A class of radiopharmaceutical labeling precursors targeting prostate specific membrane antigen and fluorine radio-labeled compounds and applications thereof

Abstract

The application discloses a kind of radiopharmaceutical labeling precursor targeted prostate specific membrane antigen, structure is as shown in following: the precursor reagent RESCA-PSMA-1802 targeted prostate specific membrane antigen is first synthesized in the application, which can be labeled by F-Al method to prepare positron imaging agent 18 F-Al method 18 FAl-RESCA-PSMA-1802, has good stability and biological activity in vivo and in vitro, has better targeting to prostate cancer cells, can reflect tumor recurrence or metastasis condition, and is very suitable for PET imaging.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a class of radiopharmaceutical precursors targeting prostate-specific membrane antigens, their fluorine radiolabeled compounds, and their applications. Background Technology

[0002] Prostate-specific membrane antigen (PSMA), also known as folic acid hydrolase 1 (FOLH1), is a transmembrane glycoprotein composed of an extracellular C-terminus, transmembrane structures, and a cytoplasmic N-terminus. The extracellular region accounts for 95% of the entire glycoprotein and serves as a major site for recognition by peptides, aptamers, small molecules, and antibodies. PSMA is overexpressed on the surface of over 90% of prostate cancer cells, with even higher expression levels in advanced and castration-resistant prostate cancer cells. PSMA expression increases with the malignancy of prostate cancer. Therefore, PSMA has become an important target for the diagnosis and treatment of prostate cancer. Positron emission tomography (PET / CT) of PSMA is used for diagnostic scanning to assess PSMA expression. Many studies have shown that PSMA PET / CT has unique advantages in detecting prostate cancer lesions compared to traditional scanning examinations, providing more effective judgment in early prostate cancer and disease staging; furthermore, PSMA PET / CT significantly improves diagnostic sensitivity and accuracy due to its high-specificity multimodal imaging. Currently, the US FDA has approved... 68 Ga-PSMA11, 18 Two positron-emitting molecular probes, F-DCFPYL (Piflufolastat), are used for the diagnosis of prostate cancer. They have shown strong diagnostic value in the clinical diagnosis of recurrent and metastatic lesions in the prostate. Other probes under development include... 68 Ga-PSMA617, 68 Ga-PSMAI&T, etc. Among these PSMA probes, 68 Ga's short half-life (68 minutes) makes it unsuitable for widespread commercialization. Furthermore, due to rinsing... 68 The radioactivity of Ga nuclide generators is limited (commonly up to 50 mCurry), making them unsuitable for large-scale clinical practice. Currently, several research institutions in China have filed multiple patent applications, among which those suitable for... 68The patent applications for the Ga mark are as follows: CN117700479A, CN117700485A, CN117338960A, CN117209560A, CN117264012A, CN117069670A, CN116730983A, CN116283754A, CN116199736A, CN115572320A, CN115057801A, CN114 CN104619A, CN114014843A, CN113679857A, CN112851637A, CN112898270A, CN112321673A, CN112062695A, CN110305187A, CN110317151A, CN106075484A, etc., although these drugs can be linked to therapeutic radionuclides, have relatively short [intercepts / lengths] for PET imaging. 68 The short half-life of Ga limits the implementation of large-scale clinical applications. Other PSMA molecular probes under development include... 18 F-PSMA1007, [ 18 F]AlF-P16-093, etc., some 18 Patent applications using the F-mark include CN117263829A, CN114671806A, CN112961173A, CN112675311A, CN112190722A, CN111548305A, CN109160898A, CN109160896A, CN107353323A, and CN110938041A. The preparation of these drugs often requires harsh reaction conditions and complex reaction and purification processes, such as high temperature, hydrolysis with strong alkalis or strong acids, and separation using high-performance liquid chromatography. Therefore, their clinical application is somewhat limited.

[0003] Patent application WO2016065435A2 discloses the room-temperature labeling preparation of the PSMA inhibitor H3L27-MPAA-PSMA. 18 f-labeled product Al 18 F-L27-PSMA exhibits high radioactivity concentrations in the liver, intestines, and muscles. This can cause radiation damage to normal organs such as the liver and intestines. Simultaneously, increased uptake in muscles leads to higher background uptake, reducing the signal-to-noise ratio and hindering clinical translation and application. Summary of the Invention

[0004] The purpose of this invention is to provide a class of radiopharmaceutical progenitors that target prostate-specific membrane antigens.

[0005] Another object of the present invention is to provide a fluorine radiolabeled compound prepared from the radiopharmaceutical precursor that targets the prostate-specific membrane antigen.

[0006] A third object of the present invention is to provide the use of the aforementioned radiolabeled compounds in the preparation of positron emission tomography (PET) imaging agents for prostate cancer.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0008] In a first aspect, the present invention provides a class of radiopharmaceutical progenitors targeting prostate-specific membrane antigens, the structure of which is shown below:

[0009]

[0010] A second aspect of the present invention provides a fluorine radiolabeled compound, prepared from the radiopharmaceutical precursor targeting prostate-specific membrane antigen and a radionuclide, wherein the radionuclide is selected from... 18 F.

[0011] The structure of the fluorine radiolabeled compound is selected from one of the following structures:

[0012]

[0013] A third aspect of the present invention provides a method for preparing the aforementioned fluorine radiolabeled compound, comprising the following steps:

[0014] A radiolabeled precursor targeting prostate-specific membrane antigen was dissolved in a buffer solution, and an acetate / sodium acetate buffer solution containing aluminum chloride was added. 18 In sterile sodium chloride injection containing F ions, the reaction is carried out at room temperature for 5 to 20 minutes (preferably 10 or 15 minutes);

[0015] The compound was purified by high-pressure liquid chromatography and solid-phase extraction, then diluted and sterilized with sodium ascorbate solution to obtain the fluorine radiolabeled compound.

[0016] Alternatively, the fluorine radiolabeled compound can be obtained by solid-phase extraction separation and purification, followed by dilution and sterilization with sterile water.

[0017] The buffer solution is an acetate / sodium acetate buffer solution with a pH of 4.0-6.0 (preferably 4.5 or 5) and a concentration of 0.05 mmol / L to 1 mol / L (preferably 0.2 mol / L).

[0018] The aluminum chloride-containing acetate / sodium acetate buffer solution has the following characteristics: the concentration of aluminum chloride is 5-15 mmol / L (preferably 5 or 10 mmol / L); and the pH is 4.0-6.0 (preferably 4.5 or 5.0).

[0019] The solid-phase extraction separation and purification steps are as follows: sterile water for injection is added to the solution after the reaction is complete, and the solid-phase extraction is performed for separation and purification. After rinsing the solid-phase extraction column with sterile water for injection, the product on the solid-phase extraction column is washed into a transfer bottle with 50% ethanol solution.

[0020] The solid-phase extraction chromatography column is selected from C-18, tC-18, HLB columns, etc.

[0021] The purification process, involving sequential high-performance liquid chromatography (HPLC) and solid-phase extraction (SPE), involves the following steps: HPLC purification (mobile phase: 30% acetonitrile aqueous solution; wavelength: 220 nm; flow rate: 4 mL / min; 25 cm × 10 mm C18 column); collection of the product with a radioactive retention time of 12-14 min in sterile water; separation and concentration using a Light-C18 SPE column; rinsing of the SPE column with sterile water for injection; and finally, washing the product from the SPE column with 50% ethanol solution into a transfer bottle.

[0022] The sodium ascorbate solution is prepared by dissolving sodium ascorbate in water at a concentration of 1–1500 mg / mL (preferably 12.5 mg / mL).

[0023] The sterilization process uses a 0.22-micron sterilization filter membrane.

[0024] The unattenuated corrected radiochemical yield of the fluorine radiolabeled compound is 10-65% (preferably 55%, 60%, 65%), and the specific activity is 1-100 GBq / umol (preferably 3.46 GBq / umol, 65.5 GBq / umol, 89.3 GBq / umol).

[0025] In a fourth aspect, the present invention provides the use of the fluorine radiolabeled compound in the preparation of a positron emission tomography (PET) imaging agent for prostate cancer.

[0026] A fifth aspect of the present invention provides the use of the fluorine radiolabeled compound in the preparation of a positron-emitting molecular probe that specifically targets the prostate-specific membrane antigen PSMA.

[0027] By adopting the above technical solution, the present invention has the following advantages and beneficial effects:

[0028] This invention provides a radiopharmaceutical prodrug labeled precursor RESCA-PSMA-1802 that targets prostate-specific membrane antigens, and employs...18 F-Al labeling method for radiolabeling to prepare positron emission tomography (PET) imaging agents at room temperature 18 FAl-RESCA-PSMA-1802, due to 18 The physical half-life of F (110 min) is greater than 68 Ga's physical half-life (68 min) can meet the routine delivery requirements for clinical drug use.

[0029] The fluorine radiolabeled compound of the present invention is simple to prepare, has low energy consumption, high labeling rate, and good in vivo and in vitro stability. After the molecular probe is incubated in fetal bovine serum for 2 hours, the prototype retention rate is greater than 95%.

[0030] This invention is the first synthesis of RESCA-PSMA-1802, a precursor reagent targeting prostate-specific membrane antigen (PSMA). This reagent can be used... 18 Positron imaging agents were prepared by labeling at room temperature using the F-Al method. 18 FAl-RESCA-PSMA-1802 exhibits good stability and bioactivity both in vitro and in vivo, and has good targeting properties for prostate cancer cells. It can reflect tumor recurrence or metastasis, making it very suitable for PET imaging.

[0031] In the preparation of radiolabeled compounds, the present invention provides a rapid, efficient, and low-energy-consumption process for radiolabeling, facilitates the separation of target compounds, produces radioactive products with high specific activity, and makes the labeled substances valuable for clinical examination and diagnosis.

[0032] The radiolabeled compounds of this invention are prepared under mild conditions, have a high labeling rate, exhibit good biological properties, and possess better in vivo stability. Attached Figure Description

[0033] Figure 1 This is a schematic diagram of the mass spectrum of compound RESCA-PSMA-1801.

[0034] Figure 2 This is a schematic diagram of the mass spectrum of compound RESCA-PSMA-1802.

[0035] Figure 3 yes 18 FAl-RESCA-PSMA-1801 and 18 HPLC chromatogram of FAl-RESCA-PSMA-1802 after incubation in fetal bovine serum for 2 hours.

[0036] Figure 4 yes 18 In vivo distribution of FAl-RESCA-PSMA-1801 in LNCap tumor model mice at 10, 30, 60, and 120 minutes.

[0037] Figure 5 yes 18 In vivo distribution of FAl-RESCA-PSMA-1802 in tumor model 22RV1 mice at 30, 60, 90, and 120 minutes. Detailed Implementation

[0038] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments, further clarifies the invention. Those skilled in the art should understand that the specific descriptions below are illustrative rather than restrictive, and should not be construed as limiting the scope of protection of the present invention.

[0039] 2,2'-(((1R,2R)-2-((carboxymethyl)(4-(2-oxo-2-(2,3,5,6-tetrafluorophenoxy)ethyl)benzyl)amino)cyclohexyl)azadiyl)diacetic acid, (((S)-5-(6-aminohexamido)-1-carboxypentyl)carbamoyl)-L-glutamic acid and (((S)-5-amino-1-carboxypentyl)carbamoyl)-L-glutamic acid were purchased from Jiangxi Nanchang Probe Biotechnology Co., Ltd.

[0040] Example 1

[0041]

[0042] 2,2'-(((1R,2R)-2-((carboxymethyl)(4-(2-oxo-2-(2,3,5,6-tetrafluorophenoxy)ethyl)benzyl)amino)cyclohexyl)azadiyl)diacetic acid (11.6 mg, 20 μmol, 1 equivalent) was dissolved in 1 mL of a mixture of dimethyl sulfoxide and 1 mL of 0.05 M sodium bicarbonate. Then, (((S)-5-(6-aminohexamido)-1-carboxypentyl)carbamoyl)-L-glutamic acid (8.7 mg, 20 μmol, 1 equivalent) was added. The mixture was stirred overnight at room temperature. The reaction solution was purified by Semi-HPLC (mobile phase: A 0.1% trifluoroacetic acid in water, B acetonitrile; 20% B for 20 min, flow rate 4 mL / min, C18-B, 250 mm × 10 mm, 5 μm). Morhchem Technologies Inc., USA; Retention time t R The reaction proceeded over 10-12 minutes to yield a white solid RESCA-PSMA-180 14.2 mg (yield: 25%). Figure 1 This is a schematic mass spectrum of compound RESCA-PSMA-1801. The theoretical molecular weight [M+H] is shown in the MS (ESI) data. + 850.40, measured molecular weight 851.0 [M+H] + .

[0043] Example 2

[0044]

[0045] 2,2'-(((1R,2R)-2-((carboxymethyl)(4-(2-oxo-2-(2,3,5,6-tetrafluorophenoxy)ethyl)benzyl)amino)cyclohexyl)azadiyl)diacetic acid (11.6 mg, 20 μmol, 1 equivalent) was dissolved in 1 mL of a mixture of dimethyl sulfoxide and 1 mL of 0.05 M sodium bicarbonate. Then, ((((S)-5-amino-1-carboxypentyl)carbamoyl)-L-glutamic acid (6.4 mg, 20 μmol, 1 equivalent) was added. The mixture was stirred overnight at room temperature. The reaction solution was purified by Semi-HPLC (mobile phase: A 0.1% trifluoroacetic acid in water, B acetonitrile; 20% B for 20 min, flow rate 4 mL / min, C18-B, 250 mm × 10 mm, 5 μm). Morhchem Technologies Inc., USA; Retention time t R (For 8-10 minutes), a white solid RESCA-PSMA-18023.1 mg was obtained (yield: 21%). Figure 2 This is a schematic mass spectrum of compound RESCA-PSMA-1802. The theoretical molecular weight [M+H] is shown in the MS (ESI) data. + 737.31, measured molecular weight 738.3 [M+H] + .

[0046] Example 3

[0047]

[0048] 100 μg of RESCA-PSMA-1801 prepared in Example 1 was dissolved in 500 μL of 0.2 mol / L acetate / sodium acetate buffer solution at pH 4.5. Then, 5 μL of 10 mmol / L aluminum chloride acetate / sodium acetate buffer solution (pH 4.5, 0.2 mol / L) was added, and the solution was transferred to a container containing… 18In a reaction flask containing 0.2 mL of sterile sodium chloride injection for F ions (740 MBq), the mixture was shaken at room temperature for 10 minutes. After complete reaction, 10 mL of sterile water for injection was added to the resulting solution. The mixture was then purified by solid-phase extraction (SPE) using a C-18 column. The column was rinsed with 10 mL of commercially available sterile water for injection, and the product was washed onto the column with 2 mL of 50% ethanol solution and transferred to a transfer bottle. The solution was diluted with 8 mL of an aqueous solution containing 100 mg of sodium ascorbate and sterilized using a 0.22 μm sterile filter membrane to obtain a radiolabeled compound of 407 MBq. 18 FAl-RESCA-PSMA-1801. Unattenuated radiochemical yield is 55.0%, and specific activity is 3.46 GBq / umol.

[0049] The radionuclide 18 Preparation of F:

[0050] Using a 10MV accelerator through nuclear reactions 18 O(p, n) 18 F production 18 F, with a target beam of 50 μA, bombardment for 10 minutes generates 3.7 GBq of [unspecified substance]. 18 F; adsorption was performed using an anion exchange solid-phase extraction column (QMA), followed by rinsing with 0.5 mL of sodium chloride aqueous solution. 18 F ions are introduced into the reaction flask.

[0051] Establishment of the LNCaP mouse tumor model: Human prostate cancer cells highly expressing PSMA (LNCaP cell line) were resuscitated, and CHO DO2 medium was added to a T75 flask. Cells were seeded and cultured in a 37°C, 5% CO2 incubator. When the cell density reached approximately 85% of the bottom of the culture dish, the cells were collected by centrifugation, diluted and resuspended with sterile PBS, and counted. A corresponding volume of cell suspension was aspirated at a seeding density of 500,000 cells per mouse and stored on ice before being transferred to the animal handling room.

[0052] Five-week-old NCG mice (purchased from Heyuan Biotechnology (Shanghai) Co., Ltd.) were selected. The mice were immobilized, and the cell suspension was thoroughly agitated using a pipette before injection. Using a sterile syringe, the cell suspension was drawn up and slowly injected subcutaneously into the axillary region of each mouse at a volume of 100-150 μL, containing the target number of cells. Vital signs and movement of the mice were observed after injection. Tumors were considered closed when the tumor volume exceeded 300 mm². 3 It was then used in subsequent small animal PET / CT imaging experiments.

[0053] The LNCap-bearing tumor model was randomly divided into two groups of 10 mice each. One group was used for static imaging at 10, 30, 60, and 120 minutes (each mouse was injected with approximately 5.55 MBq of imaging agent). 18 FAl-RESCA-PSMA-1801), another set was used for blocking experiments (after injection of imaging agent). 18 FAl-RESCA-PSMA-1801 was injected with approximately 200 μg of PSMA 11 as a blocking agent 5 minutes before the injection, and a static PET / CT scan of the small animal was performed 60 minutes after the injection of the imaging agent.

[0054] The results showed that 18 The maximum uptake value (SUVmax) of FAl-RESCA-PSMA-1801 in tumor model mice was 0.5 (60 min), and the SUVmax for blockade imaging was 0.1 (60 min). This demonstrates... 18 FAl-RESCA-PSMA-1801 is a positron-emitting molecular probe that specifically targets the prostate-specific membrane antigen PSMA.

[0055] Figure 4 yes 18 In vivo distribution of FAl-RESCA-PSMA-1801 in LNCap tumor model mice at 10, 30, 60, and 120 minutes. It can be seen that... 18 FAl-RESCA-PSMA-1801 is primarily eliminated through hepatic metabolism. Over time, the uptake of the molecular probe in the liver initially increases and then decreases, subsequently concentrating in the intestine. At the tumor site, uptake reaches its peak 30 minutes after imaging agent injection, then gradually decreases, demonstrating... 18 FAl-RESCA-PSMA-1801 has a short retention time at the tumor site and a fast clearance speed.

[0056] Example 4

[0057]

[0058] Dissolve 50 μg of RESCA-PSMA-1802 in 500 μL of 0.2 mol / L acetate / sodium acetate buffer solution (pH 5.0), then add 5 μL of 10 mmol / L aluminum chloride acetate / sodium acetate buffer solution (pH 5, 0.2 mol / L). Transfer the solution to a container containing... 18The F-ion (7.4 GBq) was reacted in a reaction flask containing 0.5 mL of sterile sodium chloride injection at room temperature with shaking for 15 minutes. Purification was performed by HPLC (mobile phase: 30% acetonitrile aqueous solution; wavelength: 220 nm; flow rate: 4 mL / min; 25 cm × 10 mm C18 column). The product with a radioactive retention time of 12–14 min was collected in 30 mL of sterile water and then concentrated using a Light-C18 solid-phase extraction column. The solid-phase extraction column was rinsed with 10 mL of sterile water for injection (commercially available), and the product was washed onto the column with 2 mL of 50% ethanol solution into a transfer bottle. The solution was diluted with 8 mL of an aqueous solution containing 100 mg of sodium ascorbate and sterilized using a 0.22 μm sterile filter membrane to obtain a radiolabeled compound of 4.44 GBq. 18 FAl-RESCA-PSMA-1802. Unattenuated radiochemical yield is 60.0%, and specific activity is 65.5 GBq / umol.

[0059] Establishment of the 22RV1 tumor model in mice: Human prostate cancer cells (22RV1 cell line) expressing high levels of PSMA were resuscitated, and CHO DO2 medium was added to T75 flasks. The cells were then seeded and cultured in a 37°C, 5% CO2 incubator. When the cell density reached approximately 85% of the bottom of the culture dish, the cells were collected by centrifugation, diluted and resuspended with sterile PBS, and the cells were counted. A corresponding volume of cell suspension was aspirated at a seeding density of 500,000 cells per mouse and stored on ice before being transferred to the animal handling room.

[0060] Five-week-old Balb / c nude mice (purchased from Heyuan Biotechnology (Shanghai) Co., Ltd.) were selected. The mice were immobilized, and the cell suspension was thoroughly agitated using a pipette before injection. Using a sterile syringe, the cell suspension, containing the target cell volume, was slowly injected subcutaneously into the axillary region of each mouse at a volume of 100-150 μL. Vital signs and movement of the mice were observed after injection. Tumors were considered closed when the tumor volume exceeded 300 mm². 3 It was then used in subsequent small animal PET / CT imaging experiments.

[0061] The 22RV1 tumor model was randomly divided into two groups of 10 mice each. One group was used for static imaging at 10, 30, 60, and 120 minutes (each mouse was injected with approximately 7.40 MBq of imaging agent). 18 FAl-RESCA-PSMA-1802), another set was used for blocking experiments (after injection of imaging agent). 18 FAl-RESCA-PSMA-1802 was injected with approximately 150 μg of PSMA 11 as a blocking agent 5 minutes before the injection, and a static PET / CT scan of the small animal was performed 60 minutes after the injection of the imaging agent.

[0062] The results showed that 18 The maximum uptake value (SUVmax) of FAl-RESCA-PSMA-1802 in tumor model mice was 0.9 (60 min), and the SUVmax for blockade imaging was 0.1 (60 min). This demonstrates... 18 FAl-RESCA-PSMA-1802 is a positron-emitting molecular probe that specifically targets the prostate-specific membrane antigen PSMA.

[0063] Figure 5 yes 18 In vivo distribution of FAl-RESCA-PSMA-1802 in the 22RV1 tumor model mouse at 30, 60, 90, and 120 minutes. It can be seen that... 18 FAl-RESCA-PSMA-1802 is primarily eliminated through renal metabolism. Uptake of the molecular probe in the kidneys initially increases and then decreases over time. Uptake at the tumor site peaks at 60 minutes and remains unchanged over time in 2-hour imaging experiments. Compared to... 18 FAl-RESCA-PSMA-1801, 18 FAl-RESCA-PSMA-1802 is a more clinically suitable positron emission tomography (PET) imaging agent for prostate cancer.

[0064] Example 5

[0065] 0.74 MBq respectively 18 FAl-RESCA-PSMA-1801 or 0.74 MBq 18 FAl-RESCA-PSMA-1802 was added to fetal bovine serum and incubated at room temperature for 2 hours. The results were then analyzed by HPLC. 18 HPLC conditions for FAl-RESCA-PSMA-1801: Mobile phase: A 0.1% trifluoroacetic acid in water, B acetonitrile; 17% B for 15 min, flow rate 1 mL / min; C18-B, 150 mm × 4.6 mm, 5 μm. Morhchem Technologies Inc., USA; 18 HPLC conditions for FAl-RESCA-PSMA-1802: 17% B for 15 min, flow rate 1 mL / min; C18-B, 150 mm × 4.6 mm, 5 μm. Morhchem Technologies Inc., USA; Figure 3 yes 18 FAl-RESCA-PSMA-1801 and 18HPLC chromatogram of FAl-RESCA-PSMA-1802 after incubation in fetal bovine serum for 2 hours. 18 FAl-RESCA-PSMA-1801 and 18 The retention times of FAl-RESCA-PSMA-1802 were 9.9 minutes and 8.8 minutes, respectively. After incubation in fetal bovine serum for 2 hours, the molecular probes maintained a prototype retention rate of over 95%. This indicates that these two positron-emitting molecular probes possess good in vitro stability. 18 FAl-RESCA-PSMA-1802 and 18 FAl-RESCA-PSMA-1801 can be used as a stable and specific positron-emitting molecular probe targeting the prostate-specific membrane antigen PSMA for further research and exploration.

[0066] Example 6

[0067] Dissolve 100 μg of RESCA-PSMA-1802 in 500 μL of 0.2 mol / L acetate / sodium acetate buffer solution (pH 5.0), then add 5 μL of 0.1 mol / L aluminum chloride acetate / sodium acetate buffer solution (pH 4.5). Transfer the solution to a container containing... 18 In a reaction flask containing 0.5 mL of sterile sodium chloride injection for F ions (18.5 GBq), the mixture was shaken at room temperature for 15 minutes. After complete reaction, 10 mL of sterile water for injection was added to the resulting solution. The solution was then purified by solid-phase extraction (SPE) using an HLB column. The column was rinsed with 10 mL of commercially available sterile water for injection, and the product was then washed onto a transfer bottle with 2 mL of 50% ethanol. The solution was diluted with 8 mL of sterile water and sterilized using a 0.22 μm sterile filter membrane to obtain a radiolabeled compound of 12.1 GBq. 18 FAl-RESCA-PSMA-1802. The unattenuated radiochemical yield was 65.0%, with a total synthesis time of 32 minutes. The attenuated radiochemical yield was 79.5%. The specific activity was 89.3 GBq / umol.

[0068] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A class of radiopharmaceutical prodrugs targeting prostate-specific membrane antigens, characterized in that, The structure is as follows:

2. A fluorine radiolabeled compound, characterized in that, It is prepared from the radiopharmaceutical precursor targeting prostate-specific membrane antigen as described in claim 1 and a radionuclide, wherein the radionuclide is selected from... 18 F; The structure of the fluorine radiolabeled compound is shown below:

3. A method for preparing the fluorine radiolabeled compound according to claim 2, characterized in that, Includes the following steps: A radiolabeled precursor targeting prostate-specific membrane antigen was dissolved in a buffer solution, and an acetate / sodium acetate buffer solution containing aluminum chloride was added. 18 In sterile sodium chloride injection containing F ions, the reaction is carried out at room temperature for 5–20 minutes. The compound was purified by high-pressure liquid chromatography and solid-phase extraction, then diluted and sterilized with sodium ascorbate solution to obtain the fluorine radiolabeled compound. Alternatively, the fluorine radiolabeled compound can be obtained by solid-phase extraction separation and purification, followed by dilution and sterilization with sterile water. The buffer solution is an acetate / sodium acetate buffer solution with a pH of 4.0-6.0 and a concentration of 0.05 mmol / L to 1 mol / L; The aluminum chloride-containing acetate / sodium acetate buffer solution has the following characteristics: the concentration of aluminum chloride is 5–15 mmol / L; and the pH is 4.0–6.

0.

4. The method for preparing the fluorine radiolabeled compound according to claim 3, characterized in that, The solid-phase extraction separation and purification steps are as follows: sterile water for injection is added to the solution after the reaction is complete, and the solid-phase extraction is performed for separation and purification. After rinsing the solid-phase extraction column with sterile water for injection, the product on the solid-phase extraction column is washed into a transfer bottle with 50% ethanol solution.

5. The method for preparing the fluorine radiolabeled compound according to claim 3, characterized in that, The steps of separation and purification by high-performance liquid chromatography and solid-phase extraction are as follows: the product with a radioactivity retention time of 12-14 min is collected in sterile water after purification by HPLC, separated and concentrated by Light-C18 solid-phase extraction column, rinsed with sterile water for injection, and then washed with 50% ethanol solution into a transfer bottle.

6. The method for preparing the fluorine radiolabeled compound according to claim 3, characterized in that, The sodium ascorbate solution is sodium ascorbate dissolved in water at a concentration of 1–1500 mg / mL; The unattenuated corrected radiochemical yield of the fluorine radiolabeled compound is 10–65%, and the specific activity is 1–100 GBq / µmol.

7. The use of the fluorine radiolabeled compound of claim 2 in the preparation of a positron emission tomography (PET) prostate cancer imaging agent.

8. The use of the fluorine radiolabeled compound of claim 2 in the preparation of a positron-emitting molecular probe that specifically targets the prostate-specific membrane antigen PSMA.

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