Novel radionuclide labeled thiol derivatives for diagnosis or therapy of prostate specific membrane antigen expressing tumors and use thereof

Abstract

The present application provides a marker inhibitor for diagnosing or treating a cancer expressing prostate-specific membrane antigen, the inhibitor being a compound represented by general formula I or a compound represented by general formula II or a compound represented by general formula III or an optical isomer, a pharmaceutically acceptable salt and / or a solvate thereof, and the present application also provides a preparation method thereof and a pharmaceutical composition containing the compound. The present application also relates to the use of the compound and a pharmaceutically acceptable salt, a solvate or a prodrug thereof in treatment as a therapeutic agent for treating a cancer expressing PSMA.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of radiolabeled compounds for cancer selective (mainly targeting prostate specific membrane antigen) imaging or therapy, and in particular to labeled inhibitors for the diagnosis or treatment of cancers expressing prostate specific membrane antigen. BACKGROUND

[0002] Worldwide, the incidence of prostate cancer ranks second among all malignant tumors in men. In the United States, the incidence of prostate cancer has exceeded lung cancer, becoming the first tumor endangering men's health. The incidence of prostate cancer in Asia is far lower than that in European and American countries, but in recent years it has shown an upward trend, and the growth is more rapid than in European and American developed countries. According to the data of the National Cancer Center, prostate cancer has been the highest incidence of tumors in the male urinary system since 2008. How to accurately stage prostate patients as early as possible and assist with effective treatment to reduce mortality is the focus of research in this field.

[0003] According to the current guidelines, ultrasound-guided biopsy is the most commonly used method for diagnosing prostate cancer. Magnetic resonance imaging (MRI) is the standard imaging method for detecting suspected early prostate cancer with negative pathological examination results. The use of MRI to locate suspected lesions to guide biopsy sampling can improve the diagnostic coincidence rate. Even with MRI, there are still missed cases. Therefore, positron emission computed tomography (PET) imaging, which can provide additional cell biological information, has gained widespread attention. The use of PET imaging based on choline and glucose metabolism for the diagnosis and staging of prostate cancer has been extensively studied and discussed, but the results are not ideal. However, PET imaging using prostate specific membrane antigen (PSMA) as a probe has gained increasing attention, offering new hope for improving the diagnosis and treatment of prostate cancer.

[0004] PSMA is highly expressed in 95% of prostate cancer patients, and the expression level is up-regulated in castration-resistant prostate cancer (mCRPC) and metastatic prostate cancer. Therefore, PSMA can be used as an ideal target for the diagnosis and treatment of prostate cancer and its metastatic lesions. At present, there are a variety of molecular probes for treating clinical experiments with PSMA as a target. Common PSMA molecular probes include monoclonal antibodies, small molecule inhibitors and the like. For example, 111In-labeled 7E11 is the first radiolabeled PSMA monoclonal antibody, and is a relatively successful drug for SPECT imaging of prostate cancer at present, but 7E11 can only bind to the intramembrane segment of PSMA, and therefore can only be taken up by necrotic and apoptotic cells, so the imaging sensitivity is not high.

[0005] PSMA small molecule inhibitors have good cell penetration and fast blood clearance, and mainly include three categories: 1. Phosphate, phosphite, phosphonate, phosphoramidate and the like; 2. Sulfhydryl, indole-sulfhydryl, hydroxamic acid, sulfonamide derivatives; 3. Urea derivatives. At present, the urea derivative small molecule inhibitors entering the clinical experiment stage mainly include PSMA-11, PSMAI&T, PSMA-617 and the like.

[0006] PSMA small molecule inhibitors can be labeled with 18 F, 68 Ga for imaging of prostate cancer, and can also be labeled with 177 Lu, 90 Y, 131 I for treatment of prostate cancer. However, the existing PSMA-targeted PET imaging agent labeled with the nuclide Ga-68 has the problems of short half-life, limited effective utilization time, and insignificant tumor uptake in a prostate cancer cell metastasis model, and the imaging effect needs to be improved.

[0007] The existing developed PSMA molecular probe tracers mainly include: 18 F-DCFBC, 18 F-DCFPyL, 18 F-PSMA-1007, but these several molecular probe tracers have low sensitivity for prostate cancer, are not specific, and also have the problems of low specific activity, low radiochemical purity (the pharmaceutical requirement is not less than 90%), poor stability, and difficulty in guaranteeing the final imaging effect. SUMMARY

[0008] In order to solve the above technical problems in the prior art, the applicant provides a novel compound.

[0009] A first object of the present application is to provide a compound of general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,

[0010]

[0011] wherein:

[0012] n is an integer from 0 to 12;

[0013] X is C=0, S=0,

[0014] A is a radionuclide;

[0015] When n = 0, the radionuclide A is then linked by a methylene group.

[0016] A second object of the present application is to provide a compound of general formula II and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,

[0017]

[0018] wherein:

[0019] X is C=0, S=0,

[0020] m is an integer from 0 to 12;

[0021] A is a radionuclide;

[0022] When m = 0, the radionuclide A is then linked by a methylene group.

[0023] A third object of the present application is to provide a compound of general formula III and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,

[0024]

[0025] wherein:

[0026] n is an integer from 0 to 12;

[0027] X is C=0, S=0,

[0028] A is a radionuclide, which can be substituted at any position of the phenyl ring;

[0029] B is

[0030] d is 0 or 1

[0031] Further, the radionuclide is selected from a diagnostic nuclide or a therapeutic nuclide, the diagnostic nuclide being mainly 18 F, and the therapeutic nuclide being mainly 131 I or 211At. Also diagnostic nuclides, therapeutic nuclides with comparable effects can be included

[0032] The compound is selected from the following structures:

[0033]

[0034]

[0035]

[0036]

[0037]

[0038] A third object of the present application is to provide a pharmaceutical composition comprising the aforementioned compound and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof.

[0039] A fourth object of the present application is to provide the use of the aforementioned compound and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof or the aforementioned pharmaceutical composition for the manufacture of a medicament for the treatment and / or amelioration and / or prevention of a cancer expressing PSMA and / or metastases thereof.

[0040] A fifth object of the present application is to provide the use of the aforementioned compound and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof or the aforementioned pharmaceutical composition for the manufacture of a diagnostic agent for a cancer expressing PSMA.

[0041] Further, the cancer expressing PSMA and / or metastases thereof is prostate cancer and / or metastases thereof.

[0042] As mentioned above, the present application also relates to a pharmaceutical composition comprising a compound as described above or below or a complex as described above or below. It is to be understood that the pharmaceutical composition comprises a therapeutically effective amount of the compound and / or the complex, respectively. The composition can further comprise at least one organic or inorganic solid or liquid and / or at least one pharmaceutically acceptable carrier.

[0043] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0044] The compounds according to the application can be formulated, if appropriate, together with the excipients and carriers customary in the art of pharmacy and medicine, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous carriers, fatty bodies of animal or vegetable origin, paraffin derivatives, glycols, especially polyethylene glycols, various plasticizers, dispersants or emulsifiers, pharmaceutically compatible gases (for example, air, oxygen, carbon dioxide, etc.), preservatives. For the preparation of liquid formulations, additives such as sodium chloride solution, ethanol, sorbitol, glycerol, olive oil, almond oil, propylene glycol or ethylene glycol can be used.

[0045] A "patient" includes an animal, such as a human, monkey, cow, horse, cat, or dog. The animal can be a mammal, such as a non-primate and a primate (e.g., a monkey and a human). In one embodiment, the patient is a human.

[0046] Generally, the compounds of Formula (I), Formula (II), and Formula (III), or a pharmaceutical composition thereof, can be administered orally or by parenteral routes, typically by injection or infusion. "Parenteral" means modes of administration other than enteral and topical administration, usually by injection. This includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinally and sternal injection and infusion.

[0047] The compounds of the present application can be synthesized in, for example, solution, although other synthetic procedures are possible and known to those skilled in the art. Preferred syntheses of the compounds of the present application are described in detail in the Examples section.

[0048] The technical scheme of the present application has the following beneficial effects relative to the prior art:

[0049] The present application provides novel compounds which are useful and advantageous radiopharmaceuticals and can be used in nuclear medicine as tracers, imaging agents and for various disease states in the treatment of PSMA-expressing cancers, in particular prostate cancer. BRIEF DESCRIPTION OF DRAWINGS

[0050] Figure 1 Representative PET imaging of LNCaP tumor-bearing mice at 3 h post-injection of ZT-002;

[0051] Figure 2 Representative PET imaging of LNCaP tumor-bearing mice at 3 h post-injection of ZT-006;

[0052] Figure 3 PET imaging of LNCaP tumor-bearing mice before and after treatment with ZT-009;

[0053] Figure 4 PET imaging of LNCaP tumor-bearing mice before and after treatment with ZT-012;

[0054] Figure 5 PET imaging of LNCaP tumor-bearing mice before and after treatment with ZT-018;

[0055] Figure 6 Representative PET imaging of LNCaP tumor-bearing mice 3h after injection of Ga-PSMA-11. 68 Ga-PSMA-11. DETAILED DESCRIPTION

[0056] The present application is further explained with the following examples, which do not limit the present application in any form.

[0057] MATERIALS AND METHODS

[0058] All commercially available chemicals were of analytical grade and used without further purification. In vitro experiments were performed in triplicate and at least three independent sets of data were obtained for each experiment.

[0059] Synthesis of general formula I

[0060]

[0061] Synthesis of intermediate I 2

[0062] p-Methylbenzylsulfonyl chloride (I 1) was added to a solution of different PEGn-OH (n = 1-12) and triethylamine in dichloromethane. The reaction mixture was stirred at room temperature overnight and washed with water and brine. After evaporation of the solvent, the intermediate I 2 was purified by column chromatography.

[0063] Synthesis of intermediate I 3

[0064] Sodium hydride was added to a solution of intermediate I 2 and divinylsulfone. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by column chromatography to obtain the intermediate I 3.

[0065] Synthesis of intermediate I 4

[0066] Intermediate I 3 was added to 30 pL TBAF (1 M TBAF in THF) in 50 pL DMSO and reacted at 75 °C for 30 min. The reaction mixture was purified on a high-performance liquid chromatography C18 column to obtain the intermediate I 4.

[0067] Synthesis of target probe I 6

[0068] The target probe was prepared by adding PSMA-SH (I 5) to a solution of intermediate I 4 in THF and adjusting the pH to 8.5 using Borate buffer.

[0069] Synthesis of general formula II

[0070]

[0071] Synthesis of intermediate II 2

[0072] Into a reaction tube was added intermediate II 1 and concentrated sulfuric acid at 0 °C. Fuming HNO3 was added dropwise to the solution using a syringe. The reaction was stirred at 60 °C for 7 h and then cooled to room temperature. The reaction mixture was then added to ice crushed and the resulting precipitate was filtered and dried under vacuum to yield intermediate II 2.

[0073] Synthesis of intermediate II 3

[0074] Into a 25 mL two necked round bottom flask was added potassium carbonate and intermediate II 2 and was fitted with a condenser and magnetic stir bar. The p-methoxybenzyl chloride in super dry DMF was added via syringe under a nitrogen atmosphere. The mixture was stirred at 115 °C overnight and then cooled in an ice bath. The resulting precipitate was filtered and washed with ethyl acetate. The filtrate was combined and concentrated and purified by column chromatography to yield intermediate II 3.

[0075] Synthesis of intermediate II 4

[0076] Into an ice bath cooled round bottom flask was added intermediate II 3 and super dry THF. The solution was stirred vigorously while adding LiAlH4. The reaction was quenched with ice water and saturated NaHCO3 at 0 °C for 2 h. The resulting bright red slurry was filtered and washed with ethyl acetate. The filtrate was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to yield intermediate II 4.

[0077] Synthesis of intermediate II 5

[0078] Into a single necked flask cooled in an ice salt bath was added CH3COOH, acetic anhydride and fuming HNO3 sequentially. The mixture was stirred at room temperature for 1 h before adding intermediate II 4. Stirring was continued at r.t. for 1.5 h and quenched with DCM. The mixture was washed with brine, the organic layer was dried over anhydrous Na2SO4, concentrated and purified by column chromatography to yield intermediate II 5.

[0079] Synthesis of intermediate II 6

[0080] Intermediate II 5 was added to a solution of different PEGm-OH (m = 1-12) and sodium hydroxide in dichloromethane. The reaction mixture was stirred under heating overnight. After evaporation of the solvent, column chromatography purification gave intermediate II 6.

[0081] Synthesis of intermediate II 7

[0082] Intermediate II 6, p-toluenesulfonyl chloride was charged into a single-necked flask. Dichloromethane and triethylamine were added successively under N2 atmosphere, stirred overnight, concentrated and column chromatography purification gave intermediate II 7.

[0083] Synthesis of intermediate II 9

[0084] Intermediate II 7 and intermediate II 8 were dissolved in HEPES buffer, pH was adjusted to 7.0, reacted at room temperature for 2 h, extracted with ethyl acetate, concentrated and column chromatography purification gave intermediate II 9.

[0085] Synthesis of target probe II 10

[0086] Intermediate II 9 was added with 30 μL TBAF (1 M TBAF in THF) in 50 μL DMSO and reacted at 75 °C for 30 min, then trifluoroacetic acid was added to remove the tert-butyl protection. The reaction mixture was purified on a high performance liquid chromatography C18 column to obtain target probe II 10.

[0087] Synthesis of general formula III in Example 3

[0088]

[0089] Synthesis of intermediate III 2

[0090] Dry lithium chloride, intermediate III 1 was dissolved in toluene in a round-bottom flask, anhydrous toluene solution of hexa-n-butyl distannane and tetrakis triphenylphosphine palladium was added successively under nitrogen protection, the reaction mixture was stirred under reflux for 24 h. The crude mixture was filtered with diatomite and ethyl acetate, concentrated under vacuum. Column chromatography purification gave intermediate III 2.

[0091] Synthesis of intermediate III 3

[0092] Intermediate III 2 was dissolved in ethanol, potassium hydroxide solid was added, heated under reflux for 2 h, cooled to room temperature, concentrated under vacuum, pH = 3 was adjusted with aqueous solution of citric acid, extracted with ethyl acetate, the extract was concentrated under vacuum to obtain intermediate III 3.

[0093] Synthesis of intermediate III 4

[0094] Intermediate III 3, HATU were added to a round bottom flask, anhydrous DMF and triethylamine were added under N2 protection, after stirring for 0.5 h, NH2-PEG n OH in anhydrous DMF was added, and the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, ethyl acetate was used for extraction, and the extract was concentrated under vacuum. Column chromatography purification was performed to obtain intermediate III 4.

[0095] Synthesis of intermediate III 5

[0096] Sodium hydride was added to a solution of intermediate III 4 and divinyl sulfone. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was purified by column chromatography to obtain intermediate III 5.

[0097] Synthesis of intermediate III 6

[0098] Intermediate III 5 was added to a THF solution containing intermediate III 5, and the pH was adjusted to 8.5 using Borate buffer to obtain intermediate III 6.

[0099]

[0100] Synthesis of intermediate III 8

[0101] Dry lithium chloride, intermediate III 7 was dissolved in toluene in a round bottom flask, under nitrogen protection, anhydrous toluene solutions of hexa-n-butyl ditin and tetrakis triphenyl phosphine palladium were added, and the reaction mixture was stirred under reflux for 24 h. The crude mixture was filtered with diatomite and ethyl acetate, and concentrated under vacuum. Column chromatography purification was performed to obtain intermediate III 8.

[0102] Synthesis of intermediate III 9

[0103] Intermediate III 8 was dissolved in 1,4-dioxane, hydrochloric acid was added after ice bath, and stirred at 50°C for 2 h. After the reaction was completed, 1,4-dioxane was evaporated, and water was added to dilute the reaction solution, which was washed with dichloromethane, and the aqueous phase was collected, the pH was adjusted to 9 with saturated sodium bicarbonate, and extracted with ethyl acetate, and concentrated under vacuum to obtain intermediate III 9.

[0104] Synthesis of intermediate III 10

[0105] COOH-PEG n-OH, HATU was added to the round bottom flask, anhydrous DMF and triethylamine were added to the flask under N2 protection, after stirring for 0.5 h, a solution of intermediate III 9 in anhydrous DMF was added, and the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, and the extract was concentrated under vacuum. The product was purified by column chromatography to obtain intermediate III 10.

[0106] Synthesis of intermediate III 11

[0107] Sodium hydride was added to a solution of intermediate III 10 and divinyl sulfone. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was purified by column chromatography to obtain intermediate III 11.

[0108] Synthesis of intermediate III 12

[0109] Intermediate III 12 was prepared by adding PSMA-SH (I 5) to a THF solution containing intermediate III 11, and adjusting the pH to 8.5 using Borate buffer.

[0110] Description of the synthesis of preferred target probes of Example 4

[0111] Description of ZT-001

[0112] ZT-001 was synthesized using the method of general formula I, using PEGn-OH (n = 2), intermediate I 5b, to obtain the target probe ZT-001.

[0113] Description of ZT-002

[0114] ZT-002 was synthesized using the method of general formula I, using PEGn-OH (n = 3), intermediate I 5d, to obtain the target probe ZT-002.

[0115] Description of ZT-003

[0116] ZT-003 was synthesized using the method of general formula I, using PEGn-OH (n = 3), intermediate I 5c, to obtain the target probe ZT-003.

[0117] Description of ZT-004

[0118] ZT-004 was synthesized using the method of general formula I, using PEGn-OH (n = 2), intermediate I 5c, to obtain the target probe ZT-004.

[0119] Description of ZT-005

[0120] ZT-005 is synthesized by the method of general formula I, using PEGn-OH (n=3), intermediate I 5b for synthesis, and the target probe ZT-005 can be obtained.

[0121] Description of ZT-006

[0122] ZT-006 is synthesized by the method of general formula II, using the method of general formula II, without connecting PEGm-OH unit, using intermediate II 8a for synthesis, and the target probe ZT-006 can be obtained.

[0123] Description of ZT-007

[0124] ZT-007 is synthesized by the method of general formula III, using III 7 as the starting material (d=0), using COOH-PEGn-OH (n=2), intermediate I 5a for synthesis, d=0, using 18 F to label the target probe, and the target probe ZT-007 can be obtained.

[0125] Description of ZT-008

[0126] ZT-008 is synthesized by the method of general formula III, using III 1 as the starting material (d=0), using NH2-PEGn-OH (n=2), intermediate I 5a for synthesis, d=0, using 18 F to label the target probe, and the target probe ZT-008 can be obtained.

[0127] Description of ZT-009

[0128] ZT-009 is synthesized by the method of general formula III, using III 7 as the starting material (d=0), using COOH-PEGn-OH (n=2), intermediate I 5a for synthesis, d=0, using 131 I to label the target probe, and the target probe ZT-009 can be obtained.

[0129] Description of ZT-010

[0130] ZT-010 is synthesized by the method of general formula III, using III 1 as the starting material (d=0), using NH2-PEGn-OH (n=3), intermediate I 5a for synthesis, d=0, using 131 I to label the target probe, and the target probe ZT-010 can be obtained.

[0131] Description of ZT-011

[0132] ZT-011 is synthesized by the method of general formula III, using III 7 as the starting material (d = 0), selecting COOH-PEGn-OH unit, selecting intermediate I 5a for synthesis, d = 0, using 211 At, the labeling of the target probe is performed, and the target probe ZT-011 is obtained.

[0133] Explanation of ZT-012

[0134] ZT-012 is synthesized by the method of general formula III, using III 1 as the starting material (d = 0), selecting NH2-PEGn-OH unit, selecting intermediate I 5a for synthesis, d = 0, using 211 At, the labeling of the target probe is performed, and the target probe ZT-012 is obtained.

[0135] Explanation of ZT-013

[0136] ZT-013 is synthesized by the method of general formula I, selecting PEGn-OH (n = 3), intermediate I 5a for synthesis, and the only difference is that 131 I, the labeling of the target probe is performed, and the target probe ZT-013 is obtained.

[0137] Explanation of ZT-014

[0138] ZT-014 is synthesized by the method of general formula I, selecting PEGn-OH (n = 2), intermediate I 5a for synthesis, and the only difference is that 131 I, the labeling of the target probe is performed, and the target probe ZT-014 is obtained.

[0139] Explanation of ZT-015

[0140] ZT-015 is synthesized by the method of general formula I, selecting PEGn-OH (n = 2), intermediate I 5b for synthesis, and the only difference is that 131 I, the labeling of the target probe is performed, and the target probe ZT-015 is obtained.

[0141] Explanation of ZT-016

[0142] ZT-016 is synthesized by the method of general formula I, selecting PEGn-OH (n = 2), intermediate I 5b for synthesis, and the only difference is that 211 At, the labeling of the target probe is performed, and the target probe ZT-016 is obtained.

[0143] Explanation of ZT-017

[0144] ZT-017 is synthesized using general formula I, selecting PEGn-OH (n=3) and intermediate I 5c. The only difference is the use of... 211 By marking the target probe with At, the target probe ZT-017 can be obtained.

[0145] ZT-018 Description

[0146] ZT-018 was synthesized using general formula II, without the PEGm-OH unit linked, and intermediate II 8b was selected for synthesis. The only difference is the use of... 211 By marking the target probe with At, the target probe ZT-018 can be obtained.

[0147] Example 5: In vitro competitive binding assay and internalization rate

[0148] Incubate MultiScreenHTS-DV filter plates at room temperature for 30 minutes with 100 μL PBS containing 1% BSA in each well. After removing the PBS / BSA solution, add 1 × 10⁻⁶ BSA solution to each well of the Opti-MEM. 5 C4-2 cells. Using 0.75 nM... 68 Ga-labeled PSMA-HBED-CC dimer ( 68 The inhibitory efficacy of synthesized compounds was determined using Ga-PSMA-11 as a standard. All compounds not labeled with radionuclides, i.e., those in ZT-001–ZT-006 and ZT-013–ZT-018 with the replacement of radionuclides with p-toluenesulfonate groups (-OTs) and those in ZT-007–ZT-012 with tin compounds, were dissolved in Opti-MEM at 300 μL volumes at the following concentrations: 0 nM, 0.5 nM, 1 nM, 2.5 nM, 5 nM, 10 nM, 25 nM, 50 nM, 100 nM, 500 nM, 1000 nM, and 5000 nM. Then, 3 μL of each was added... 68 Ga-PSMA-11 or radiolabeled compounds (i.e., ZT-001 to ZT-018). 50 μL of this mixture was used to obtain a radiolabeled ligand concentration of 0.75 nM. After incubation at 37°C for 45 min, cells were washed twice with PBS in a multi-screen vacuum manifold (Millipore, Billerica, Massachusetts). Cell-binding radioactivity was measured using a gamma counter (Packard Cobra II, GMI, Minnesota, USA), and KB was calculated using a nonlinear regression algorithm (Graph Pad Prism 5.01 software). i The experiment was conducted four times.

[0149] For determining a specific internalization rate, a 24-well plate was incubated for 20 minutes at room temperature with 0.1% poly-L-lysine in PBS, followed by a single wash with PBS. In the next step, 1 × 10⁻⁶ poly-L-lysine was added to each well. 5 C4-2B cells were cultured overnight in 1 mL of RPMI medium. During the experiment, the conditions for each compound were: incubation at 37°C or 4°C with or without receptor blocking by 2-(phosphonomethyl)glutaric acid (2-PMPA; Axxora) at a final concentration of 500 μM. Cells were then incubated with 250 μL of a 30 nM labeled compound solution. Plates were incubated for 45 min in a 37°C water bath or on ice at 4°C. Cells were then washed three times with 1 mL of ice-cold PBS and incubated for 5 min with glycine (50 mM in HCl, pH 2.8). After an additional washing step with 1 mL of ice-cold PBS, cells were lysed with 0.5 mL of 0.3 M NaOH, collected, and radioactively measured for 1 min using a gamma counter. The binding was calculated by subtracting the appropriate uptake under the blocking conditions to reach 10-1. 6 Cells (%IA / 10) 6 The percentage of initial radioactivity added to cells was determined by measuring the uptake of specific cells. All experiments were performed three times. The results are shown in Table 2. i Measurements showed that the synthetic ligands had a nanomolar binding affinity for PSMA.

[0150] Table 2: Data on compound Ki and its binding and internalization to cell surface

[0151]

[0152] Data are mean ± SD (n = 3), nd = not determined

[0153] Example 6: In vivo PET imaging study

[0154] Tumor-bearing nude mice were placed in an anesthesia box and pre-anesthetized for 5-10 minutes with a 3% (v / v) isoflurane-oxygen mixture. The mice were then placed on a scanning table, their limbs secured with medical tape, and anesthesia maintained using the isoflurane-oxygen mixture. The position was adjusted to be centered within the field of view of the micro-PET scanner. A 1mL insulin syringe was used to draw up insulin diluted with physiological saline. 18 The radioactivity of the F-labeled target probe ZT-002 and ZT-006 solutions was measured, and the measurement time was recorded. After injection into tumor-bearing mice via the tail vein, the injection time was recorded, and then the residual radioactivity in the insulin injector was measured and the measurement time was recorded. Static scans were performed for 10 minutes at 30, 90, and 180 minutes after probe injection, in three-dimensional mode. Image reconstruction was performed using the three-dimensional ordered subset expectation-maximization (3D OSEM) algorithm. Representative PET imaging results are shown below.Figure 1 , Figure 2 .

[0155] The results showed that, using diagnostic probes such as ZT-002 and ZT-006 from this embodiment, 3-hour representative PET images revealed significant uptake at the tumor location in the LNCaP-bearing mouse model over time, with no decreasing trend, while uptake in the liver, kidneys, and muscle was less. Compared to similar probes... 68 Ga-PSMA-11 ( Figure 6 With a longer half-life and better imaging quality, ZT-002 and ZT-006 have significantly better performance than similar probes, and are taken up better by the kidneys.

[0156] Example 7 Treatment

[0157] Tumor-bearing nude mice were placed in an anesthesia box and pre-anesthetized for 5-10 minutes with a 3% (v / v) isoflurane-oxygen mixture. The mice were then placed on a scanning table, their limbs secured with medical tape, and anesthesia was maintained using the isoflurane-oxygen mixture. A 1 mL insulin syringe was used to draw insulin diluted with physiological saline. 131 I / 211 At-labeled target probe solutions ZT-009, ZT-012, and ZT-018 were used to measure radioactivity and record the measurement time. (The text abruptly ends here, likely due to an incomplete sentence or missing information.) 131 I / 211 At-labeled target probes were subjected to 24h and 48h. 18 F-FDG PET imaging showed that the tumor site shrank significantly, and the tumor almost disappeared after one week. The therapeutic probes of this invention, such as ZT-008, ZT-012, and ZT-018, have significant therapeutic effects. Figure 3 , Figure 4 , Figure 5 ).

[0158] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. Compounds of general formula II and their stereoisomers, and pharmaceutically acceptable salts, characterized in that, (II), in: X is , , ,and ; m is an integer between 0 and 12; A is a radioactive nuclide; When m=0, radioactive nuclide A is linked by a methylene group; The radionuclide is selected from diagnostic or therapeutic radionuclides, wherein the diagnostic radionuclide is... 18 F, the therapeutic nuclide is 131 I or 211 At.

2. The compound according to claim 1, characterized in that, The compound is selected from the following structures: 。 3. Compounds of general formula III and their stereoisomers, and pharmaceutically acceptable salts, characterized in that, (III), in: n is an integer between 0 and 12; X is , , , ; A is a radioactive nuclide, and A can be substituted at any position on the benzene ring; B is , ; d is 0 or 1; The radionuclide is selected from diagnostic or therapeutic radionuclides, wherein the diagnostic radionuclide is... 18 F, the therapeutic nuclide is 131 I or 211 At.

4. The compound according to claim 3, characterized in that, The compound is selected from the following structures: 。 5. A pharmaceutical composition, characterized in that, The pharmaceutical composition includes the aforementioned compounds and their stereoisomers, and pharmaceutically acceptable salts.

6. The use of the compound of any one of claims 1 to 4, its stereoisomers, pharmaceutically acceptable salts, or the pharmaceutical composition of claim 5 in the preparation of a medicament for treating and / or improving and / or preventing PSMA-expressing cancers and / or their metastases.

7. The use of the compound of any one of claims 1 to 4, its stereoisomers, pharmaceutically acceptable salts, or the pharmaceutical composition of claim 5 in the preparation of diagnostic reagents for cancers expressing PSMA.

8. The application according to claim 6 or 7, characterized in that, The cancers and / or metastases expressing PSMA are prostate cancer and / or metastases.

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