experiment in mice was conducted as follows: 0.20 mL of physiological saline containing 500 μg 2-PMPA was injected via the tail vein, followed by an injection of 0.10 mL of saline solution 30 min later. 99m Tc-DELH-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, tumors, 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. Three mice were included in each group. The results are shown in Table 2.

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

[0070]

[0071] As can be seen from Table 2, 99m Tc-DELH-EDDA effectively inhibited both tumors and kidneys (where PSMA is highly expressed), with blockade rates of 95% and 73% in the kidneys and tumors, respectively, indicating its good targeting ability to PSMA.

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

[0073] Tail vein injection in Balb / c model mice bearing 22Rv1 tumors 99m 0.5 mL of Tc-DELH-EDDA 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 for SPECT / CT imaging of the control group. First, 0.20 mL of physiological saline containing 500 μg 2-PMPA was injected via the tail vein into the Balb / c model mice bearing 22Rv1 tumors. Thirty minutes later, 0.50 mL of saline solution was injected. 99m Tc-DELH-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-DELH-EDDA showed significant accumulation in tumors and exhibited good tumor-retention effects, while uptake by other non-target tissues was very low. However, 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.

[0074] 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-proline 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 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 0 or 1.

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

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

4. The radioactive agent according to claim 3, characterized in that, The structural formula of the radioactive agent is (II): In the formula, n represents 0 or 1.

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

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