PSMA-targeted radiometal complexes containing nitroaromatic heterocyclic groups and their preparation

Abstract

The present invention discloses a PSMA-targeted radiometal complex containing a nitroaromatic heterocyclic group and its preparation, which belongs to the technical fields of radiopharmaceuticals and medical imaging. The general formula of the PSMA-targeted radiometal complex containing a nitroaromatic heterocyclic group of the present invention is shown in Formula I and Formula II. The present invention is the first to link both a nitroaromatic group and a PSMA-targeting group to a metal chelator (such as HBED-CC, DOTA, DOTA(GA)2, NOTA, AAZTA, etc.) and to target a radiometal nuclide, e.g. 68 Ga, 18 F-AlF, 177 Lu, 90 Y, 44 Sc, 225 Ac, 212 Pb, 213 The radioactive metal marker is labeled with Bi, etc. The synergistic effect of the nitroaromatic heterocyclic group in vivo is expected to increase the uptake of the radioactive metal marker by prostate cancer, promoting metabolism in non-target organs and improving the therapeutic efficacy of radiopharmaceuticals against tumors. JPEG2026508753000106.jpg2835JPEG2026508753000107.jpg2145 (wherein the R1 and R2 groups are nitroaromatic heterocyclic groups; L2 is a linking group between the R1 group and L1, where L1 is a linking group between the chelator and the structure PSMA targeting structure; L4 is a linking group between the R2 group and L3, where L3 is a linking group between the chelator and the structure PSMA targeting structure; and ChelatoR1 and ChelatoR2 are chelators or chelating structures.)

Description

[Technical Field]

[0001] The present invention relates to PSMA-targeted radiometal complexes containing nitroaromatic heterocyclic groups and their preparation, which belong to the technical fields of radiopharmaceuticals and medical imaging. [Background technology]

[0002] Prostate cancer (PCa) is one of the most common malignant tumors in the male genitourinary system. While early-stage prostate cancer can be cured with radical prostatectomy, prostate cancer is highly susceptible to systemic metastasis. By the time of diagnosis, 60–80% of patients have already progressed to late-stage disease and metastasized. Therefore, early diagnosis of prostate cancer is crucial. Existing conventional diagnostic methods include serum prostate-specific antigen (PSA) level screening, transrectal prostate ultrasound, pelvic MRI, and prostate needle biopsy. However, these conventional diagnostic methods are invasive and uncertain, making early and accurate diagnosis difficult. Compared to conventional diagnostic methods, modern nuclear medicine offers the advantages of precision and minute amounts. Radionuclide-labeled probe molecules can specifically identify and accumulate at the lesion site. By adjusting the type of nuclide used, the treatment of oncological diseases can be achieved synergistically, realizing early and accurate diagnosis of cancer and providing patients with more appropriate individualized treatment plans.

[0003] Prostate-specific membrane antigen (PSMA) is currently an ideal target in the clinical treatment of prostate cancer. It is selectively overexpressed on the surface of prostate cancer cells and in lymph node and bone metastases, and its expression level in cancer cells is 100-1000 times higher than in normal tissues. PSMA is expressed at almost all stages of prostate cancer, and its expression level significantly correlates with disease progression, providing a reliable criterion for tumor grading and pathological staging. Furthermore, the transmembrane structure of PSMA allows internalization after binding to target molecules, contributing to the high intracellular accumulation of targeted drugs, making it highly attractive for targeted tumor therapy.

[0004] The Glu-Urea-Lys (GUL) structure is the main unit of PSMA targeting agents. Various PSMA-targeting molecular probes based on the Glu-Urea-Lys (GUL) structure have been developed. Among them, [ 68 Ga]Ga-HBED-CC-PSMA-11([ 68 [Ga]Ga-PSMA-11) is currently the most widely used PSMA-targeted small molecule PET probe for PET imaging of prostate cancer and received marketing approval from the US Food and Drug Administration (FDA) on December 1, 2020. 68 [Ga]Ga-HBED-CC-PSMA-11 can rapidly and efficiently label PSMA-positive cells, has high affinity for PSMA-positive cells in in vitro cell experiments, and exhibits high tumor uptake, low liver accumulation, and a faster blood clearance rate in vivo, but is primarily metabolized via the urinary tract and is relatively highly uptaken by the kidney and bladder. 68 Ga]Ga-HBED-CC-PSMA-093([ 68 Ga]Ga-PSMA-093) 68This is a very promising probe molecule following [Ga]Ga-HBED-CC-PSMA-11, and was published in 2017 by Kung, Hank F. et al. (Patent title: Urea-Based Prostate Specific Membrane Antigen (PSMA) Inhibitors for Imaging and Therapy, Patent number: EP33979) 68 B1), which is currently undergoing Phase II / III clinical trials. 68 Ga]Ga-HBED-CC-PSMA-093 68 It has the same pharmacophore and bifunctional chelator as [Ga]Ga-HBED-CC-PSMA-11, and the addition of O-(carboxymethyl)-L-tyrosine as a linker improves tumor uptake, thereby addressing the issues of high bladder uptake, which is disadvantageous for primary prostate cancer lesions, and poor imaging of local recurrences. 68 The problem of Ga]Ga-HBED-CC-PSMA-11 is improved.

[0005] On the other hand, the bifunctional chelator of HBED-CC-PSMA-11 ligand is HBED-CC, which is not suitable for therapeutic metal nuclide labeling (e.g., Lu-177), and cannot meet the needs of clinical radioactive targeted therapy. Based on this, Benesova, M. et al. have developed a novel radioactive therapeutic agent targeting prostate cancer [ 177 Lu]Lu-DOTA-PSMA-617([ 177 We designed a complex ([Lu]Lu-PSMA-617). This molecule maintains the original pharmacophore GUL, but replaces the bifunctional chelator with DOTA. 68 Ga and 177 Both Lu and PSMA-617 can be simultaneously labeled. Metal nuclide-labeled PSMA-617 prolongs tumor uptake and promotes renal clearance, making this probe more suitable for clinical targeted therapy of prostate cancer. March 2022, [ 177 Lu]Lu-PSMA-617 has received FDA approval for the treatment of PSMA-positive prostate cancer.

[0006] Prostate cancer is a solid tumor. Ideally, a PSMA-targeted radiopharmaceutical should achieve high tumor uptake, low uptake in non-target tissues, or rapid clearance from non-target tissues after injection. 68 Ga]Ga-PSMA-11 and [ 177 Lu]Lu-PSMA-617 has received FDA marketing approval and 68 Ga]Ga-PSMA-093 is in Phase II / III clinical studies, but both have drawbacks. 68 Ga]Ga-PSMA-11 and [ 68 Ga]Ga-PSMA-093 is limited to diagnostic PET imaging and [ 177 Lu]Lu-PSMA-617 needs to be increased in tumor uptake as a therapeutic agent.

[0007] Therefore, modifying the structure of compounds to provide novel PSMA-targeting radiometal ligands and their complexes containing nitroaromatic heterocyclic groups, improving their in vivo metabolic properties, and thereby enhancing the uptake and retention of target molecules in tumors, is an important means for discovering new radionuclide drugs with excellent properties for oncology treatment. Summary of the Invention [Problem to be solved by the invention]

[0008] One of the objectives of the present invention is to provide novel PSMA-targeting radiometal ligands containing a nitroaromatic heterocyclic group and their complexes, which show high affinity and specificity for prostate-specific membrane antigen (PSMA), and the introduction of the nitroaromatic heterocyclic group can improve the retention of the complex in target tissues and increase the uptake of the target molecule into tumors, making them promising compounds for targeting the prostate-specific membrane antigen receptor. [Means for solving the problem]

[0009] The above object of the present invention is achieved by the following technical solutions.

[0010] Technical solution 1: PSMA-targeting radiometallic ligands and complexes thereof containing a nitroaromatic heterocyclic group whose general formula is shown in Formula I: JPEG2026508753000002.jpg2536 (wherein ChelatoR1 is a chelating group or a chelating structure of a chelating radionuclide, and is any one selected from the following: JPEG2026508753000003.jpg1660JPEG2026508753000004.jpg1542JPEG2026508753000005.jpg1543JPEG2026508753000006.jpg1834JPEG2026508753000007.jpg1643Here, M is 68 Ga, 18 F-AlF, 177 Lu, 90 Y, 44 Sc, 225 Ac, 212 Pb, 213 These include, but are not limited to, Bi, etc. R1 is a nitroaromatic heterocyclic group selected from the following: JPEG2026508753000008.jpg1476JPEG2026508753000009.jpg1472L1 is a linking group between ChelatoR1 and the PSMA targeting group and is any one selected from the following: JPEG2026508753000010.jpg5390L2 is a linking group between ChelatoR1 and the R1 group, and is one selected from the following: JPEG2026508753000011.jpg2364 where n is an integer between 0 and 6.

[0011] Technical solution 2: PSMA-targeting radiometallic ligands containing a nitroaromatic heterocyclic group and complexes thereof, the general formula of which is shown in Formula II. JPEG2026508753000012.jpg2351 (wherein Chelator2 is a chelating group or a chelating structure of a chelating radionuclide, and is any one selected from the following: JPEG2026508753000013.jpg1966JPEG2026508753000014.jpg2049JPEG2026508753000015.jpg2134Here, M is 68 Ga, 18 F-AlF, 177 Lu, 90 Y, 44 Sc, 225 Ac, 212 Pb, 213 These include, but are not limited to, Bi, etc. R2 is a nitroaromatic heterocyclic group selected from the following: JPEG2026508753000016.jpg1476JPEG2026508753000017.jpg1472L3 is a linking group between Chelator2 and the PSMA targeting group, and is selected from: JPEG2026508753000018.jpg5385L4 is a linking group between Chelator2 and the R2 group, and is one selected from the following: JPEG2026508753000019.jpg2364 where n is an integer between 0 and 6.

[0012] Another object of the present invention is to provide a method for preparing novel PSMA-targeted radiometal complexes containing the above-mentioned nitroaromatic heterocyclic groups.

[0013] The above object of the present invention is achieved by the following technical solutions.

[0014] Technical solution 1: Preparation of a PSMA-targeted radiometal complex containing a nitroaromatic heterocyclic group (shown in general formula I), the steps of which are as follows: (1) Triphosgene was dissolved in dichloromethane, and N(ε)-benzyloxycarbonyl-L-lysine tert-butyl ester hydrochloride (H-Lys(Z)-Ot-Bu HCl) dissolved in dichloromethane and triethylamine were slowly added dropwise to the above solution. L-glutamic acid di-tert-butyl ester hydrochloride and triethylamine dissolved in dichloromethane were slowly added dropwise to the above solution. The reaction mixture was stirred at room temperature to react, and the mixture was distilled under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1, v / v) to obtain a colorless oily product. The colorless oily product was dissolved in tetrahydrofuran and 10% Pd / C was added, and the mixture was stirred under a hydrogen atmosphere at room temperature to react. The resulting reaction solution was suction filtered through diatomaceous earth, and the filtrate was rotary evaporated under reduced pressure to remove the solvent, yielding a brown oily compound, Lys(t-Bu)-CO-Glu(t-Bu)2. Lys(t-Bu)-CO-Glu(t-Bu)2 and Cbz-L1-NH2 were dissolved in anhydrous DMF, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate and N,N'-diisopropylethylamine were added under an ice bath. The reaction was allowed to proceed at room temperature, and the mixture was separated and purified overnight to yield a pale yellow oily compound. The resulting pale yellow oily compound was dissolved in methanol, Pd / C powder was added, and the mixture was reduced under a hydrogen atmosphere overnight to yield NH2-L1-Lys(t-Bu)-CO-Glu(t-Bu)2. (2) (S)-4-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxovaleric acid was dissolved in ultra-dry N,N-dimethylformamide, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate and N,N'-diisopropylethylamine were added under ice bath conditions. The mixture was stirred in an ice bath, and then R1-L2-NH2 was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with ethyl acetate and saturated brine, and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was filtered to remove the anhydrous sodium sulfate. The filtrate was subjected to rotary evaporation under reduced pressure to remove the solvent. The resulting mixture was purified by silica gel column chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v=25 / 1 / 0.1) to give a pale yellow solid. The resulting pale yellow solid was dissolved in trifluoroacetic acid, stirred at room temperature, and distilled under reduced pressure to give a pale yellow solid compound. The resulting pale yellow solid compound was then purified by ultra-dry N,N-dimethylformamide. The reaction mixture was dissolved in formamide, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate and N,N'-diisopropylethylamine were added under ice bath conditions. The mixture was stirred in an ice bath, and NH2-L1-Lys(t-Bu)-CO-Glu(t-Bu)2 dissolved in ultra-dry N,N-dimethylformamide was added to the reaction mixture. The mixture was reacted at room temperature overnight. The reaction mixture was washed with ethyl acetate and saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, and filtered to obtain a pure methylcellulose. The aqueous sodium sulfate was removed, and the filtrate was subjected to rotary evaporation under reduced pressure to remove the solvent. The residue was purified by high-performance chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v=15 / 1 / 0.1) to obtain a pale yellow solid compound. The obtained pale yellow solid compound was dissolved in dichloromethane, and diethylamine was added dropwise. The mixture was stirred at room temperature and then subjected to rotary evaporation under reduced pressure to remove the solvent to obtain R1-L2-NH-L1-Lys(t-Bu)-CO-Glu(t-Bu)2. JPEG2026508753000020.jpg2338(3) The chelating agent HBED-CC, AAZTA, DOTA, or NOTA was dissolved in anhydrous DMF, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate and N,N'-diisopropylethylamine were added in an ice bath. The mixture was stirred in an ice bath, and then R1-L2-NH-L1-Lys(t-Bu)-CO-Glu(t-Bu)2 obtained in step (2) was added. The mixture was stirred at room temperature overnight and then purified by silica gel column chromatography. The resulting R1-L2-NH-L1(chelatoR1)-Lys(t-Bu)-CO-Glu(t-Bu)2 was dissolved in trifluoroacetic acid, stirred at room temperature, and evaporated under reduced pressure to remove the solvent. The resulting solution was purified by semi-preparative HPLC to obtain the labeled ligand R1-L2-NH-L1(chelatoR1)-Lys-CO-Glu, shown in Structure-1. (4) The labeled ligand obtained in step (3) is dissolved in a sodium acetate buffer solution, and the solution is 68 Ga]GaCL3 or [ 177 A solution of the radionuclide containing [Lu]LuCL3 is added and reacted under heating conditions for 5-15 min to obtain the corresponding radiometal complex shown in structure I-2.

[0015] Technical solution 2: Preparation of a PSMA-targeted radiometal complex containing a nitroaromatic heterocyclic group (shown in general formula II), the steps of which are as follows: (1) Triphosgene was dissolved in dichloromethane, and N(ε)-benzyloxycarbonyl-L-lysine tert-butyl ester hydrochloride (H-Lys(Z)-Ot-Bu HCl) dissolved in dichloromethane and triethylamine were slowly added dropwise to the above solution. L-glutamic acid di-tert-butyl ester hydrochloride and triethylamine dissolved in dichloromethane were slowly added dropwise to the above solution. The reaction mixture was stirred at room temperature to react, and the mixture was distilled under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1, v / v) to obtain a colorless oily product. The colorless oily product was dissolved in tetrahydrofuran and 10% Pd / C was added, and the mixture was stirred under a hydrogen atmosphere at room temperature to react. The resulting reaction solution was suction filtered through diatomaceous earth, and the filtrate was subjected to rotary evaporation under reduced pressure to remove the solvent, yielding a brown oily compound, Lys(t-Bu)-CO-Glu(t-Bu)2. Lys(t-Bu)-CO-Glu(t-Bu)2 and Cbz-L3-NH2 were dissolved in anhydrous DMF, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate and N,N'-diisopropylethylamine were added in an ice bath. The reaction was allowed to proceed at room temperature overnight, and the compound was separated and purified to yield a pale yellow oily compound. The resulting pale yellow oily compound was dissolved in methanol, and Pd / C powder was added. The mixture was reduced under a hydrogen atmosphere overnight to yield NH2-L3-Lys(t-Bu)-CO-Glu(t-Bu)2. (2) The chelating agent HBED-CC, AAZTA, DOTA, or NOTA was dissolved in anhydrous DMF, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate and N,N'-diisopropylethylamine were added under ice bath conditions. The mixture was stirred in an ice bath, and then R2-L4-NH2 was added. The reaction mixture was stirred at room temperature overnight, washed with ethyl acetate and saturated brine, and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was filtered to remove the anhydrous sodium sulfate. The filtrate was subjected to rotary evaporation under reduced pressure to remove the solvent. After that, the chelating agent R2-L4-NH-ChelatoR2 was purified by silica gel column chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v=90 / 10 / 0.1) to obtain a pale yellow solid. 4-NH-(ChelatoR2) was dissolved in anhydrous DMF, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate and N,N'-diisopropylethylamine were added under ice bath conditions. The mixture was stirred in an ice bath, and then NH2-L3-Lys(t-Bu)-CO-Glu(t-Bu)2 obtained in step (1) was added, followed by R2-L4-NH2. The reaction mixture was stirred at room temperature overnight, washed with ethyl acetate and saturated brine, and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was filtered to remove the anhydrous sodium sulfate. The filtrate was rotary evaporated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v=90 / 10 / 0.1) to give a pale oily liquid. R2-L4-NH-ChelatoR2-NH-L3-Lys(t-Bu)-CO-Glu(t-Bu)2 was obtained, and the obtained R2-L4-NH-ChelatoR2-NH-L3-Lys(t-Bu)-CO-Glu(t-Bu)2 was dissolved in trifluoroacetic acid, stirred at room temperature, distilled under reduced pressure to remove the solvent, and purified by semi-preparative HPLC to obtain the labeled ligand R2-L4-NH-ChelatoR2-NH-L3-Lys-CO-Glu shown in Structure II-1. (4) The labeled ligand obtained in step (3) is dissolved in a sodium acetate buffer solution, and the solution is 68 Ga]GaCL3 or [ 177A solution of the radionuclide containing Lu]LuCL3 is added and reacted under heating conditions for 5-15 minutes to obtain the corresponding radiometal complex shown in structure II-2. [Effects of the Invention]

[0016] The novel radiometal ligands containing nitroaromatic heterocyclic groups of the present invention targeting PSMA can be labeled with various radionuclides. The prepared radiometal complexes have high affinity and specificity for prostate-specific membrane antigen (PSMA). The introduction of nitroaromatic heterocyclic groups can improve the retention of the complexes in target tissues and increase the uptake of target molecules into tumors. These compounds are promising compounds for targeting the prostate-specific membrane antigen receptor.

[0017] The present invention will be further described below with reference to the drawings and specific embodiments, which do not limit the protection scope of the present invention. [Brief explanation of the drawings]

[0018] [Figure 1] 1 shows the radioactive HPLC spectrum of the [68Ga]Ga-HBED-CC-NI-PSMA labeling reaction solution prepared in Example 1 of the present invention. [Figure 2] 1 shows the radioactive HPLC spectrum of the [68Ga]Ga-AAZTA-NI-PSMA labeling reaction solution prepared in Example 2 of the present invention. [Figure 3] 1 shows the radioactive HPLC spectrum of the [68Ga]Ga-DOTA-NI-PSMA labeling reaction solution prepared in Example 3 of the present invention. [Figure 4] 1 shows the radioactive HPLC spectrum of the [68Ga]Ga-HBED-CC-NI-PSMA-11 labeling reaction solution prepared in Example 4 of the present invention. [Figure 5] 1 shows the radioactive HPLC spectrum of the [68Ga]Ga-AAZTA-NI-PSMA-11 labeling reaction solution prepared in Example 5 of the present invention. [Figure 6]1 shows the radioactive HPLC spectrum of the [68Ga]Ga-DOTA-NI-PSMA-11 labeling reaction solution prepared in Example 6 of the present invention. [Figure 7] 1 shows the radioactive HPLC spectrum of the labeling reaction solution of [68Ga]Ga-AAZTA-NI-PSMA-093 prepared in Example 7 of the present invention. [Figure 8] 1 shows the radioactive HPLC spectrum of the [68Ga]Ga-NI-HBED-CC-PSMA-11 labeling reaction solution prepared in Example 8 of the present invention. [Figure 9] 1 shows the radioactive HPLC spectrum of the [68Ga]Ga-NI-DOTAGA2-PSMA-11 labeling reaction solution prepared in Example 9 of the present invention. [Figure 10] 1 shows the radioactive HPLC spectrum of the labeling reaction solution of [68Ga]Ga-NI-HBED-CC-PSMA-093 prepared in Example 10 of the present invention. [Figure 11] 1 shows the radioactive HPLC spectrum of the [68Ga]Ga-NI-DOTAGA2-PSMA-093 labeling reaction solution prepared in Example 11 of the present invention. [Figure 12] In Example 1 of the present invention, this shows the uptake-time curves (n=3) of [68Ga]Ga-AAZTA-NI-PSMA, [68Ga]Ga-AAZTA-NI-PSMA-11, and [68Ga]Ga-HBED-CC-PSMA-11 taken up by 22RV1-FOLH1-oe cells in vitro. [Figure 13] FIG. 1 shows the specific binding of [68Ga]Ga-AAZTA-NI-PSMA, [68Ga]Ga-AAZTA-NI-PSMA-11, and [68Ga]Ga-HBED-CC-PSMA-11 to the prostate-specific membrane antigen receptor (n=3) as analyzed by in vitro 22RV1-FOLH1-oe cell uptake experiments in Example 1 of the present invention. [Figure 14]1 shows the uptake-time curves (n=3) of [68Ga]Ga-AAZTA-NI-PSMA, [68Ga]Ga-DOTA-NI-PSMA, [68Ga]Ga-HBED-CC-NI-PSMA, and [68Ga]Ga-HBED-CC-PSMA-11 taken up by 22RV1-FOLH1-oe cells in vitro in Example 2 of the present invention. [Figure 15] FIG. 10 shows the specific binding of [68Ga]Ga-AAZTA-NI-PSMA, [68Ga]Ga-DOTA-NI-PSMA, [68Ga]Ga-HBED-CC-NI-PSMA, and [68Ga]Ga-HBED-CC-PSMA-11 to the prostate-specific membrane antigen receptor, analyzed by an in vitro 22RV1-FOLH1-oe cell uptake experiment in Example 2 of the present invention (n=3). [Figure 16] This is an uptake-time curve (n=3) of [68Ga]Ga-AAZTA-NI-PSMA-093 and [68Ga]Ga-HBED-CC-PSMA-11 taken up by 22RV1-FOLH1-oe cells in vitro in Example 3 of the present invention. [Figure 17] FIG. 1 shows the specific binding of [68Ga]Ga-AAZTA-NI-PSMA-093 and [68Ga]Ga-HBED-CC-PSMA-11 to the prostate-specific membrane antigen receptor (PSMA) in vitro (n=3) as analyzed by uptake experiments in 22RV1-FOLH1-oe cells in Example 3 of the present invention. [Figure 18] 1 shows the uptake-time curves (n=3) of [68Ga]Ga-NI-HBED-CC-PSMA-11, [68Ga]Ga-HBED-CC-PSMA-11, [68Ga]Ga-NI-HBED-CC-PSMA-093, and [68Ga]Ga-HBED-CC-PSMA-093 taken up by 22RV1-FOLH1-oe cells in vitro in Example 4 of the present invention. [Figure 19]FIG. 10 shows the specific binding of [68Ga]Ga-NI-HBED-CC-PSMA-11, [68Ga]Ga-HBED-CC-PSMA-11, [68Ga]Ga-NI-HBED-CC-PSMA-093, and [68Ga]Ga-HBED-CC-PSMA-093 to prostate-specific membrane antigen receptors (n=3) as analyzed by in vitro 22RV1-FOLH1-oe cell uptake experiments in Example 4 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0019] Unless otherwise specified, the raw materials and reagents referred to in the examples of the present invention are conventional raw materials and reagents available on the market, the test methods used are all conventional methods used in the relevant field, and the instruments and devices used are conventional instruments and devices in the relevant field.

[0020] Example 1: 68 Preparation of [Ga]GaHBED-CC-NI-PSMA Step 1: Synthesis of PSMA-targeting radioligand HBED-CC-NI-PSMA containing a nitroaromatic heterocyclic group: The synthetic route is as follows: JPEG2026508753000021.jpg1963JPEG2026508753000022.jpg1878JPEG2026508753000023.jpg2473JPEG2026508753000024.jpg2185Specifically, it includes the following steps. (1) Synthesis of Compound 1 Triphosgene (1.20 g, 4.03 mmol) was dissolved in 10 mL of dichloromethane and stirred at -20 °C for 20 min to give N(ε)-benzyloxycarbonyl-L-lysine tert-butyl ester hydrochloride (H-Lys(Z)-Ot-Bu) dissolved in 75 mL of dichloromethane. HCl, 4.47 g, 12.0 mmol) and triethylamine (2.80 mL, 2.04 g, 20.2 mmol) were slowly added dropwise to the above solution, and L-glutamic acid di-tert-butyl ester hydrochloride (Glu-Ot-Bu(Ot-Bu)HCl, 2.90 g, 9.83 mmol) and triethylamine (2.80 mL, 2.04 g, 20.2 mmol) dissolved in 50 mL of dichloromethane were slowly added dropwise to the above solution, and the reaction solution was stirred at room temperature for 18 hours, distilled under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to obtain a colorless oily product (3.04 g, 4.89 mmol) in a yield of 48.9%. The colorless oily product (2.25 g, 3.62 mmol) was dissolved in 20 mL of tetrahydrofuran, and 10% Pd / C (192 mg) was added. The mixture was stirred under a hydrogen atmosphere at room temperature for 12 hours. The resulting reaction solution was suction filtered through diatomaceous earth, and the filtrate was rotary evaporated under reduced pressure to remove the solvent, yielding brown oily compound 1 (1.20 g, 2.46 mmol) in a yield of 68.0%. Confirmation of the structure of compound 1: HRMS C 24 HC 46 N3O7[M+H] + Theoretical molecular weight: 488.3330, Measured molecular weight: 488.3334. 1HNMR(600 MHz, CDCL3) δ: 5.36 (t, 2H, J =7.8 Hz), 4.30 (dq, 2H, J =7.5, 5.3 Hz), 2.65 (t, 2H, J =6.9 Hz), 2.33-2.20 (m, 2H), 2.06-2.00 (m, 2H), 1.85-1.77 (m, 1H), 1.73 (ddt, 1H, J =13.5, 10.4, 5.3 Hz), 1.67 (s, 2H), 1.61-1.53 ​​(m, 1H), 1.42 (d, 18H, J =0.5 Hz), 1.39 (s, 9H), 1.33-1.26 (m, 1H). (2) Synthesis of Compound 2 2-Nitroimidazole (1.14 g, 10.09 mmol) was dissolved in 15 mL of ultra-dry N,N-dimethylformamide, anhydrous potassium carbonate (4.89 g, 35.38 mmol) was added, and the mixture was stirred at room temperature for 30 min. tert-Butyl N-(3-bromopropyl)carbamate (3.57 g, 14.99 mmol) dissolved in ultra-dry N,N-dimethylformamide (10 mL) was added to the reaction mixture. After stirring overnight at room temperature, the mixture was filtered through diatomaceous earth with suction. The filtrate was rotary evaporated under reduced pressure to remove most of the solvent. The residue was washed with ethyl acetate and saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 1 / 1) to give 2 (2.36 g, 8.74 mmol) as a yellow-green oil in 87% yield. Confirmation of the structure of compound 2: HRMS C 11 H 19 N4O4[M+H] + Theoretical molecular weight: 271.1400, measured molecular weight: 271.1408. 1 H NMR (600 MHz, CDCL3) δ 7.27 (s,1H), 7.14 (s,1H), 4.75 (s,1H), 4.46 (t, J=7.0 Hz,2H), 3.20 (t, J=6.2 Hz,2H), 2.08-2.01 (m,2H), 1.44 (s,9H). (3) Synthesis of Compound 3 Compound 2 (432 mg, 1.60 mmol) was dissolved in 4 mL of trifluoroacetic acid, stirred at room temperature for 30 min, and the solvent was removed by rotary evaporation under reduced pressure to obtain a white solid intermediate. (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxovaleric acid (1.5 g, 3.53 mmol) was dissolved in 10 mL of ultra-dry N,N-dimethylformamide, and the resulting mixture was stirred under ice bath with O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU, 1.61 g, 4.23 mmol) and N,N'-diisopropylethylamine (DI The resulting mixture was stirred in an ice bath for 25 minutes, and then the above white solid intermediate (603 mg, 3.55 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed five times with ethyl acetate and saturated brine, and the organic phase was collected and dried over anhydrous sodium sulfate. The filtrate was subjected to rotary evaporation under reduced pressure to remove the solvent. The resulting mixture was purified by silica gel column chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v=25 / 1 / 0.1) to give a pale yellow solid 3 (1.5 g, 2.60 mmol) in a 74% yield. Confirmation of the structure of compound 3: HRMS C 30 H 36 N5O7[M+H] + Theoretical molecular weight: 578.2609, Measured molecular weight: 578.2609. 1H NMR (400 MHz, CDCL3) δ 7.76 (d, J=7.6 Hz,2H), 7.59 (t, J=7.2 Hz,2H), 7.40 (t, J=7.5 Hz,2H), 7.35-7.28 (m,2H), 7.27 (s,1H), 7.09 (s,1H), 6.57 (s,1H), 5.65 (d, J=7.2 Hz,1H), 4.41 (dd, J=12.1, 7.0 Hz,4H), 4.21 (t, J=7.0 Hz,2H), 3.42-3.32 (m,1H), 3.31-3.21 (m,1H), 2.35-2.18 (m,3H), 2.10-1.99 (m,2H), 1.92-1.81 (m,1H), 1.47 (s,9H). (4) Synthesis of Compound 4 Compound 3 (602 mg, 1.04 mmol) was dissolved in 10 mL of dichloromethane, and diethylamine (2.49 g, 33.98 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours, and the solvent was removed by rotary evaporation under reduced pressure to obtain a pale yellow solid intermediate. Fmoc-L-phenylalanine (327 mg, 0.84 mmol) was dissolved in 3 mL of ultra-dry N,N-dimethylformamide, and the resulting mixture was mixed with O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU) (386 mg, 1.02 mmol) and N,N-diisopropyl methylcellulose in an ice bath. Diethylamine (DIPEA) (218 mg, 1.69 mmol) was added and stirred in an ice bath for 25 minutes. The pale yellow solid intermediate (300 mg, 0.84 mmol) dissolved in 3 mL of ultra-dry N,N-dimethylformamide was added to the above reaction solution, and the reaction solution was reacted at room temperature overnight. The reaction solution was washed five times with ethyl acetate and saturated brine, and the organic phase was collected and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated by rotary evaporation under reduced pressure to precipitate compound 4 (362 mg, 0.50 mmol) as a white solid in a 60% yield. Confirmation of the structure of compound 4: HRMS C 39 H 45 N6O8[M+H] + Theoretical molecular weight: 725.3298, measured molecular weight: 725.3300. 1H NMR (400 MHz, (CD3)2SO) δ 8.42 (d, J=7.3 Hz,1H), 7.97-7.77 (m,3H), 7.68 (s,1H), 7.66-7.56 (m,3H), 7.44-7.37 (m,2H), 7.36-7.31 (m,2H), 7.30-7.23 (m,4H), 7.22-7.15 (m,2H), 4.45-4.24 (m,3H), 4.23-3.97 (m,4H), 3.05 (dd, J=13.6, 8.7 Hz,3H), 2.78 (t, J=12.5 Hz,1H), 2.18 (t, J=7.4 Hz,2H), 2.05-1.94 (m,1H), 1.94-1.76 (m,3H), 1.40 (s,9H). (5) Synthesis of Compound 5 Compound 4 (500 mg, 0.69 mmol) was dissolved in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was removed by rotary evaporation under reduced pressure to obtain an orange-yellow oily intermediate. The intermediate (358 mg, 0.54 mmol) was dissolved in 4 mL of ultra-dry N,N-dimethylformamide, and HATU (240 mg, 0.63 mmol) and DIPEA (134 mg, 1.04 mmol) were added in an ice bath. The mixture was stirred in an ice bath for 30 minutes. The compound was dissolved in 3 mL of ultra-dry N,N-dimethylformamide. Compound 1 (276 mg, 0.57 mmol) was added to the above reaction solution and reacted overnight at room temperature. The reaction solution was washed five times with ethyl acetate and saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration. The filtrate was concentrated by rotary evaporation under reduced pressure and evaporated to remove the solvent. The residue was purified by high-performance purification chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v=15 / 1 / 0.1) to obtain pale yellow solid compound 5 (408 mg, 0.36 mmol) in a yield of 67%. Confirmation of the structure of compound 5: HRMS C 59 H 80 N9O 14 [M+H] + Theoretical molecular weight: 1138.5819, measured molecular weight: 1138.5824. 11H NMR (400 MHz, CDCL3) δ 7.90 (s, 1H), 7.73 (d, J = 7.4 Hz, 2H), 7.50 (d, J = 7.2 Hz, 2H), 7.37 (t, J = 7.3 Hz, 2H), 7.30 - 7.21 (m, 1H), 7.08 (d, J = 12.1 Hz, 1H), 6.97 (s, 1H), 5.79 (s, 1H), 5.29 (s, 1H), 4.54 - 4.29 (m, 6H), 4.27 - 4.09 (m, 3H), 3.43 - 2.90 (m, 6H), 2.30 (s, 4H), 2.18 - 1.92 (m, 6H), 1.91 - 1.75 (m, 1H), 1.74 - 1.54 (m, 2H), 1.46 - 1.37 (m, 27H), 1.25 (t, J = 7.1 Hz, 2H). (6) Synthesis of HBED-CC-NI-PSMA Compound 5 (191 mg, 0.17 mmol) was dissolved in 3 mL of dichloromethane, 1 mL of diethylamine was added, and the mixture was stirred at room temperature for 3 hours. The solvent was removed by rotary evaporation under reduced pressure to obtain a yellow oily intermediate. HBED-CC (39 mg, 0.06 mmol) was dissolved in 2 mL of ultra-dry N,N-dimethylformamide, and HATU (27.4 mg, 0.07 mmol) and DIPEA (15.51 mg, 0.12 mmol) were added in an ice bath. The mixture was stirred in an ice bath for 30 minutes, and then compound 5 (61.9 mg, 0.07 mmol) was dissolved in 2 mL of ultra-dry N,N-dimethylformamide. The reaction mixture was added to the above reaction mixture and allowed to react overnight at room temperature. The reaction mixture was washed five times with ethyl acetate and saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration. The filtrate was concentrated by rotary evaporation under reduced pressure and evaporated to remove the solvent. The resulting yellow oil was purified by high-performance liquid chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v = 9 / 1 / 0.1). The crude product was further deprotected using trifluoroacetic acid to obtain the HBED-CC-NI-PSMA. The crude product was purified by high-performance liquid chromatography. The semi-preparative chromatography column was an Eclipse XDB-C18, 5 μm column, 9.4 × 250 mm column. Separation conditions were: Phase A: 0.1% TFA in water; Phase B: 0.1% TFA in acetonitrile. Gradient: 0-12 min, 5% to 55% B; 12-13 min, 55% to 100% B; 13-16 min, 100% B; 16-17 min, 100% to 5% B; 17-20 min, 5% B. Flow rate: 4 mL / min. UV: 280 nm. The target compound was lyophilized to obtain the white solid compound HBED-CC-NI-PSMA. Confirmation of the structure of HBED-CC-NI-PSMA: HRMS C 58 H 77 N 11 O 21 [M+H] + Theoretical molecular weight: 1262.5211, measured molecular weight: 1262.5220. Step 2: Preparation of PSMA-targeting radioligand HBED-CC-NI-PSMA containing a nitroaromatic heterocyclic group 68 Ga label: 68The Ga labeling route is as follows: JPEG2026508753000025.jpg2184 Dissolve the HBED-CC-NI-PSMA obtained in step 1 in dimethyl sulfoxide to prepare a 1 μg / μL precursor solution. Transfer 4 μL of the precursor solution to a 10 mL vial, add 135 μL of 3 M sodium acetate solution, and rinse the germanium gallium generator (iThemba) with 6 mL of 0.6 M high-purity hydrochloric acid solution. 68 The radiochemical purity of the mixture was measured by high performance liquid chromatography equipped with a radioactivity detector. The radiochemical yield was found to be over 98%. 68 Ga]Ga HBED-CC-NI-PSMA was obtained. FIG. 1 shows the [ 68 The radioactive HPLC spectrum of the labeling reaction mixture of [Ga]Ga-HBED-CC-NI-PSMA is shown. 68 The radiochemical purity of Ga]Ga-HBED-CC-NI-PSMA was shown to be greater than 98%.

[0021] Example 2: 68 Preparation of [Ga]Ga-AAZTA-NI-PSMA Step 1: Synthesis of PSMA-targeting radioligand AAZTA-NI-PSMA containing a nitroaromatic heterocyclic group The synthetic route is as follows: JPEG2026508753000026.jpg2384Specifically, it includes the following steps. Synthesis of AAZTA-NI-PSMA Compound 5 (191 mg, 0.17 mmol) was dissolved in 3 mL of dichloromethane, 1 mL of diethylamine was added, and the mixture was stirred at room temperature for 3 hours. The solvent was removed by rotary evaporation under reduced pressure to obtain a yellow oily intermediate. AAZTA (41 mg, 0.06 mmol) was dissolved in 2 mL of ultra-dry N,N-dimethylformamide, and HATU (27.4 mg, 0.07 mmol) and DIPEA (15.51 mg, 0.12 mmol) were added in an ice bath. The mixture was stirred in an ice bath for 30 minutes, and the yellow oily intermediate (61.9 mg, 0.12 mmol) dissolved in 2 mL of ultra-dry N,N-dimethylformamide was obtained. 07 mmol) was added to the above reaction solution and reacted at room temperature overnight. The reaction solution was washed five times with ethyl acetate and saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate, filtered to remove the anhydrous sodium sulfate, and the filtrate was rotary evaporated under reduced pressure to remove the solvent. The resulting product was purified by high-performance liquid chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v=10 / 1 / 0.1) to obtain a yellow oily product, which was then deprotected with trifluoroacetic acid to obtain the crude AAZTA-NI-PSMA product, which was then purified by high-performance liquid chromatography. Semi-preparative chromatography column: Eclipse XDB-C18, 5 μm, 9.4 × 250 mm. Separation conditions: Phase A: 0.1% TFA water, Phase B: 0.1% TFA acetonitrile; Gradient: 0–16 min, 5%–41% B; 16–16.5 min, 41%–100% B; 16.5–20 min, 100% B; 20–20.5 min, 100%–5% B; 20.5–23 min, 5% B; Flow rate: 4 mL / min; UV: 280 nm. The target compound was lyophilized to obtain the white solid compound AAZTA-NI-PSMA. Confirmation of the structure of AAZTA-NI-PSMA: Purity was greater than 98% as determined by LC-MS. Step 2: Preparation of PSMA-targeting radioligand AAZTA-NI-PSMA containing a nitroaromatic heterocyclic group 68 Ga labeling 68 The Ga labeling route is as follows: JPEG2026508753000027.jpg1985 Dissolve the AAZTA-NI-PSMA obtained in step 1 in dimethyl sulfoxide to prepare a 1 μg / μL precursor solution. Transfer 10 μL of the precursor solution to a 10 mL vial, add 135 μL of 3 M sodium acetate solution, and rinse the germanium gallium generator (iThemba) with 6 mL of 0.6 M high-purity hydrochloric acid solution. 68 The radiochemical purity of the mixture was measured by high performance liquid chromatography equipped with a radioactivity detector. The radiochemical yield was found to be over 98%. 68 Ga]Ga AAZTA-NI-PSMA was obtained. FIG. 2 shows the [ 68 The radioactive HPLC spectrum of the labeling reaction of [Ga]Ga AAZTA-NI-PSMA is shown. 68 The radiochemical purity of Ga]Ga AAZTA-NI-PSMA was shown to be greater than 98%.

[0022] Example 3: 68 Preparation of [Ga]GaDOTA-NI-PSMA Step 1: Synthesis of PSMA-targeting radioligand DOTA-NI-PSMA containing a nitroaromatic heterocyclic group: The synthetic route is as follows: JPEG2026508753000028.jpg2273Synthesis of DOTA-NI-PSMA Compound 5 (191 mg, 0.17 mmol) was dissolved in 3 mL of dichloromethane, 1 mL of diethylamine was added, and the mixture was stirred at room temperature for 3 hours. The solvent was removed by rotary evaporation under reduced pressure to obtain a yellow oily intermediate. 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetate tri-tert-butyl (DOTA, 34.34 mg, 0.06 mmol) was dissolved in 2 mL of ultra-dry N,N-dimethylformamide, and HATU (29.66 mg, 0.08 mmol) and DIPEA (15.51 mg, 0.12 mmol) were added in an ice bath. The mixture was stirred in an ice bath for 30 minutes, and the resulting mixture was purified by ultra-dry N,N-dimethylformamide. The yellow oily intermediate (50 mg, 0.05 mmol) dissolved in 2 mL of HCl was added to the reaction mixture and allowed to react overnight at room temperature. The reaction mixture was washed five times with ethyl acetate and saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate. The solution was filtered to remove the anhydrous sodium sulfate. The filtrate was then rotary evaporated under reduced pressure to remove the solvent. The resulting yellow oil was purified by high-performance liquid chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v = 10 / 1 / 0.1) to give the crude DOTA-NI-PSMA. The crude product was then deprotected with trifluoroacetic acid and purified by high-performance liquid chromatography. The semi-preparative chromatography column was Eclipse XDB-C18, 5 μm, 9.4 × 250 mm. Separation conditions were: Phase A: 0.1% TFA in water, Phase B: 0.1% TFA in acetonitrile. Gradient: 0-15 min, 5%-100% B; 15-17 min, 100% B; 17-17.5 min, 100%-5% B; 17.5-20 min, 5% B. Flow rate: 4 mL / min. UV: 280 nm. The target component was lyophilized to obtain the white solid compound DOTA-NI-PSMA. Confirmation of the structure of DOTA-NI-PSMA: HRMS C 48 H 73 N 13 O 19 [M+H] + Theoretical molecular weight: 1134.5061, measured molecular weight: 1134.5046. Step 2: Preparation of PSMA-targeting radioligand DOTA-NI-PSMA containing a nitroaromatic heterocyclic group 68 Ga labeling 68The Ga labeling route is as follows: JPEG2026508753000029.jpg2386 Dissolve the DOTA-NI-PSMA obtained in step 1 in dimethyl sulfoxide to prepare a 1 μg / μL precursor solution. Transfer 17 μL of the precursor solution to a 10 mL vial, add 72 μL of 3 M sodium acetate solution, and rinse the germanium gallium generator (iThemba) with 6 mL of 0.6 M high-purity hydrochloric acid solution. 68 The radiochemical purity of the mixture was measured by high performance liquid chromatography equipped with a radioactivity detector. The radiochemical yield was found to be over 98%. 68 Ga]Ga DOTA-NI-PSMA was obtained. FIG. 3 shows the [ 68 The radioactive HPLC spectrum of the labeling reaction solution of [Ga]Ga DOTA-NI-PSMA is shown. 68 The radiochemical purity of Ga]Ga DOTA-NI-PSMA was shown to be greater than 98%.

[0023] Example 4: 68 Preparation of [Ga]GaHBED-CC-NI-PSMA-11 Step 1: Synthesis of PSMA-targeting radioligand HBED-CC-NI-PSMA-11 containing a nitroaromatic heterocyclic group The synthetic route is as follows: JPEG2026508753000030.jpg2187JPEG2026508753000031.jpg2184Specifically, it includes the following steps. (1) Synthesis of Compound 6 CBz-6 aminocaproic acid (356 mg, 1.34 mmol) was dissolved in 7 mL of ultra-dry N,N-dimethylformamide, and HATU (245 mg, 0.64 mmol) and DIPEA (150 mg, 1.16 mmol) were added under ice bath conditions. The mixture was stirred in an ice bath for 30 min. Compound 1 (259 mg, 0.53 mmol) dissolved in 5 mL of ultra-dry N,N-dimethylformamide was then added to the reaction mixture. The mixture was allowed to react at room temperature overnight. The reaction mixture was washed with saturated brine and ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v=1 / 3) to give a colorless oil, which was then reduced with hydrogen gas to give compound 6. Confirmation of the structure of compound 6: HRMS C 30 H 57 N4O8[M+H] + Theoretical molecular weight: 601.417; measured molecular weight: 601.4177. 1 H NMR (400 MHz, (CD3)2SO) δ 7.83-7.64 (m,1H), 6.30 (dd, J=16.2, 8.3 Hz,2H), 4.02 (dd, J=8.5, 5.3 Hz,1H), 3.94 (dd, J=13.5, 7.7 Hz,1H), 2.99 (dd, J=12.3, 5.5 Hz,4H), 2.52-2.46 (m,2H), 2.34-2.09 (m,3H), 2.01 (t, J=7.5 Hz,2H), 1.86 (ddd, J=20.7, 10.4, 6.2 Hz,1H), 1.72-1.44 (m,6H), 1.41-1.36 (m,27H), 1.31-1.13 (m,6H). (2) Synthesis of Compound 7 Compound 4 (500 mg, 0.69 mmol) was dissolved in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was removed by rotary evaporation under reduced pressure to obtain an orange-yellow oily intermediate. The orange-yellow oily intermediate (287 mg, 0.43 mmol) was dissolved in 3 mL of ultra-dry N,N-dimethylformamide, and HATU (183 mg, 0.48 mmol) and DIPEA (105 mg, 0.81 mmol) were added in an ice bath. The mixture was stirred in an ice bath for 30 minutes, and the ultra-dry N,N-dimethylformamide was used to obtain the orange-yellow oily intermediate. Compound 6 (240 mg, 0.40 mmol) dissolved in 3 mL of ethanol was added to the above reaction solution and reacted overnight at room temperature. The reaction solution was washed five times with ethyl acetate and saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration. The filtrate was subjected to rotary evaporation under reduced pressure to remove the solvent. The residue was purified by high-performance chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v, 10 / 1 / 0.1) to obtain pale yellow solid compound 7 (305 mg, 0.24 mmol) in a yield of 61%. Confirmation of the structure of compound 7: HRMS C 65 H 91 N 10 O 15 [M+H] + Theoretical molecular weight: 1251.6659, measured molecular weight: 1251.6666. 11H NMR (600 MHz, CDCL3) δ 7.85 (s, 1H), 7.74 (d, J = 7.6 Hz, 2H), 7.51 (d, J = 7.5 Hz, 2H), 7.37 (ddd, J = 7.6, 5.5, 2.0 Hz, 2H), 7.31 (s, 1H), 7.29 - 7.26 (m, 3H), 7.26 - 7.24 (m, 1H), 7.24 - 7.17 (m, 2H), 7.08 (s, 1H), 6.96 (s, 1H), 5.86 (d, J = 5.2 Hz, 1H), 4.54 - 4.44 (m, 2H), 4.44 - 4.38 (m, 3H), 4.37 - 4.28 (m, 2H), 4.23 - 4.10 (m, 2H), 3.37 - 3.23 (m, 3H), 3.22 - 3.11 (m, 4H), 3.08 - 3.00 (m, 1H), 2.36 - 2.26 (m, 4H), 2.22 (t, J = 6.3 Hz, 2H), 2.13 - 1.91 (m, 6H), 1.88 - 1.74 (m, 2H), 1.70 - 1.63 (m, 1H), 1.62 - 1.56 (m, 2H), 1.55 - 1.48 (m, 3H), 1.47 - 1.42 (m, 20H), 1.40 (s, 10H), 1.35 - 1.24 (m, 6H). (3) Synthesis of HBED-CC-NI-PSMA-11 Compound 7 (305 mg, 0.24 mmol) was dissolved in 5 mL of dichloromethane, 1 mL of diethylamine was added, and the mixture was stirred at room temperature for 3 hours. The solvent was removed by rotary evaporation under reduced pressure to obtain a yellow oily intermediate. HBED-CC (33 mg, 0.05 mmol) was dissolved in 2 mL of ultra-dry N,N-dimethylformamide, and HATU (25 mg, 0.07 mmol) and DIPEA (13 mg, 0.10 mmol) were added in an ice bath. The mixture was stirred in an ice bath for 30 minutes. The yellow oily intermediate (50 mg, 0.05 mmol) was dissolved in 2 mL of ultra-dry N,N-dimethylformamide. The reaction mixture was added to the above solution and allowed to react overnight at room temperature. The reaction mixture was washed five times with ethyl acetate and saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration. The filtrate was then rotary evaporated under reduced pressure to remove the solvent. The resulting yellow oil was purified by high-performance liquid chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v = 10 / 1 / 0.1). The crude product was further deprotected using trifluoroacetic acid to give the crude HBED-CC-PSMA-11. The crude product was purified by high-performance liquid chromatography. The semi-preparative chromatography column was an Eclipse XDB-C18, 5 μm column, 9.4 × 250 mm column. Separation conditions were: Phase A: 0.1% TFA in water; Phase B: 0.1% TFA in acetonitrile. Gradient: 0-15 min, 5% to 65% B; 15-16 min, 65% to 100% B; 16-19 min, 100% B; 19-20 min, 100% to 5% B; 20-23 min, 5% B. Flow rate: 4 mL / min. UV: 280 nm. The target compound was lyophilized to obtain the white solid compound HBED-CC-NI-PSMA-11. Confirmation of the structure of compound HBED-CC-NI-PSMA-11: HRMS C 64 H 87 N 12 O 22 [M+H] + Theoretical molecular weight: 1375.6052, Measured molecular weight: 1375.60 68 . Step 2: Preparation of PSMA-targeting radioligand HBED-CC-NI-PSMA-11 containing a nitroaromatic heterocyclic group 68 Ga labeling 68The Ga labeling route is as follows: JPEG2026508753000032.jpg2085 Dissolve the HBED-CC-NI-PSMA-11 obtained in step 1 in dimethyl sulfoxide to prepare a 1 μg / μL precursor solution. Transfer 5 μL of the precursor solution to a 10 mL vial, add 135 μL of 3 M sodium acetate solution, and rinse the germanium gallium generator (iThemba) with 6 mL of 0.6 M high-purity hydrochloric acid solution. 68 The radiochemical purity of the mixture was measured by high performance liquid chromatography equipped with a radioactivity detector. The radiochemical yield was found to be over 98%. 68 Ga]Ga HBED-CC-NI-PSMA-11 was obtained. FIG. 4 shows the [ 68 The radioactive HPLC spectrum of the labeling reaction mixture of [Ga]Ga HBED-CC-NI-PSMA-11 is shown. 68 The radiochemical purity of Ga]Ga HBED-CC-NI-PSMA-11 was shown to be greater than 98%.

[0024] Example 5: 68 Preparation of [Ga]Ga-AAZTA-NI-PSMA-11 Step 1: Synthesis of PSMA-targeting radioligand AAZTA-NI-PSMA-11 containing a nitroaromatic heterocyclic group The synthetic route is as follows: JPEG2026508753000033.jpg2183 Compound 7 (305 mg, 0.24 mmol) was dissolved in 5 mL of dichloromethane, 1 mL of diethylamine was added, and the mixture was stirred at room temperature for 3 hours. The solvent was removed by rotary evaporation under reduced pressure to obtain a yellow oily intermediate. AAZTA (33.57 mg, 0.05 mmol) was dissolved in 2 mL of ultra-dry N,N-dimethylformamide, and HATU (25 mg, 0.07 mmol) and DIPEA (13 mg, 0.10 mmol) were added in an ice bath. The mixture was stirred in an ice bath for 30 minutes. The yellow oily intermediate was dissolved in 2 mL of ultra-dry N,N-dimethylformamide. The compound (50 mg, 0.05 mmol) was added to the reaction mixture and allowed to react overnight at room temperature. The reaction mixture was washed five times with ethyl acetate and saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. The filtrate was rotary evaporated under reduced pressure to remove the solvent. The resulting yellow oil was purified by high-performance liquid chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v = 10 / 1 / 0.1). The crude product was further deprotected with trifluoroacetic acid to give the crude AAZTA-NI-PSMA-11. The crude product was purified by high-performance liquid chromatography (HPLC) using a semi-preparative chromatography column: Eclipse XDB-C18, 5 μm, 9.4 × 250 mm. Separation conditions: Phase A: 0.1% TFA in water, Phase B: 0.1% TFA in acetonitrile. Gradient: 0-15 min, 5%-100% B; 15-17 min, 100% B; 17-17.5 min, 100%-5% B; 17.5-20 min, 5% B. Flow rate: 4 mL / min. UV: 280 nm. The target compound was lyophilized to obtain the white solid compound AAZTA-NI-PSMA-11. Confirmation of the structure of compound AAZTA-NI-PSMA-11: HRMS C 56 H 84 N 13 O 22 [M+H] + Theoretical molecular weight: 1290.5848, measured molecular weight: 1290.5859. Step 2: Preparation of PSMA-targeting radioligand AAZTA-NI-PSMA-11 containing a nitroaromatic heterocyclic group 68 Ga label: 68The Ga labeling route is as follows: JPEG2026508753000034.jpg2086 AAZTA-NI-PSMA-11 obtained in step 1 was dissolved in dimethyl sulfoxide to prepare a 1 μg / μL precursor solution. 10 μL of the precursor solution was placed in a 10 mL vial, 135 μL of 3 M sodium acetate solution was added, and a germanium gallium generator (iThemba) was rinsed with 6 mL of 0.6 M high-purity hydrochloric acid solution. 68 The radiochemical purity of the obtained solution was measured by high-performance liquid chromatography equipped with a radioactivity detector. The radiochemical yield was found to be over 98%. 68 Ga]Ga AAZTA-NI-PSMA-11 was obtained. FIG. 5 shows the [ 68 The radioactive HPLC spectrum of the labeling reaction solution of Ga]Ga AAZTA-NI-PSMA-11 is shown. 68 The radiochemical purity of Ga]Ga AAZTA-NI-PSMA-11 was shown to be greater than 98%.

[0025] Example 6: 68 Preparation of [Ga]GaDOTA-NI-PSMA-11 Step 1: Synthesis of PSMA-targeting radioligand DOTA-NI-PSMA-11 containing a nitroaromatic heterocyclic group The synthetic route is as follows: JPEG2026508753000035.jpg2182 Compound 7 (305 mg, 0.24 mmol) was dissolved in 5 mL of dichloromethane, 1 mL of diethylamine was added, and the mixture was stirred at room temperature for 3 hours. The solvent was removed by rotary evaporation under reduced pressure to obtain a yellow oily intermediate. DOTA (29 mg, 0.05 mmol) was dissolved in 2 mL of ultra-dry N,N-dimethylformamide, and HATU (25 mg, 0.07 mmol) and DIPEA (13 mg, 0.10 mmol) were added in an ice bath. The mixture was stirred in an ice bath for 30 minutes. The yellow oily intermediate was dissolved in 2 mL of ultra-dry N,N-dimethylformamide. The compound (50 mg, 0.05 mmol) was added to the above reaction solution and reacted at room temperature overnight. The reaction solution was washed five times with ethyl acetate and saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration. The filtrate was evaporated under reduced pressure to remove the solvent. The resulting product was purified by high-performance liquid chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v=10 / 1 / 0.1) to obtain a yellow oily product. The product was further deprotected with trifluoroacetic acid to obtain a crude DOTA-NI-PSMA-11 product, which was then purified by high-performance liquid chromatography. Semi-preparative chromatography column: Eclipse XDB-C18, 5 μm, 9.4 × 250 mm. Separation conditions: Phase A: 0.1% TFA water, Phase B: 0.1% TFA acetonitrile. Gradient: 0–15 min, 5–100% B; 15–17 min, 100% B; 17–17.5 min, 100%–5% B; 17.5–20 min, 5% B. Flow rate: 4 mL / min. UV: 280 nm. The target compound was lyophilized to obtain the white solid compound DOTA-NI-PSMA-11. Confirmation of the structure of compound DOTA-NI-PSMA-11: HRMS C 54 H 83 N 14 O 20 [M+H] + Theoretical molecular weight: 1247.5902, measured molecular weight: 1247.5896. Step 2: Preparation of PSMA-targeting radioligand DOTA-NI-PSMA-11 containing a nitroaromatic heterocyclic group 68 Ga label: 68The Ga labeling route is as follows: JPEG2026508753000036.jpg1978 Dissolve the DOTA-NI-PSMA-11 obtained in step 1 in dimethyl sulfoxide to prepare a 1 μg / μL precursor solution. Transfer 25 μL of the precursor solution to a 10 mL vial, add 72 μL of 3 M sodium acetate solution, and rinse a germanium gallium generator (iThemba) with 6 mL of 0.6 M high-purity hydrochloric acid solution. 68 The radiochemical purity of the mixture was measured by high performance liquid chromatography equipped with a radioactivity detector. The radiochemical yield was found to be over 98%. 68 Ga]Ga DOTA-NI-PSMA-11 was obtained. FIG. 6 shows the [ 68 The radioactive HPLC spectrum of the labeling reaction solution of [Ga]Ga DOTA-NI-PSMA-11 is shown. 68 The radiochemical purity of Ga]Ga DOTA-NI-PSMA-11 was shown to be greater than 98%.

[0026] Example 7: 68 Preparation of [Ga]Ga-AAZTA-NI-PSMA-093 Step 1: Synthesis of PSMA-targeting radioligand AAZTA-NI-PSMA-093 containing a nitroaromatic heterocyclic group The synthetic route is as follows: JPEG2026508753000037.jpg4667JPEG2026508753000038.jpg3385Specifically, it includes the following steps. (1) Synthesis of Compound 8 N-Benzyloxycarbonyl-L-phenylalanine (N-Cbz-L-Phe, 1.42 g, 4.73 mmol) was dissolved in 11 mL of N,N-dimethylformamide, and 1-hydroxybenzotriazole (HOBt, 872 mg, 6.45 mmol), N,N-diisopropylethylamine (DIPEA, 2.20 mL, 1.72 g, 12.9 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl, 1.24 g, 6.45 mmol) were added at 0 °C. Compound 1 (2.10 g, 4.30 mmol) was dissolved in 15 mL of N,N-dimethylformamide, and the above solution was added dropwise. The reaction solution was stirred at room temperature for 27 hours, and then extracted with saturated sodium chloride solution and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then purified by silica gel column chromatography (dichloromethane / methanol / aqueous ammonia = 95 / 5 / 0.5, v / v / v) to obtain a white solid compound (1.29 g, 1.67 mmol, yield: 38.9%). The white solid compound (1.29 g, 1.67 mmol) was dissolved in 20 mL of absolute ethanol and 10% Pd / C (88.1 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 27 hours. The resulting reaction solution was suction filtered through diatomaceous earth, and the filtrate was rotary evaporated under reduced pressure to remove the solvent, yielding brown oily compound 8 (981 mg, 1.55 mmol) in a yield of 92.5%. Confirmation of the structure of compound 8: HRMS C 33 H 55 N4O8[M+H] + Theoretical molecular weight: 635.4014, Measured molecular weight: 635.4011. 1HNMR(600 MHz, CDCL3) δ: 7.33-7.18 (m, 5H), 5.40 (dd, 2H, J=10.6, 8.1 Hz), 4.30 (dtd, 2H, J 28.9, 8.0, 4.9 Hz), 3.59 (dd, 1H, J=9.3, 4.2 Hz), 3.30-3.16 (m, 3H), 2.67 (dd, 1H, J=13.7, 9.3 Hz), 2.37-2.23 (m, 2H), 2.09-2.01 (m, 1H), 1.88-1.70 (m, 3H), 1.65-1.56 (m, 1H), 1.51-1.46 (m, 2H), 1.45-1.41 (m, 27H), 1.37-1.28 (m, 2H). (2) Synthesis of Compound 10 Compound 8 (959 mg, 1.51 mmol) was dissolved in 15 mL of N,N-dimethylformamide, and 1-hydroxybenzotriazole (HOBt, 237 mg, 1.75 mmol), N,N-diisopropylethylamine (DIPEA, 0.60 mL, 469 mg, 3.63 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl, 337 mg, 1.75 mmol) were added at 0°C. Compound 9 (569 mg, 1.17 mmol) was dissolved in N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 13.5 hours, and then extracted with saturated sodium chloride solution and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then purified by silica gel column chromatography (dichloromethane / methanol / aqueous ammonia=95 / 5 / 0.5, v / v / v) to give compound 10 (725 mg, 0.657 mmol) as a white solid in a yield of 56.2%. Confirmation of the structure of compound 10: HRMS theoretical molecular weight C 58 H 83 NO 15 [M+H] + 1103.5910, measured molecular weight 1103.5927. 1HNMR(600 MHz, CDCL3) δ: 8.09 (br s,1H), 7.56 (br s, 1H), 7.39-7.28 (m, 5H), 7.28-7.17 (m, 5H), 6.87 (d, 2H, J=7.7 Hz), 6.59 (d, 2H, J=7.8 Hz), 5.80 (br s, 1H), 5.06 (d, 2H, J=12.1 Hz), 4.92 (d, 1H, J=12.0 Hz), 4.81 (br s, 1H), 4.76-4.59 (m, 1H), 4.52 (br s, 1H), 4.41 (br s, 2H), 4.05 (d, 1H, J=14.3 Hz), 3.86 (dd, 1H, J=17.4, 3.3 Hz), 3.44 (br s, 2H), 3.27-3.17 (m, 2H), 3.15-2.96 (m, 2H), 2.88 (br s, 1H), 2.44-2.28 (m, 2H), 2.12-2.02 (m, 1H), 1.87-1.79 (m, 1H), 1.58 (d, 2H, J=6.3 Hz), 1.53-1.28 (m, 36H), 1.28-1.19 (m, 2H), 1.05 (brs, 1H). (6) Synthesis of Compound 11 Compound 2 (432 mg, 1.60 mmol) was dissolved in 4 mL of trifluoroacetic acid, stirred at room temperature for 30 minutes, and then rotary evaporated under reduced pressure to remove the solvent, giving a white solid intermediate. The white solid intermediate (812 mg, 3.00 mmol) was dissolved in 6 mL of dichloromethane, and 2.5 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 40 minutes to react, and then rotary evaporated under reduced pressure to remove the solvent, giving a yellow oily compound, which was ready for use. N-tert-Butyloxycarbonyl-L-glutamic acid 5-methyl ester (530 mg, 2.03 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and 1-hydroxybenzotriazole (HOBt, 410 mg, 3.03 mmol), N,N-diisopropylethylamine (DIPEA, 0.90 mL, 704 mg, 5.45 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl, 572 mg, 2.99 mmol) were added at 0°C to give the above yellow oil. The mixture was dissolved in 10 mL of N,N-dimethylformamide, and the above solution was added dropwise. The reaction mixture was stirred at room temperature for 26 h. Saturated sodium chloride solution and ethyl acetate were added for extraction. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM / MeOH / NH4OH = 90 / 9 / 0.9, v / v / v) to give compound 11 (434 mg, 1.05 mmol) as a yellow oil in a 35.0% yield. Confirmation of the structure of compound 11: HRMS C 17 H 28 N5O7[M+H] + Theoretical molecular weight: 414.1983, Measured molecular weight: 414.1978. 1HNMR(400MHz, CDCL3) δ: 7.32 (s, 1H), 7.14 (s, 1H), 6.71 (br s, 1H), 5.36 (d, 1H, J=7.1 Hz), 4.44 (t, 2H, J=6.9 Hz), 4.11 (q, 1H, J=7.1 Hz), 3.69 (s, 3H), 3.34 (dd, 2H, J=12.5, 6.2 Hz), 2.58-2.36 (m, 2H), 2.20-2.02 (m, 3H), 2.01-1.86 (m, 1H), 1.43 (s, 9H). (7) Synthesis of Compound 12 Compound 12 (152 mg, 0.367 mmol) was dissolved in 6 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was then rotary evaporated under reduced pressure to remove the solvent, obtaining a yellow oily compound ready for use. AAZTA (149 mg, 0.223 mmol) was dissolved in 7 mL of N,N-dimethylformamide, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU, 161 mg, 0.423 mmol) and N,N-diisopropylethylamine (DIPEA, 0.05 mL, 37.1 mg, 0.287 mmol) were added at 0 °C. The mixture was stirred and reacted for 30 min. The above yellow oily compound was dissolved in 5 mL of N,N-dimethylformamide. The above solution was added dropwise, and the reaction mixture was stirred at room temperature for 27 h. Saturated sodium chloride solution and ethyl acetate were added for extraction. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM / MeOH / NH4OH = 100 / 5 / 0.5, v / v / v) to give compound 12 (71.9 mg, 0.0743 mmol) as a yellow oil in a 33.8% yield. Confirmation of the structure of compound 12: HRMS C 46 H 79 N8O 14 [M+H] + Theoretical molecular weight: 967.5710, Measured molecular weight: 967.5715. 1HNMR(600 MHz, CDCL3) δ: 7.43 (s, 1H), 7.11 (s, 1H), 6.88-6.78 (m, 1H), 6.74-6.66 (m, 1H), 4.50-4.30 (m, 3H), 3.68 (s, 3H), 3.66-3.55 (m, 2H), 3.54 (s, 2H), 3.47-3.36 (m, 3H), 3.34-3.25 (m, 3H), 3.08-2.98 (m, 2H), 2.90-2.81 (m, 1H), 2.73-2.66 (m, 1H), 2.52-2.39 (m, 2H), 2.37-2.25 (m, 2H), 2.11-1.99 (m, 4H), 1.72 (s, 8H), 1.50-1.41 (m, 36H). (8) Synthesis of Compound 13 Compound 12 (56.4 mg, 58.3 μmol) was dissolved in 3 mL of tetrahydrofuran, and 1 M sodium hydroxide solution (1.0 mL, 1.0 mmol) was added dropwise. The mixture was stirred at room temperature for 8 h. 1 M hydrochloric acid was added dropwise to the resulting reaction mixture to adjust the pH to 6. The resulting solution was extracted with saturated brine and ethyl acetate. The aqueous phase was washed three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was rotary evaporated under reduced pressure to remove the solvent. The concentrate was purified by silica gel column chromatography (DCM / MeOH / NH₃·HO=90 / 9 / 0.9, v / v / v) to give compound 13 (18.6 mg, 19.5 μmol) as a white solid in 32.5% yield. Confirmation of the structure of compound 13: HRMS C 45 H 77 N8O 14 [M+H] + Theoretical molecular weight: 953.5553, measured molecular weight: 953.5543. (9) Synthesis of compound AAZTA-NI-PSMA-093 Compound 13 (18.6 mg, 19.5 μmol) was dissolved in 3 mL of N,N-dimethylformamide at 0 °C. O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU, 10.2 mg, 26.8 μmol) and N,N-diisopropylethylamine (DIPEA, 8.30 mg, 64.2 μmol) were added and the mixture was stirred for 30 min. Compound 10 was dissolved in 2 mL of N,N-dimethylformamide, and the above solution was added dropwise. The reaction mixture was stirred at room temperature for 24 h. The mixture was extracted with saturated sodium chloride solution and ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (DCM / MeOH / NH4OH = 100 / 5 / 0.5, v / v / v) to give a yellow oily compound (11.5 mg, 6.04 μmol, yield: 30.2%). The yellow oily compound (11.5 mg, 6.04 μmol) was dissolved in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 h. The reaction solution was then rotary evaporated under reduced pressure to remove the solvent. The resulting yellow solid was dissolved in 1.0 mL of dimethyl sulfoxide, and the solution was purified by semi-preparative HPLC to give the white solid compound AAZTA-NI-PSMA-093 (2.50 mg, 4.54 μmol) in a yield of 75.2%. Confirmation of the structure of compound AAZTA-NI-PSMA-093: HRMS C 63 H 87 N 14 O 26 [M+H] + Theoretical molecular weight: 1511.6536, measured molecular weight: 1511.6548. Step 2: Preparation of PSMA-targeting radioligand AAZTA-NI-PSMA-093 containing a nitroaromatic heterocyclic group 68 Ga label: 68 The Ga labeling route is as follows: JPEG2026508753000039.jpg4470 A dimethyl sulfoxide solution containing 20 nmol of radioactive ligand AAZTA-NI-PSMA-093 was added to 150 μL of 3 M sodium acetate buffer solution, and a germanium gallium generator (iThemba Laboratories, 740 MBq, 20 mCi) was rinsed with high-purity hydrochloric acid solution to obtain [ 68 Add 300 μL of the [Ga]GaCl3 hydrochloride solution to the sodium acetate buffer solution of the radioactive ligand, mix evenly, add water to dilute the reaction solution to a total volume of 500 μL, react at 50°C for 10 minutes, cool to room temperature, and measure the labeling rate by high-performance liquid chromatography (radio-HPLC) equipped with a radioactivity detector. The radiochemical purity is more than 95%. 68 Ga]Ga-AAZTA-NI-PSMA-093 was obtained. The figure shows the [ 68 The radio-HPLC spectrum of the labeled reaction solution of [Ga]Ga-AAZTA-NI-PSMA-093 is shown. 68 The radiochemical purity of Ga]Ga-AAZTA-NI-PSMA-093 was shown to be greater than 98%.

[0027] Example 8: 68 Preparation of [Ga]Ga-NI-HBED-CC-PSMA-11 Step 1: Synthesis of PSMA-targeting radioligand NI-HBED-CC-PSMA-11 containing a nitroaromatic heterocyclic group: The synthetic route is as follows: JPEG2026508753000040.jpg3886Specifically, it includes the following steps. (1) Synthesis of Compound 14 HBED-CC (200 mg, 0.310 mmol) was dissolved in 10 mL of anhydrous N,N-dimethylformamide. O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU, 141 mg, 0.372 mmol) and N,N'-diisopropylethylamine (DIPEA, 80.0 mg, 0.620 mmol) were added to the solution in an ice bath, and compound 2 was dissolved in 2 mL of trifluoroacetic acid. After stirring for 1 h, the mixture was distilled under reduced pressure to obtain a white intermediate. The white solid intermediate (52.8 mg, 0.310 mmol) was dissolved in anhydrous DMF. The solution was dissolved in 5 mL of HCl and added dropwise to the above solution. After stirring at room temperature for 4 h, 30 mL of saturated saline was added to the solution, extracted with ethyl acetate, and the organic phase was washed with deionized water (30 mL × 2). The organic phase was concentrated by distillation under reduced pressure and purified by silica gel chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v = 90 / 10 / 1) to obtain a colorless substance, Compound 14 ( 68 0.7 mg, 0.0863 mmol) was obtained in a yield of 27.8%. Confirmation of the structure of compound 14: HRMS C 50 H 76 NO 13 [M+H] + Theoretical molecular weight: 969.5543, Measured molecular weight: 969.5542. 11H NMR (400 MHz, CD3OD) δ 7.71 (d, 1H, J = 2.1 Hz), 7.39 - 7.28 (m, 1H), 7.23 - 7.09 (m, 3H), 7.06 - 6.93 (m, 1H), 6.89 (d, 1H, J = 8.4 Hz), 6.70 (d, 1H, J = 8.4 Hz), 6.47 (s, 1H), 5.77 (d, 1H, J = 4.5 Hz), 5.16 - 4.85 (m, 1H), 4.74 (dd, 1H, J = 14.1, 5.9 Hz), 4.56 - 4.19 (m, 3H), 3.94 - 3.74 (m, 1H), 3.39 (d, 2H, J = 16.3 Hz), 3.26 - 2.82 (m, 4H), 2.34 (ddd, 2H, J = 30.4, 18.4, 13.8 Hz), 2.08 (tdd, 1H, J = 14.7, 10.1, 4.6 Hz), 1.84 (ddd, 1H, J = 19.8, 12.3, 7.9 Hz), 1.72 - 1.00 (m, 36H). (2): Synthesis of NI-HBED-CC-PSMA-11 Compound 14 (20.1 mg, 25.1 μmol) was dissolved in 5 mL of anhydrous DMF, and under ice-bath conditions, O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU, 14.3 mg, 30.1 μmol), N,N'-diisopropylethylamine (DIPEA, 6.49 mg, 50.2 μmol), and compound 6 (15.1 mg, 25.0 μmol) were added sequentially. The mixture was stirred at room temperature overnight, and the solution was added with 10 mL of saturated brine. The mixture was extracted with ethyl acetate, washed with deionized water (20 mL × 2), concentrated by vacuum distillation, and purified by silica gel chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v = 90 / 10 / 1) to give the colorless solid compound (19.0 mg, 13.8 μmol) in a 55.0% yield. The colorless solid compound was dissolved in 2 mL of trifluoroacetic acid and stirred at room temperature for 1 h. The reaction mixture was then diluted with anhydrous dichloromethane and evaporated under reduced pressure to remove the organic solvent. The residue was purified by semi-pre-HPLC (A: 0.1% TFA aqueous solution, B: 0.1% TFA acetonitrile solution, 0-20 min B 5%-100%, UV = 280 nm, flow rate 4 mL / min) to give compound 25 (3.5 mg, 3.18 μmol) as a white solid in a 54.8% yield. Confirmation of the structure of NI-HBED-CC-PSMA-11: HRMS C 50 H 71 N 10 O 18 [M+H] + Theoretical molecular weight: 1099.4942, measured molecular weight: 1099.4940. Step 2: Preparation of PSMA-targeting radioligand NI-HBED-CC-PSMA-11 containing a nitroaromatic heterocyclic group 68 Ga labeling 68 The Ga labeling route is as follows: JPEG2026508753000041.jpg3154 15 μg of the radioligand NI-HBED-CC-PSMA-11 prepared in step 1 was dissolved in 135 μL of 3N sodium acetate buffer, and a germanium gallium generator (iThemba Laboratories, 740 MBq, 20 mCi) was rinsed with 6 mL of high-purity 0.6N hydrochloric acid solution to obtain [ 68 300 μL of the hydrochloric acid solution of [Ga]GaCl3 was added to the precursor sodium acetate solution, mixed uniformly, and reacted at 50 °C for 10 min. After cooling to room temperature, the labeling rate was measured by high-performance liquid chromatography (radio-HPLC) equipped with a radioactivity detector. A radiochemical yield of >98% was obtained. 68 Ga]Ga-NI-HBED-CC-PSMA-11 was obtained. FIG. 8 shows the [ 68 The radioactive HPLC spectrum of the labeling reaction solution of [Ga]Ga-NI-HBED-CC-PSMA-11 is shown. 68 The radiochemical purity of Ga]Ga-NI-HBED-CC-PSMA-11 was shown to be greater than 98%.

[0028] Example 9: 68 Preparation of [Ga]Ga-NI-DOTAGA2-PSMA-11 Step 1: Synthesis of PSMA-targeting radioligand NI-DOTAGA2-PSMA-11 containing a nitroaromatic heterocyclic group: The synthetic route is as follows: JPEG2026508753000042.jpg3881Specifically, it includes the following steps. (1) Synthesis of Compound 15 DOTAGA2 (200 mg, 0.259 mmol) was dissolved in 10 mL of anhydrous N,N-dimethylformamide. O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU, 141 mg, 0.372 mmol) and N,N'-diisopropylethylamine (DIPEA, 66.8 mg, 0.518 mmol) were added to the solution in an ice bath. Compound 2 was dissolved in 2 mL of trifluoroacetic acid, stirred for 1 h, and then distilled under reduced pressure to obtain a white solid intermediate. The solid intermediate (44.1 mg, 0.259 mmol) was dissolved in 5 mL of anhydrous DMF and added dropwise to the above solution. After stirring at room temperature for 4 h, 30 mL of saturated brine was added to the solution, extracted with ethyl acetate, and the organic phase was washed with deionized water (30 mL × 2), concentrated by distillation under reduced pressure, and purified by silica gel chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v = 90 / 10 / 1) to give compound 15 (86.5 mg, 0.0935 mmol) as a colorless substance in a 36.1% yield. Confirmation of the structure of compound 15: HRMS C 44 H 77 N8O 13 [M+H] + Theoretical molecular weight: 925.5605, Measured molecular weight: 925.5600. (6) Synthesis of NI-DOTAGA2-PSMA-11 Compound 15 (25.6 mg, 27.6 μmol) was dissolved in 5 mL of anhydrous DMF, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU, 14.3 mg, 30.1 μmol) and N,N'-diisopropylethylamine (DIPEA, 6.49 mg, 50.2 μmol) were added sequentially under ice-bath conditions. Compound 15 (15.1 mg, 25.0 μmol) was added and stirred at room temperature overnight. 10 mL of saturated brine was added to the solution, and the solution was extracted with ethyl acetate. The organic phase was washed with deionized water (20 mL × 2), concentrated by distillation under reduced pressure, and purified by silica gel chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v = 90 / 10 / 1) to obtain a colorless solid compound. The colorless solid compound was dissolved in 2 mL of trifluoroacetic acid and stirred at room temperature for 1 h. Anhydrous dichloromethane was added to the reaction mixture, which was then dilute and evaporated under reduced pressure to remove the organic solvent. The resulting mixture was purified by semi-pre-HPLC (A: 0.1% TFA aqueous solution, B: 0.1% TFA acetonitrile solution, 0-20 min B 5%-100%, UV = 280 nm, flow rate 4 mL / min) to give the white solid compound NI-DOTAGA2-PSMA-11 (4.8 mg, 3.18 μmol) in a 54.8% yield. Confirmation of the structure of NI-DOTAGA2-PSMA-11: HRMS C 46 H 75 N 12 O 20 [M+H] + Theoretical molecular weight: 1115.5215, Measured molecular weight: 1115.5210. Step 2: Preparation of PSMA-targeting radioligand NI-DOTAGA2-PSMA-11 containing a nitroaromatic heterocyclic group 68 Ga label: 68 The Ga labeling route is as follows: JPEG2026508753000043.jpg3663 15 μg of the radioactive ligand NI-DOTAGA2-PSMA-11 prepared in step 1 was dissolved in 135 μL of 3N sodium acetate buffer, and a germanium gallium generator (iThemba Laboratories, 740 MBq, 20 mCi) was rinsed with 6 mL of high-purity 0.6N hydrochloric acid solution to obtain [ 68 300 μL of the hydrochloric acid solution of [Ga]GaCl3 was added to the precursor sodium acetate solution, mixed uniformly, and reacted at 50 °C for 10 min. After cooling to room temperature, the labeling rate was measured by high-performance liquid chromatography (radio-HPLC) equipped with a radioactivity detector. A radiochemical yield of >98% was obtained. 68 Ga]Ga-NI-DOTAGA2-PSMA-11 was obtained. FIG. 9 shows the [ 68 The radioactive HPLC spectrum of the labeling reaction solution of [Ga]Ga-NI-HBED-CC-PSMA-11 is shown. 68 The radiochemical purity of Ga]Ga-NI-HBED-CC-PSMA-11 was shown to be greater than 98%.

[0029] Example 10: 68 Preparation of [Ga]Ga-NI-HBED-CC-PSMA-093 Step 1: Synthesis of PSMA-targeting radioligand NI-HBED-CC-PSMA-093 containing a nitroaromatic heterocyclic group: The synthesis steps are as follows: JPEG2026508753000044.jpg4884 Compound 14 (20.1 mg, 25.1 μmol) was dissolved in 5 mL of anhydrous N,N-dimethylformamide, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU, 14.3 mg, 30.1 μmol) and N,N'-diisopropylethylamine (DIPEA, 6.49 mg, 50.2 μmol) were added sequentially under ice bath conditions to form the compound. Compound 10 (29.2 mg, 30.1 μmol) was added, and the mixture was stirred at room temperature overnight. 10 mL of saturated brine was added to the solution, which was then extracted with ethyl acetate. The organic phase was washed with deionized water (20 mL × 2), concentrated by distillation under reduced pressure, and purified by silica gel chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v, 90 / 10 / 1) to give a colorless solid compound (16.8 mg, 9.61 μmol) in a yield of 38.3%. The colorless solid compound (11.3 mg, 6.47 μmol) was dissolved in 2 mL of trifluoroacetic acid and stirred at room temperature for 1 h. Anhydrous dichloromethane was then added to the reaction mixture, which was then dilution by vacuum distillation to remove the organic solvent. The resulting mixture was purified by semi-preparative HPLC (A: 0.1% TFA aqueous solution, B: 0.1% TFA acetonitrile solution, 0-20 min B 5%-100%, UV = 280 nm, flow rate 4 mL / min) to give the white solid compound NI-HBED-CC-PSMA-093 (4.40 mg, 3.31 μmol) in a 51.1% yield. Confirmation of the structure of NI-HBED-CC-PSMA-093: HRMS C 66 H 83 N 12 O 23 [M+H] + Theoretical molecular weight 1411.5 68 8, Measured molecular weight 1411.5703. Step 2: Preparation of PSMA-targeting radioligand NI-HBED-CC-PSMA-093 containing a nitroaromatic heterocyclic group 68 Ga label: 68 The Ga labeling route is as follows: JPEG2026508753000045.jpg4479 15 μg of the radioligand NI-HBED-CC-PSMA-093 prepared in step 1 was dissolved in 135 μL of 3N sodium acetate buffer, and a germanium gallium generator (iThemba Laboratories, 740 MBq, 20 mCi) was rinsed with 6 mL of high-purity 0.6N hydrochloric acid solution to obtain [ 68 300 μL of the hydrochloric acid solution of [Ga]GaCl3 was added to the precursor sodium acetate solution, mixed uniformly, and reacted at 50 °C for 10 min. After cooling to room temperature, the labeling rate was measured by high-performance liquid chromatography (radio-HPLC) equipped with a radioactivity detector. A radiochemical yield of >98% was obtained. 68 Ga]Ga-NI-HBED-CC-PSMA-093 was obtained. FIG. 10 shows the [ 68 The radioactive HPLC spectrum of the labeling reaction solution of [Ga]Ga-NI-HBED-CC-PSMA-093 is shown. 68 The radiochemical purity of Ga]Ga-NI-HBED-CC-PSMA-093 was shown to be greater than 98%.

[0030] Example 11: 68 Preparation of [Ga]Ga-NI-DOTAGA2-PSMA-093 Step 1: Synthesis of PSMA-targeting radioligand NI-DOTAGA2-PSMA-093 containing a nitroaromatic heterocyclic group: The synthesis scheme is as follows: Compound 15 (23.2 mg, 25.1 μmol) was dissolved in 5 mL of anhydrous N,N-dimethylformamide, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU, 14.3 mg, 30.1 μmol) and N,N'-diisopropylethylamine (DIPEA, 6.49 mg, 50.2 μmol) were added sequentially under ice bath conditions to form a compound. Compound 10 (29.2 mg, 30.1 μmol) was added, and the mixture was stirred at room temperature overnight. 10 mL of saturated brine was added to the solution, which was then extracted with ethyl acetate. The organic phase was washed with deionized water (20 mL × 2), concentrated by distillation under reduced pressure, and purified by silica gel chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v, 90 / 10 / 1) to give a colorless solid compound (18.0 mg, 9.61 μmol) in a yield of 38.3%. The colorless solid compound (11.3 mg, 6.01 μmol, 1 eq.) was dissolved in 2 mL of trifluoroacetic acid and stirred at room temperature for 1 h. Anhydrous dichloromethane was then added to the reaction mixture, which was then dilution by vacuum distillation to remove the organic solvent. The resulting mixture was purified by semi-pre-HPLC (A: 0.1% TFA aqueous solution, B: 0.1% TFA acetonitrile solution, 0-20 min B 5%-100%, UV = 280 nm, flow rate 4 mL / min) to give the white solid compound NI-DOTAGA2-PSMA-093 (3.98 mg, 2.79 μmol) in a 46.4% yield. Confirmation of the structure of NI-DOTAGA2-PSMA-093: HRMS C 62 H 87 N 14 O 25 [M+H] + Theoretical molecular weight: 1427.5961, Measured molecular weight: 1427.5956. Step 2: Preparation of PSMA-targeting radioligand NI-DOTAGA2-PSMA-093 containing a nitroaromatic heterocyclic group 68 Ga label: 68 The Ga labeling route is as follows: JPEG2026508753000047.jpg3765 15 μg of the radioactive ligand NI-DOTAGA2-PSMA-093 prepared in step 1 was dissolved in 135 μL of 3N sodium acetate buffer, and a germanium gallium generator (iThemba Laboratories, 740 MBq, 20 mCi) was rinsed with 6 mL of high-purity 0.6N hydrochloric acid solution to obtain [ 68 300 μL of the hydrochloric acid solution of [Ga]GaCl3 was added to the precursor sodium acetate solution, mixed uniformly, and reacted at 50 °C for 10 min. After cooling to room temperature, the labeling rate was measured by high-performance liquid chromatography (radio-HPLC) equipped with a radioactivity detector. A radiochemical yield of >98% was obtained. 68 Ga]Ga-NI-DOTAGA2-PSMA-093 was obtained. FIG. 11 shows the [ 68 The radioactive HPLC spectrum of the labeling reaction solution of [Ga]Ga-NI-HBED-CC-PSMA-093 is shown. 68 The radiochemical purity of Ga]Ga-NI-HBED-CC-PSMA-093 was shown to be greater than 98%.

[0031] Application Example 1 [ 68 Ga]Ga-AAZTA-NI-PSMA,[ 68 In vitro 22RV1-FOLH1-oe cell uptake of [Ga]Ga-AAZTA-NI-PSMA-11: 1 × 10 22RV1-FOLH1-oe cells 5 The cells were suspended in a cell suspension of 500 μL per well and inoculated into six 12-well plates. Each well was inoculated with 37 KBq of [ 68 Ga]Ga-AAZTA-NI-PSMA,[ 68 Ga]Ga-AAZTA-NI-PSMA-11 and [ 68[Ga]Ga-HBED-CC-PSMA-11 solution was added, and the cells were incubated at 37°C for 15, 30, 60, 90, and 120 minutes. The uptake was terminated with PBS solution, the cells were lysed with 1M NaOH, and the cell lysate was absorbed with filter paper and placed in a plastic test tube for radioactivity counting. Cell uptake was inhibited at 60 minutes using excess unlabeled PSMA-11. After the incubation period, the uptake was terminated with PBS solution, the cells were lysed with 1M NaOH, and the cell lysate was absorbed with filter paper and placed in a plastic test tube for radioactivity counting. FIG. 12 shows the results of the uptake by 22RV1-FOLH1-oe cells in vitro in Example 1 of the present invention. 68 Ga]Ga-AAZTA-NI-PSMA,[ 68 Ga]Ga-AAZTA-NI-PSMA-11, and [ 68 The uptake-time curves of [Ga]Ga-HBED-CC-PSMA-11 (n=3) are shown. FIG. 13 shows the results of an in vitro 22RV1-FOLH1-oe cell uptake experiment in Example 1 of the present invention. 68 Ga]Ga-AAZTA-NI-PSMA,[ 68 Ga]Ga-AAZTA-NI-PSMA-11, and [ 68 A diagram (n=3) showing the specific binding of Ga]Ga-HBED-CC-PSMA-11 to the prostate-specific membrane antigen receptor is shown. As can be seen from the results of in vitro cellular uptake experiments, in 22RV1-FOLH1-oe cells, [ 68 Ga]Ga-AAZTA-NI-PSMA,[ 68 Ga]Ga-AAZTA-NI-PSMA-11, and [ 68 The uptake of [Ga]Ga-HBED-CC-PSMA-11 increased and then decreased with increasing incubation time, where [ 68At all time points, cellular uptake of [Ga]Ga-HBED-CC-PSMA-11 was higher than that of other radioactive metal complexes. In the presence of excess non-radiolabeled PSMA-11, uptake of the radioactive metal complex was significantly reduced, demonstrating that all complex uptake by 22RV1-FOLH1-oe cells was specific and that binding between PSMA and the radioactive metal complex of the present invention was specific.

[0032] Application Example 2: [ 68 Ga]Ga-AAZTA-NI-PSMA,[ 68 Ga]Ga-DOTA-NI-PSMA, and [ 68 In vitro 22RV1-FOLH1-oe cell uptake of [Ga]Ga-HBED-CC-NI-PSMA: 1.5 × 10 22RV1-FOLH1-oe cells 5 The cells were suspended in a cell suspension of 500 μL per well and inoculated into six 12-well plates. Each well was then inoculated with 37 KBq of [ 68 Ga]Ga-AAZTA-NI-PSMA,[ 68 Ga]Ga-DOTA-NI-PSMA,[ 68 Ga]Ga-HBED-CC-NI-PSMA, and [ 68 [Ga]Ga-HBED-CC-PSMA-11 solution was added, and the cells were incubated at 37°C for 15, 30, 60, 90, and 120 minutes. The uptake was terminated with PBS solution, the cells were lysed with 1M NaOH, and the cell lysate was absorbed with filter paper and placed in a plastic test tube for radioactivity counting. Cell uptake was inhibited at 60 minutes using excess unlabeled PSMA-11. After the incubation period, the uptake was terminated with PBS solution, the cells were lysed with 1M NaOH, and the cell lysate was absorbed with filter paper and placed in a plastic test tube for radioactivity counting. FIG. 14 shows the results of the uptake by 22RV1-FOLH1-oe cells in vitro in Example 2 of the present invention. 68Ga]Ga-AAZTA-NI-PSMA,[ 68 Ga]Ga-DOTA-NI-PSMA,[ 68 Ga]Ga-HBED-CC-NI-PSMA, and [ 68 The uptake-time curves of [Ga]Ga-HBED-CC-PSMA-11 (n=3) are shown. FIG. 15 shows the results of an in vitro 22RV1-FOLH1-oe cell uptake experiment in Example 2 of the present invention. 68 Ga]Ga-AAZTA-NI-PSMA,[ 68 Ga]Ga-DOTA-NI-PSMA,[ 68 Ga]Ga-HBED-CC-NI-PSMA, and [ 68 A diagram (n=3) showing the specific binding of Ga]Ga-HBED-CC-PSMA-11 to the prostate-specific membrane antigen receptor is shown. As can be seen from the results of in vitro cellular uptake experiments, in 22RV1-FOLH1-oe cells, [ 68 Ga]Ga-AAZTA-NI-PSMA,[ 68 Ga]Ga-DOTA-NI-PSMA,[ 68 Ga]Ga-HBED-CC-NI-PSMA, and [ 68 The uptake of [Ga]Ga-HBED-CC-PSMA-11 increased and then decreased with increasing incubation time, where [ 68 GA]Ga-HBED-CC-NI-PSMA demonstrated cellular uptake at multiple time points and was approved by the FDA [ 68 The uptake of the radioactive metal complex was significantly lower than that of [Ga]Ga-HBED-CC-PSMA-11. In the presence of excess non-radiolabeled PSMA-11, the uptake of the radioactive metal complex was significantly reduced, demonstrating that the uptake of the complex by 22RV1-FOLH1-oe cells was entirely specific and that the binding between PSMA and the radioactive metal complex of the present invention was specific.

[0033] Application Example 3 [ 68In vitro 22RV1-FOLH1-oe cell uptake of [Ga]Ga-AAZTA-NI-PSMA-093: 1 × 10 22RV1-FOLH1-oe cells 5 The cells were suspended in a cell suspension of 500 μL each and inoculated into three 12-well plates. Each set of well plates was inoculated with 37 KBq of [ 68 Ga]Ga-AAZTA-NI-PSMA-093, and [ 68 [Ga]Ga-HBED-CC-PSMA-11 solution was added, and the cells were incubated at 37°C for 15, 30, 60, 90, and 120 minutes. The uptake was terminated with PBS solution, the cells were lysed with 1M NaOH, and the cell lysate was absorbed with filter paper and placed in a plastic test tube for radioactivity counting. Cell uptake was inhibited at 60 minutes using excess unlabeled PSMA-11. After the incubation period, the uptake was terminated with PBS solution, the cells were lysed with 1M NaOH, and the cell lysate was absorbed with filter paper and placed in a plastic test tube for radioactivity counting. FIG. 16 shows the results of the uptake by 22RV1-FOLH1-oe cells in vitro in Example 2 of the present invention. 68 Ga]Ga-AAZTA-NI-PSMA-093, and [ 68 The uptake-time curves of [Ga]Ga-HBED-CC-PSMA-11 (n=3) are shown. FIG. 17 shows the results of an in vitro 22RV1-FOLH1-oe cell uptake experiment in Example 2 of the present invention. 68 Ga]Ga-AAZTA-NI-PSMA-093, and [ 68 A diagram (n=3) showing the specific binding of Ga]Ga-HBED-CC-PSMA-11 to the prostate-specific membrane antigen receptor is shown. As can be seen from the results of in vitro cellular uptake experiments, in 22RV1-FOLH1-oe cells, [ 68 Ga]Ga-HBED-CC-PSMA-11, and [ 68The uptake of [Ga]Ga-AAZTA-NI-PSMA-093 increased and then decreased with increasing incubation time, where [ 68 GA]Ga-AAZTA-NI-PSMA-093 demonstrated cellular uptake at multiple time points and was approved by the FDA [ 68 The uptake of the radioactive metal complex was significantly lower than that of [Ga]Ga-HBED-CC-PSMA-11. In the presence of excess non-radiolabeled PSMA-11, the uptake of the radioactive metal complex was significantly reduced, demonstrating that the uptake of the complex by 22RV1-FOLH1-oe cells was entirely specific and that the binding between PSMA and the radioactive metal complex of the present invention was specific.

[0034] Application Example 4 [ 68 Ga]Ga-NI-HBED-CC-PSMA-11, and [ 68 In vitro 22RV1-FOLH1-oe cell uptake of [Ga]Ga-NI-HBED-CC-PSMA-093: 2 × 10 22RV1-FOLH1-oe cells 5 The cells were suspended in a cell suspension of 500 μL per well and inoculated into six 12-well plates. Each well was then inoculated with 37 KBq of [ 68 Ga]Ga-HBED-CC-PSMA-11, 68 Ga]Ga-NI-HBED-CC-PSMA-11, 68 Ga]Ga-HBED-CC-PSMA-093, and [ 68[Ga]Ga-NI-HBED-CC-PSMA-093 solution was added, and the cells were incubated at 37°C for 15, 30, 60, 90, and 120 minutes. The uptake was terminated with PBS solution, the cells were lysed with 1M NaOH, and the cell lysate was absorbed with filter paper and placed in a plastic test tube for radioactivity counting. Cell uptake was inhibited at 60 minutes using excess unlabeled PSMA-11. After the incubation period, the uptake was terminated with PBS solution, the cells were lysed with 1M NaOH, and the cell lysate was absorbed with filter paper and placed in a plastic test tube for radioactivity counting. FIG. 18 shows the results of the in vitro uptake by 22RV1-FOLH1-oe cells in Example 2 of the present invention. 68 Ga]Ga-HBED-CC-PSMA-11, 68 Ga]Ga-NI-HBED-CC-PSMA-11, 68 Ga]Ga-HBED-CC-PSMA-093, and [ 68 The uptake-time curves of Ga]Ga-NI-HBED-CC-PSMA-093 (n=3) are shown. FIG. 19 shows the results of an in vitro 22RV1-FOLH1-oe cell uptake experiment in Example 2 of the present invention. 68 Ga]Ga-HBED-CC-PSMA-11, 68 Ga]Ga-NI-HBED-CC-PSMA-11, 68 Ga]Ga-HBED-CC-PSMA-093, and [ 68 A diagram (n=3) showing the specific binding of Ga]Ga-NI-HBED-CC-PSMA-093 to the prostate-specific membrane antigen receptor is shown. As can be seen from the results of in vitro cellular uptake experiments, in 22RV1-FOLH1-oe cells, [ 68 Ga]Ga-HBED-CC-PSMA-11, 68 Ga]Ga-NI-HBED-CC-PSMA-11, 68 Ga]Ga-HBED-CC-PSMA-093, and [ 68The uptake of [Ga]Ga-NI-HBED-CC-PSMA-093 gradually increased with increasing incubation time, where [ 68 At each time point, cellular uptake of [Ga]Ga-HBED-CC-PSMA-093 was significantly higher than that of other radioactive metal complexes. In the presence of excess non-radiolabeled PSMA-11, uptake of the radioactive metal complex was significantly reduced, demonstrating that all complex uptake by 22RV1-FOLH1-oe cells was specific and that binding between PSMA and the radioactive metal complex of the present invention was specific. The prostate-specific membrane antigen-targeting radiometal complexes and radioligands containing a nitroaromatic heterocyclic group of the present invention contain various chelating agents and can chelate with almost all radiometal nuclides currently used in clinical practice. N,N'-bis[2-hydroxy5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) is a chelating agent for Ga. 3+ The thermodynamic stability constant is high (logK ML :38.5), since the energy required for coordination is small, [ 68 The labeling of [Ga]Ga-HBED-CC is rapid and efficient. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracarboxylic acid (DOTA), 2,2'-(4,10-dicarboxymethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)diglutaric acid (DOTAGA), and 2,2'-(6-(dicarboxymethyl)amino)-6-(4-carboxybutyl)-1,4-diazepane-1,4-diacetic acid (AAZTA) can be realized to label various medical radioactive metal ions, including β-hydroxybenzoates for diagnostic purposes. + Emitting Lines 68 Ga, [ 18 F]AlF, 44 Sc, and 64 Nuclides such as Cu, β for diagnostic purposes - Emitting Lines 177 Lu and 90 Nuclides such as Y emit alpha rays for therapeutic purposes. 225 Ac and 212 / 213The nuclides include Bi, etc. Compared with DOTA, AAZTA can realize labeling of metal nuclides under relatively mild conditions. The prostate-specific membrane antigen-targeting radiometal complex of the present invention containing a nitroaromatic heterocyclic group contains a Lys-CO-Glu structure that targets the prostate-specific membrane antigen, and can bind to tumor cells that overexpress the prostate-specific membrane antigen and be taken up into the cells together with the prostate-specific membrane antigen receptor, and the nitroaromatic heterocyclic group can improve the retention of the complex in the tumor cells. In the present invention, 68 Ga]Ga-NI-HBED-CC-PSMA-093,[ 68 Ga]Ga-AAZTA-NI-PSMA-093, and [ 68 GA]Ga-HBED-CC-NI-PSMA is FDA approved for uptake into prostate-specific membrane antigen-positive cells [ 68 β-HBED-CC-PSMA-11. The prostate-specific membrane antigen-targeting radiometallic ligand containing a nitroaromatic heterocyclic group of the present invention allows for labeling of various radioactive diagnostic nuclides. By using a labeled imaging nuclide as an imaging radiometallic ligand, images with high imaging contrast can be obtained. By using a labeled therapeutic nuclide as a radionuclide therapeutic drug, drug retention at tumor sites can be improved, resulting in improved therapeutic efficacy. Therefore, the prostate-specific membrane antigen-targeting radiometallic ligand containing a nitroaromatic heterocyclic group of the present invention can more effectively integrate the medical treatment of prostate-specific membrane antigen receptor-positive tumors. The above description is only a preferred embodiment of the present invention, which does not limit the scope of the present invention. That is, the equivalent changes and modifications made within the scope of the patent and the content of this specification should still be included in the scope of the present invention.

Claims

1. A PSMA-targeting radiometal ligand containing a nitroaromatic heterocyclic group, the general formula of which is shown in Formula I-1. (Here, ChelatoR 1 is a bifunctional chelating agent structure selected from the following: R 1 is a nitroaromatic heterocyclic group selected from the following: L 1 is ChelatoR 1 and the PSMA targeting group, which is selected from: L 2 is ChelatoR 1 and R 1 is a linking group between the aryl group and the aryl group, and is any one selected from the following: Here, n is an integer from 0 to 6.

2. A PSMA-targeting radiometal ligand containing a nitroaromatic heterocyclic group, the general formula of which is shown in Formula II-1. (Here, ChelatoR 2 is a chelating group or a chelating structure of a chelating radionuclide, and is one selected from the following: R 2 is a nitroaromatic heterocyclic group selected from the following: L 3 is ChelatoR 2 and the PSMA targeting group, which is selected from: L 4 is ChelatoR 2 and R 2 is a linking group between the aryl group and the aryl group, and is any one selected from the following: Here, n is an integer from 0 to 6.

3. A PSMA-targeted radiometal complex containing a nitroaromatic heterocyclic group, the general formula of which is shown in Formula I-2. (Here, ChelatoR 1 is the chelate structure of the chelated radionuclide, and is one selected from the following: Here, M is 68 Ga, 18 F-AlF, 177 Lu, 90 Y. 44 Sc, 225 Ac, 212 Pb or 213 including, but not limited to, Bi, R 1 is a nitroaromatic heterocyclic group selected from the following: L 1 is ChelatoR 1 and the PSMA targeting group, which is selected from: L 2 is ChelatoR 1 and R 1 is a linking group between the aryl group and the aryl group, and is one selected from the following: Here, n is an integer from 0 to 6.

4. A PSMA-targeted radiometal complex containing a nitroaromatic heterocyclic group, the general formula of which is shown in Formula II-2. (Here, ChelatoR 2 is a chelating group or a chelating structure of a chelating radionuclide, and is one selected from the following: Here, M is 68 Ga, 18 F-AlF, 177 Lu, 90 Y. 44 Sc, 225 Ac, 212 Pb or 213 including, but not limited to, Bi, R 2 is a nitroaromatic heterocyclic group selected from the following: L 3 is ChelatoR 2 and the PSMA targeting group, which is selected from: L 4 is ChelatoR 2 and R 2 is a linking group between the aryl group and the aryl group, and is any one selected from the following: Here, n is an integer from 0 to 6.

5. 3. The PSMA-targeting radiometallic ligand containing a nitroaromatic heterocyclic group according to claim 1 or 2, the specific structure of which is as follows: or

6. 5. The PSMA-targeted radiometal complex containing a nitroaromatic heterocyclic group according to claim 3 or 4, the specific structure of which is as follows: or

7. The steps are as follows: (1) Triphosgene was dissolved in dichloromethane, and N(ε)-benzyloxycarbonyl-L-lysine tert-butyl ester hydrochloride (H-Lys(Z)-Ot-Bu HCl) dissolved in dichloromethane and triethylamine were slowly added dropwise to the above solution. L-glutamic acid di-tert-butyl ester hydrochloride and triethylamine dissolved in dichloromethane were slowly added dropwise to the above solution. The reaction mixture was stirred at room temperature to react, distilled under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1, v / v) to obtain a colorless oily product. The colorless oily product was dissolved in tetrahydrofuran, and 10% Pd / C was added. The mixture was stirred at room temperature in a hydrogen atmosphere to react, and the resulting reaction mixture was suction filtered through diatomaceous earth. The filtrate was rotary evaporated under reduced pressure to remove the solvent, yielding a brown oily compound, Lys(t-Bu)-CO-Glu(t-Bu) 2 Lys(t-Bu)-CO-Glu(t-Bu) 2 and Cbz-L 1 -NH 2 was dissolved in anhydrous DMF, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate and N,N'-diisopropylethylamine were added under ice bath, and the mixture was reacted at room temperature, separated overnight, and purified to obtain a pale yellow oily compound. The obtained pale yellow oily compound was dissolved in methanol, and Pd / C powder was added, and the mixture was reduced overnight in a hydrogen atmosphere with NH 2 -L 1 -Lys(t-Bu)-CO-Glu(t-Bu) 2 Obtained, (2) (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxovaleric acid was dissolved in ultra-dry N,N-dimethylformamide, and O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate and N,N'-diisopropylethylamine were added in an ice bath, followed by stirring in an ice bath. 1 -L 2 -NH 2 The reaction mixture was stirred at room temperature overnight, washed with ethyl acetate and saturated brine, and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was filtered to remove the anhydrous sodium sulfate. The filtrate was subjected to rotary evaporation under reduced pressure to remove the solvent, and then purified by silica gel column chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v=25 / 1 / 0.1) to obtain a pale yellow solid. The obtained pale yellow solid was dissolved in trifluoroacetic acid, stirred at room temperature, and distilled under reduced pressure to obtain a pale yellow solid compound. The obtained pale yellow solid compound was dissolved in ultra-dry N,N-dimethylformamide, and O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate and N,N'-diisopropylethylamine were added in an ice bath, and the mixture was stirred in an ice bath. NH 2 -L 1 -Lys(t-Bu)-CO-Glu(t-Bu) 2 was added to the reaction solution and reacted at room temperature overnight, the reaction solution was washed with ethyl acetate and saturated brine, the organic phase was collected and dried over anhydrous sodium sulfate, filtered to remove the anhydrous sodium sulfate, the filtrate was rotary evaporated under reduced pressure to remove the solvent, and the residue was purified by high-performance purification chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v=15 / 1 / 0.1) to obtain a pale yellow solid compound, the obtained pale yellow solid compound was dissolved in dichloromethane, diethylamine was added dropwise, the mixture was stirred at room temperature, and the solvent was removed by rotary evaporation under reduced pressure, and R １ -L 2 -NH-L 1 -Lys(t-Bu)-CO-Glu(t-Bu) 2 Obtained, (3) A chelating agent HBED-CC, AAZTA, DOTA, or NOTA is dissolved in anhydrous DMF, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate and N,N'-diisopropylethylamine are added thereto under ice bath conditions, followed by stirring in an ice bath. 1 -L 2 -NH-L 1 -Lys(t-Bu)-CO-Glu(t-Bu) 2 The mixture was stirred at room temperature overnight and purified by silica gel column chromatography to give a pale yellow oily liquid R 1 -L 2 -NH-L 1 (chelatoR 1 )-Lys(t-Bu)-CO-Glu(t-Bu) 2 Obtained, obtained R 1 -L 2 -NH-L 1 (chelatoR 1 )-Lys(t-Bu)-CO-Glu(t-Bu) 2 is dissolved in trifluoroacetic acid, stirred at room temperature, evaporated under reduced pressure to remove the solvent, and purified by semi-preparative HPLC to give the labeled ligand R 1 -L 2 -NH-L 1 (chelatoR 1 2. A method for preparing a PSMA-targeting radiometallic ligand containing a nitroaromatic heterocyclic group according to claim 1, wherein the PSMA-targeting radiometallic ligand is prepared by the method of ...

8. The steps are as follows: (1) Triphosgene was dissolved in dichloromethane, and N(ε)-benzyloxycarbonyl-L-lysine tert-butyl ester hydrochloride (H-Lys(Z)-Ot-Bu HCl) dissolved in dichloromethane and triethylamine were slowly added dropwise to the above solution. L-glutamic acid di-tert-butyl ester hydrochloride and triethylamine dissolved in dichloromethane were slowly added dropwise to the above solution. The reaction mixture was stirred at room temperature to react, distilled under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1, v / v) to obtain a colorless oily product. The colorless oily product was dissolved in tetrahydrofuran, and 10% Pd / C was added. The mixture was stirred at room temperature in a hydrogen atmosphere to react, and the resulting reaction mixture was suction filtered through diatomaceous earth. The filtrate was rotary evaporated under reduced pressure to remove the solvent, yielding a brown oily compound, Lys(t-Bu)-CO-Glu(t-Bu) 2 Lys(t-Bu)-CO-Glu(t-Bu) 2 and Cbz-L 3 -NH 2 was dissolved in anhydrous DMF, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate and N,N'-diisopropylethylamine were added under an ice bath, and the mixture was reacted overnight at room temperature, separated, and purified to obtain a pale yellow oily compound. The obtained pale yellow oily compound was dissolved in methanol, and Pd / C powder was added, and the mixture was reduced overnight under a hydrogen atmosphere to obtain NH 2 -L 3 -Lys(t-Bu)-CO-Glu(t-Bu) 2 Obtained, (2) The chelating agent HBED-CC, AAZTA, DOTA, or NOTA is dissolved in anhydrous DMF, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate and N,N'-diisopropylethylamine are added in an ice bath, followed by stirring in an ice bath. 2 -L 4 -NH 2 The reaction mixture was stirred at room temperature overnight, washed with ethyl acetate and saturated brine, and the organic phase was collected and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration. The filtrate was subjected to rotary evaporation under reduced pressure to remove the solvent. The resulting solution was purified by silica gel column chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v=90 / 10 / 0.1) to give a pale yellow solid, R 2 -L 4 -NH-CelatoR 2 The pale yellow solid R 2 -L 4 -NH-(CelatoR 2 ) was dissolved in anhydrous DMF, and O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate and N,N'-diisopropylethylamine were added thereto under ice bath conditions, followed by stirring in an ice bath. 2 -L 3 -Lys(t-Bu)-CO-Glu(t-Bu) 2 Then add R 2 -L 4 -NH 2 The reaction mixture was stirred at room temperature overnight, washed with ethyl acetate and saturated brine, and the organic phase was collected and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration. The filtrate was subjected to rotary evaporation under reduced pressure to remove the solvent. The mixture was then purified by silica gel column chromatography (dichloromethane / methanol / aqueous ammonia, v / v / v=90 / 10 / 0.1) to give a pale oily liquid R 2 -L 4 -NH-CelatoR 2 -NH-L 3 -Lys(t-Bu)-CO-Glu(t-Bu) 2 Obtained, obtained R 2 -L 4 -NH-CelatoR 2 -NH-L 3 -Lys(t-Bu)-CO-Glu(t-Bu) 2 is dissolved in trifluoroacetic acid, stirred at room temperature, evaporated under reduced pressure to remove the solvent, and purified by semi-preparative HPLC to give the labeled ligand R 2 -L 4 -NH-CelatoR 2 -NH-L 3 3. A method for preparing a PSMA-targeting radiometallic ligand containing a nitroaromatic heterocyclic group according to claim 2, wherein the PSMA-targeting radiometallic ligand is -Lys-CO-Glu.

9. The steps are as follows: Based on claim 7, The labeled ligand R obtained in step (3) 1 -L 2 -NH-L 1 (chelatoR 1 )-Lys-CO-Glu was dissolved in sodium acetate buffer solution, and the solution was 68 Ga]GaCL 3 or[ 177 Lu]LuCL 3 4. The method for preparing a PSMA-targeted radiometal complex containing a nitroaromatic heterocyclic group according to claim 3, further comprising the step of adding a solution of the contained radionuclide and reacting under heating for 5 to 15 minutes to obtain the corresponding radiometal complex shown in structure II-1.

10. The steps are as follows: Based on claim 8, the labeled ligand R obtained in step (3) 2 -L 4 -NH-CelatoR 2 -NH-L 3 -Lys-CO-Glu was dissolved in a sodium acetate buffer solution, and the solution was 68 Ga]GaCL 3 or[ 177 Lu]LuCL 3 5. The method for preparing a PSMA-targeted radiometal complex containing a nitroaromatic heterocyclic group according to claim 4, further comprising the step of adding a solution of the contained radionuclide and reacting under heating for 5 to 15 minutes to obtain the corresponding radiometal complex shown in structure II-2.

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