Prostate-specific membrane antigen inhibitor, and radiomarker, preparation method and application thereof

Abstract

The invention discloses a prostate specific membrane antigen inhibitor as well as a radiomarker, a preparation method and application thereof, and belongs to the technical field of biological medicines. The structure of the prostate specific membrane antigen inhibitor is shown as a formula I in the specification. The structure of the radioactive marker of the prostate specific membrane antigen inhibitor disclosed by the invention is shown as a formula II. The invention discloses a preparation method of a compound shown as a formula I. The preparation method of the compound as shown in the formula II comprises the following steps: reacting a compound as shown in the formula I with radioactive metal salt to generate the radiomarker compound as shown in the formula II of the compound as shown in the formula I. The invention discloses application of a radioactive marker of a compound shown in a formula I or a prostate specific membrane antigen inhibitor shown in a formula II in preparation of a prostate cancer diagnostic reagent / medicine or / and a therapeutic medicine. The radiomarker of the compound shown in the formula I has high tumor uptake and enhanced tumor to background ratio in a prostate cancer animal model.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and specifically relates to a prostate specific membrane antigen inhibitor, a radioactive marker thereof, a preparation method and an application thereof. Background Art

[0002] Prostate cancer is an epithelial malignant tumor that occurs in the prostate gland and is the most common malignant tumor in the male urogenital system. The incidence of prostate cancer is extremely high in elderly men. The incidence of the disease is horizontal before the age of 50, and the incidence gradually increases with age. 80% of cases occur in men over 65 years old. The global incidence of prostate cancer continues to rise. According to statistics, there were nearly 1.3 million new cases and 359,000 deaths in the world in 2018, accounting for 13.5% of the incidence of male malignant tumors, ranking second; accounting for 6.7% of the mortality rate of male malignant tumors, ranking fifth.

[0003] In the prior art, drugs based on positron emission tomography (PET) imaging with prostate cancer-specific membrane antigen (PSMA) as a probe are used for the diagnosis and treatment of prostate cancer. For example, the applicant's prior application CN115010629A discloses a prostate-specific membrane antigen inhibitor, its radionuclide marker, preparation method and application. Its prostate-specific membrane antigen inhibitor is a polyamine carboxylic acid short peptide, and its molecular skeleton is composed of polyamine polyacid, fatty amine linking group, and monoamide adipic acid. Among them, lysine-monoamide-adipic acid is the PSMA targeting part, polyamine carboxylic acid is the chelating group of the radionuclide, and fatty amine is the linking group. Its positron marker labeled product is stable in PBS buffer solution and fetal bovine serum. The positron marker has high tumor uptake and enhanced tumor-to-background ratio in prostate cancer animal models, and can be used in the diagnosis, staging, efficacy evaluation and treatment of clinical prostate cancer. However, there is still a need for more PSMA small molecule inhibitors with novel structures, high uptake rates and reasonable metabolic properties in clinical practice. Summary of the invention

[0004] One of the purposes of the present invention is to provide a prostate-specific membrane antigen inhibitor as shown in Formula I, which has a novel structure and stable physicochemical properties and can be used in the diagnosis, staging, efficacy evaluation and treatment of prostate cancer.

[0005] The second object of the present invention is to provide a radioactive marker of the above-mentioned prostate-specific membrane antigen inhibitor. The structure of the radioactive marker is shown in Formula II. It has a high labeling rate, high cellular uptake and internalization, a long drug retention time in the tumor, and clear imaging of prostate cancer. It can be used in the diagnosis, staging, efficacy evaluation and treatment of prostate cancer.

[0006] The third object of the present invention is to provide a method for preparing the prostate specific membrane antigen inhibitor represented by formula I.

[0007] A fourth object of the present invention is to provide a method for preparing the radionuclide label represented by formula II.

[0008] A fifth object of the present invention is to provide an application of the prostate specific membrane antigen inhibitor represented by formula I.

[0009] A sixth object of the present invention is to provide an application of the radionuclide label pair represented by formula II.

[0010] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0011] The present invention discloses a prostate specific membrane antigen inhibitor as shown in formula I,

[0012]

[0013]

[0014]

[0015] Wherein X is alkyl or halogen;

[0016]

[0017] Wherein: when a=b=e=0, d=1, c=an integer from 1 to 8;

[0018] When c=e=0, a=d=1, b=an integer from 1 to 8;

[0019] When c=d=0, a=e=1, b=an integer from 1 to 8.

[0020] In some embodiments of the present invention, X is C1-C4 alkyl or halogen;

[0021] Preferably, the halogen is I;

[0022] Preferably, the alkyl group is methyl.

[0023] The compound of formula I of the present invention is a polyamine carboxylic acid short peptide, and its molecular skeleton is composed of polyamine polyacid, fatty amine linking group, and monoamide adipic acid. Lysine-monoamide-adipic acid is the PSMA targeting part, and polyamine carboxylic acid is 68 Ga, 177 Lu, 64 Cu, 18 F and 225 The chelating group of Ac, aliphatic amine or amide or polyethylene glycol is the connecting group. It has a novel structure and stable physical and chemical properties and is used in the diagnosis, staging, efficacy evaluation and treatment of prostate cancer.

[0024] The radioactive marker of the prostate-specific membrane antigen inhibitor disclosed in the present invention has a structure as shown in Formula II:

[0025]

[0026]

[0027] Where M is the radionuclide;

[0028] R1, A, B, C, D, E, X, a, b, c, d, and e are all defined as above.

[0029] In some embodiments of the present invention, when R3=DOTA-M, M= 68 Ga, 177 Lu, 225 Ac or 64 Cu;

[0030] When R3=DOTAGA-M, M= 68 Ga, 177 Lu, 225 Ac or 64 Cu;

[0031] When R3=NOTA-M, M= 68 Ga or 18 F;

[0032] When R3=DATA-M, M= 68 Ga, 177 Lu, 225 Ac or 64 Cu;

[0033] When R3=DATAM-C, C= 68 Ga, 177 Lu, 225 Ac or 64 Cu;

[0034] When R3=HBED-CC-M, M= 68 Ga.

[0035] The compound of formula II of the present invention is a polyaminocarboxylic acid short peptide radionuclide label, and the molecular skeleton is composed of a polyaminocarboxylic acid labeled with a radioactive metal M or C, a fatty amine / amide / polyethylene glycol linking group, lysine, and monoamide adipic acid. Among them, lysine-monoamide adipic acid is the PSMA targeting part, the radionuclide label is the imaging function module or the therapeutic function module of the drug, and the fatty amine / amide / polyethylene glycol is the linking group. When the radionuclide = 68 Ga, 18 F or64 Cu, the radionuclide is labeled as the imaging function module of the drug; when the radionuclide = 177 Lu or 225 Ac, the radionuclide is labeled as the therapeutic functional module of the drug. The marker has a novel structure, stable physical and chemical properties, high labeling rate, high affinity for cells with high PSMA expression, clear imaging of tumor-bearing mice, good tumor uptake, and long retention time in the tumor. It can be used in the diagnosis, staging, efficacy evaluation and other imaging and treatment fields of prostate cancer.

[0036] The preparation method of the compound of formula I disclosed in the present invention comprises the following steps:

[0037] Step 1. Compound b6 reacts with b7 to generate compound b8 through nucleophilic substitution reaction;

[0038] Step 2. Compound b8 is deprotected to generate compound b9;

[0039] Step 3. Compound b9 and b10 undergo peptide coupling reaction to generate compound b11;

[0040] Step 4. Removing the protecting group from compound b11 to generate compound I;

[0041] The reaction route is as follows:

[0042]

[0043] ; Wherein, R1, R2, A, B, C, D, E, X, a, b, c, d, and e are defined as above.

[0044] In some embodiments of the present invention, in step 1, compound b6 and compound b7 are coupled to generate compound b8 in the presence of a basic solvent and a condensing agent; preferably, the molar ratio of compound b7 to compound b6 is 1.0 to 2.0;

[0045] or / and in said step 2, compound b8 is subjected to reduction reaction with a reducing agent in a solvent to generate compound b9;

[0046] or / and in step 3, compound b9 and compound b10 are subjected to coupling reaction in the presence of a basic solvent and a condensing agent to generate compound b11; preferably, the molar ratio of compound b9 to compound b10 is 1.0 to 2.0;

[0047] Or / and in step 4, compound b11 is subjected to a deprotection reaction under acidic solvent conditions to generate compound of formula I;

[0048] Preferably, the base in step 1 and step 3 comprises at least one of triethylamine, diethylamine, diethanolamine, pyridine, diisopropylamine, ethylenediamine, and cyclohexylamine; further preferably, the molar ratio of the base to b6 or b9 is 1.0 to 5.0;

[0049] Preferably, the condensing agent used in the coupling reaction in step 1 and step 3 includes at least one of HATU, HBTU, HOBT, DCC, and EDCI;

[0050] The solvent in steps 1 to 4 is an aprotic polar solvent, and more preferably, comprises at least one of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, and acetonitrile;

[0051] The reaction temperature of step 1 to step 4 is 0 to 60° C., and the reaction time is 1 to 24 hours.

[0052] In some embodiments of the present invention, the preparation method of compound 6 comprises the following steps:

[0053] S1-1. Compound b1 and b2-1 undergo a Mannich reaction to generate compound b3-1;

[0054] S1-2. Compound b3-1 undergoes a nucleophilic substitution reaction with b4 to generate compound b5-1;

[0055] S1-3. Compound b5-1 undergoes azide reduction reaction to generate compound b6;

[0056] The reaction route is:

[0057]

[0058] Wherein, R1, A, B, C, a, b, c, are as defined above, and n is an integer from 1 to 6;

[0059] Preferably, in S1-1, compound b1 reacts with compound b2-1 and CH3BNNa in an organic solvent to generate compound b3-1 by Mannich reaction; preferably, the molar ratio of compound b1 to compound b2-1 is 1.0 to 3.0; preferably, the molar ratio of compound b1 to CH3BNNa is 1.0 to 3.0; preferably, the organic solvent used in S1-1 is a polar solvent; further preferably, it includes any one or more of dimethylformamide, methanol, ethanol, water, formic acid, acetic acid, and hydrochloric acid; preferably, the reaction temperature in S1-1 is 0 to 80°C, and the reaction time is 4 to 24 hours;

[0060] Preferably, in S1-2, compound b3-1 reacts with b4 in a basic organic solvent to generate compound b5-1 by nucleophilic substitution reaction; preferably, the molar ratio of compound b3-17 to compound b4 is 1.0 to 3.5; preferably, the base is one or more of triethylamine, diethylamine, diethanolamine, pyridine, diisopropylamine, ethylenediamine, and cyclohexylamine, and the molar ratio thereof to compound b3-1 is 1.0 to 5.0; preferably, the organic solvent in S1-2 is an aprotic polar solvent, and further preferably, includes any one or more of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, and acetonitrile; preferably, the reaction temperature of S1-2 is 0-60°C, and the reaction time is 4 to 48 hours;

[0061] Preferably, in S1-3, compound b5-1 is reduced with a reducing agent in an alkaline organic solvent to generate b6; preferably, the reducing agent is Pd / C and hydrogen or triphenylphosphine, the amount of Pd / C is 1.25-20.50% of the molar number of compound b5-1, the amount of hydrogen is 1.0-20.0% of the molar number of compound b5-1, and the molar ratio of triphenylphosphine to compound b5-1 is 1.0-5.0; preferably, the organic solvent is a polar solvent, and further preferably, includes any one or more of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile, water, methanol, and ethanol; preferably, the reaction temperature of S1-3 is 0-90°C, and the reaction time is 1-20 hours.

[0062] In some embodiments of the present invention, the preparation method of compound 6 comprises the following steps:

[0063] S2-1. Compound b1 and b2-2 undergo a Mannich reaction to generate compound b3-2;

[0064] S2-2. Compound b3-2 undergoes a nucleophilic substitution reaction with b4 to generate compound b5-2-1;

[0065] S2-3. Compound b5-2-1 is deprotected to generate compound b5-2-2;

[0066] S2-4. Compound b5-2-2 undergoes peptide coupling reaction with b5-2-3 to generate compound b5-2-4;

[0067] S2-5. Compound b5-2-4 is deprotected to generate compound b6;

[0068] The reaction route is as follows:

[0069]

[0070] Wherein, R1, A, B, C, a, b, c, are as defined above, and n is an integer from 1 to 6;

[0071] Preferably, in S2-1, compound b1 reacts with compound b2-2 and NaBH4 in an organic solvent to generate compound b3-2 by Mannich reaction; preferably, the molar ratio of compound b1 to compound b2-2 is 1.0 to 3.0; preferably, the molar ratio of compound b1 to NaBH4 is 1.0 to 3.0; preferably, the organic solvent is a polar organic solvent; further preferably, it includes any one or more of dimethylformamide, methanol, ethanol, water, formic acid, acetic acid, and hydrochloric acid; preferably, the reaction temperature of S2-1 is 0 to 80°C, and the reaction time is 4 to 24 hours;

[0072] Preferably, in S2-2, compound b3-2 reacts with b4 in a basic organic solvent to generate compound b5-2-1 by nucleophilic substitution reaction; preferably, the molar ratio of compound b3-2 to compound b4 is 1.0 to 3.5; preferably, the base is one or more of triethylamine, diethylamine, diethanolamine, pyridine, diisopropylamine, ethylenediamine, and cyclohexylamine, and the molar ratio thereof to compound b3-2 is 1.0 to 5.0; preferably, the organic solvent in S2-2 is an aprotic polar solvent; further preferably, it includes any one or more of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, and acetonitrile; preferably, the reaction temperature in S2-2 is 0-60°C, and the reaction time is 4 to 48 hours;

[0073] Preferably, in S2-3, compound b5-2-1 is deprotected under alkaline solvent conditions to generate compound b5-2-2; preferably, the base is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide, and the molar ratio thereof to compound b5-2-1 is 1.0 to 5.0; preferably, the solvent is a protonic polar solvent, and further preferably, includes any one or more of water, methanol, ethanol, isopropanol, and n-butanol; preferably, the reaction temperature in S2-3 is 0 to 90° C., and the reaction time is 1 to 20 hours;

[0074] Preferably, in S2-4, compound b5-2-2 and compound b5-2-3 are coupled to generate compound b5-2-4 in the presence of an alkaline solvent and a condensing agent; preferably, the molar ratio of compound b5-2-3 to compound b5-2-2 is 1.0 to 3.0; preferably, the base is one or more of triethylamine, diethylamine, diethanolamine, pyridine, diisopropylamine, ethylenediamine, and cyclohexylamine, and the molar ratio of the base to compound b5-2-2 is 1.0 to 3.0. 5.0; preferably, the coupling agent used is one or more of HATU, HBTU, HOBT, DCC, EDCI, and the molar ratio thereof to compound b5-2-2 is 1.0 to 5.0; preferably, the solvent is an aprotic polar solvent, and further preferably, includes any one or more of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, and acetonitrile; preferably, the reaction temperature of S2-4 is 0 to 60° C., and the reaction time is 1 to 24 hours;

[0075] Preferably, in S2-5, compound b5-2-4 is deprotected under alkaline solvent conditions to generate compound b6; preferably, the base is one or more of triethylamine, diethylamine, diethanolamine, pyridine, diisopropylamine, ethylenediamine, and cyclohexylamine, and the molar ratio thereof to compound b5-2-4 is 1.0 to 5.0; preferably, the solvent is a non-protonic polar solvent, and further preferably, includes any one or more of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, and acetonitrile; preferably, the reaction temperature of S2-5 is 0 to 90°C, and the reaction time is 1 to 24 hours.

[0076] The present invention discloses a method for preparing a compound of formula II, comprising the following steps: reacting a compound of formula I with a radioactive metal salt to generate a radioactive labeled compound of formula I, wherein the reaction formula is:

[0077]

[0078] Among them, R1, R 2、 R 3、 The definitions of A, B, C, D, E, a, b, c, d, and e are the same as above.

[0079] In some embodiments of the present invention, in the method for preparing the radionuclide label of the compound of formula I, the pH value of the reaction system is 3.5 to 10.0, the reaction temperature is 25 to 95° C., and the reaction time is 5 to 60 min;

[0080] Preferably, the reaction system also includes a stabilizer. More preferably, the stabilizer is selected from any one or more of ethanol, vitamin C, tyrosine, cysteine, serine, and gentisic acid.

[0081] The present invention adjusts the pH value by adding a buffer solution into the reaction system, wherein the buffer solution is selected from a sodium acetate / acetic acid system, an ammonium acetate / acetic acid system, a sodium acetate / hydrochloric acid system, a HEPES system or a Tris system.

[0082] In some embodiments of the present invention, in the method for preparing the radionuclide label of the compound of formula I, the reaction solvent is one or a combination of any two or three of a buffer solution, pure water, and 0.85% to 0.9% physiological saline.

[0083] The invention discloses an application of a radioactive marker of a compound represented by formula I or a prostate specific membrane antigen inhibitor represented by formula II in the preparation of a diagnostic reagent / drug and / or a therapeutic drug for prostate cancer.

[0084] The Chinese names corresponding to the English abbreviations of the compounds or groups described in the present invention are:

[0085] HBTU: benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HOBT: 1-hydroxybenzotriazole; DCC: N,N'-dicyclohexylcarbodiimide; EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; tBu: tert-butyl; TEA: triethylamine; DEA: diethanolamine; TFA: trifluoroacetic acid; DMF: N,N-dimethylformamide; EA: ethyl acetate; EtOH: ethanol; THF: tetrahydrofuran.

[0086] Compared with the prior art, the present invention has the following beneficial effects:

[0087] The polyaminocarboxylic acid short peptide compound of formula I synthesized by the present invention is easy to prepare, has a short preparation cycle, a simple radioactive labeling process, mild conditions, and the labeled product is stable in PBS buffer solution and fetal bovine serum. The positron-labeled substance has high tumor uptake and an enhanced tumor-to-background ratio in a prostate cancer animal model, and can be used in the diagnosis, staging, efficacy evaluation and treatment of clinical prostate cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Attached Figure 1 It is the LC-MS mass spectrum of formula Ⅰ-1-5-BD-WJ-DOTA.

[0089] Attached Figure 2 This is the LC-MS mass spectrum of formula Ⅰ-2-4-BD-WJ-DOTA.

[0090] Attached Figure 3 This is the LC-MS mass spectrum of formula Ⅰ-2-4-PN-WJ-DOTA.

[0091] Attached Figure 4 for 68 Radioactive HPLC chromatogram of Ga-Formula Ⅱ-1-5-BD-WJ-DOTA.

[0092] Attached Figure 5 for 68 Radioactive HPLC chromatogram of Ga-formula Ⅱ-2-4-BD-WJ-DOTA.

[0093] Attached Figure 6 for 68 Radioactive HPLC chromatogram of Ga-formula ⅠI-2-4-PN-WJ-DOTA.

[0094] Attached Figure 7 for 177 Radioactive HPLC chromatogram of Lu-Formula Ⅱ-1-5-BD-WJ-DOTA.

[0095] Attached Figure 8 for 177 Radioactive HPLC chromatogram of Lu-Formula ⅠI-2-4-BD-WJ-DOTA.

[0096] Attached Fig. 9 for 177 Radioactive HPLC chromatogram of Lu-Formula ⅠI-2-4-PN-WJ-DOTA.

[0097] Attached Fig.10 for 68 Radioactive HPLC chromatogram of Ga-Formula Ⅱ-1-5-BD-WJ-DOTA in fetal bovine serum (120 minutes).

[0098] Attached Fig.11 for 68 Radioactive HPLC chromatogram of Ga-formula II-2-4-BD-WJ-DOTA in fetal bovine serum (120 minutes)

[0099] Attached Fig.12 for 68 Radioactive HPLC chromatogram of Ga-Formula II-2-4-PN-WJ-DOTA in fetal bovine serum (120 minutes).

[0100] Attached Fig.13 for 68 PET / CT images of Ga-Formula Ⅱ-1-5-BD-WJ-DOTA, wherein the animal model is NOD / SCID double-deficient mice inoculated with LNCaP, and the imaging time is 10 minutes, 30 minutes, 60 minutes and 120 minutes after administration (from left to right).

[0101] Attached Fig.14 for 68PET / CT images of Ga-formula II-2-4-BD-WJ-DOTA, wherein the animal model is NOD / SCID double-deficient mice inoculated with LNCaP, and the imaging time is 10 minutes, 30 minutes, 60 minutes and 120 minutes after administration (from left to right).

[0102] Attached Fig.15 for 68 PET / CT images of Ga-formula Ⅱ-2-4-PN-WJ-DOTA, wherein the animal model is NOD / SCID double-deficient mice inoculated with LNCaP, and the imaging time is 10 minutes, 30 minutes, 60 minutes and 120 minutes after administration (from left to right).

[0103] Attached Fig.16 for 177 SPECT / CT images of Lu-Formula Ⅱ-1-5-BD-WJ-DOTA, wherein the animal model is NOD / SCID double-deficient mice inoculated with LNCaP, and the imaging time is 1 hour, 4 hours, 24 hours, 48 ​​hours and 96 hours after administration (from left to right).

[0104] Attached Fig.17 for 177 SPECT / CT images of Lu-Formula Ⅱ-2-4-BD-WJ-DOTA, where the animal model is NOD / SCID double-deficient mice inoculated with LNCaP, and the imaging time is 1 hour, 4 hours, 24 hours, 48 ​​hours and 96 hours after administration (from left to right).

[0105] Attached Fig.18 for 177 SPECT / CT images of Lu-Formula Ⅱ-2-4-PN-WJ-DOTA, wherein the animal model is NOD / SCID double-deficient mice inoculated with LNCaP, and the imaging time is 1 hour, 4 hours, 24 hours, 48 ​​hours and 96 hours after administration (from left to right).

[0106] Attached Fig.19 For Test Example 15 177 Figure 2 shows the results of investigating the in vivo distribution of Lu-PSMA-617.

[0107] Attached Fig. 20 For Test Example 15 177 Figure 2 shows the results of investigating the in vivo distribution of Lu-Flu-1.

[0108] Attached Fig.21 For Test Example 15 177 Results of the investigation of the in vivo distribution of Lu-Formula II-1-5-BD-WJ-DOTA;

[0109] Attached Fig. 22For Test Example 15 177 Results of the investigation of the in vivo distribution of Lu-Formula II-2-4-BD-WJ-DOTA;

[0110] Attached Fig.23 For Test Example 15 177 Results of the investigation of the in vivo distribution of Lu-Formula II-2-4-PN-WJ-DOTA;

[0111] Attached Fig.24 The overall trend graph of tumor volume change (A) and body weight change trend graph (B) of each group of animals at a dose of 37MBq; the trend graph of individual tumor change in each treatment group at the corresponding dose (C-H).

[0112] Attached Fig.25 The overall trend graph of tumor volume change (A) and body weight change trend graph (B) of each group of animals at a dose of 18.5MBq; the trend graph of individual tumor change in each treatment group at the corresponding dose (C-H).

[0113] Attached Fig.26 The overall trend graph of tumor volume change (A) and body weight change trend graph (B) of each group of animals at a dose of 7.4MBq; the trend graph of individual tumor change in each treatment group at the corresponding dose (C-H). DETAILED DESCRIPTION

[0114] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0115] Example 1-1

[0116] This example discloses the synthesis of compound b3-1-3 (i.e., in compound b3-1, n=3), and the reaction formula is:

[0117]

[0118] Specifically: Compound b1 (1.224 g, 2.513 mmol) and b2-1-3 (335 mg, 2.639 mmol) were dissolved in methanol (40 mL) and stirred at 0°C for 30 minutes. CH3BNNa (241 mg, 3.77 mmol) was added to the above solution and stirred at room temperature for 4 hours. The above reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight. The organic phase was separated by filtration and the organic solvent was removed by rotary evaporation. The product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain a yellow oily liquid b3-1-3 totaling 1.15 g, with a yield of 55.3%.

[0119] Example 2-1

[0120] This example discloses the synthesis of compound b5-1-3-WJ (i.e., in compound b5-1, n=3, R1=WJ), and the reaction formula is:

[0121]

[0122] Specifically, b3-1-3 (220 mg, 0.367 mmol) and b4-WJ (101 mg, 0.441 mmol) were dissolved in dichloromethane (3 mL), and triethylamine (75 mg, 0.735 mmol) was added and stirred at room temperature for 12 hours. After the reaction was completed, the mixture was washed with saturated potassium carbonate solution for 3 times, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate overnight. The organic phase was evaporated to remove the organic solvent. The product was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain a yellow oily liquid product b5-1-3-WJ totaling 187 mg with a yield of 64.4%.

[0123] Example 3-1

[0124] This example discloses the synthesis of compound b6-1-5-WJ (i.e., in compound b6, a=b=0, c=5, R1=WJ), and the reaction formula is:

[0125]

[0126] Specifically: the reactant b5-1-3-WJ (158 mg, 0.200 mmol) and triphenylphosphine (90 mg, 0.343 mmol) were dissolved in tetrahydrofuran (2 ml) and water (1 ml), and stirred for 5 hours at room temperature. After the reaction was completed, the reaction solution was poured into ice water, extracted with dichloromethane, washed with saturated brine 3 times, and the organic phase was dried over anhydrous sodium sulfate overnight. The organic phase was collected by filtration, and the organic solvent was removed by rotary evaporation. Column chromatography (dichloromethane / methanol = 15 / 1) obtained a yellow oily liquid product b6-1-5-WJ, a total of 135 mg, with a yield of 88.4%.

[0127] Example 1-2

[0128] This example discloses the synthesis of compound b3-2, and its reaction formula is:

[0129]

[0130] Specifically: Compound b1 (1.15 g, 2.358 mmol) and b2-2 (250 mg, 2.83 mmol) were dissolved in methanol (10 mL) and stirred at 0°C for 30 minutes. NaBH4 (134 mg, 3.537 mmol) was added to the above solution and stirred at room temperature for 6 hours. The reaction was quenched with a saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. The organic phase was separated by filtration and the organic solvent was removed by rotary evaporation. The product was purified by column chromatography (dichloromethane / methanol = 30 / 1) to obtain a transparent, colorless oily liquid b3-2 totaling 877 mg, with a yield of 66.7%.

[0131] Example 2-2

[0132] This example discloses the synthesis of compound b5-2-1-WJ (i.e., in compound b5-2-1, R1=WJ), and the reaction formula is:

[0133]

[0134] Specifically, b3-2 (430 mg, 0.768 mmol) and b4-WJ (210 mg, 0.922 mmol) were dissolved in dichloromethane (4 mL), and triethylamine (94 mg, 0.922 mmol) was added and stirred at room temperature for 10 hours. After the reaction was completed, the mixture was washed with saturated potassium carbonate solution for 3 times, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate overnight. The organic phase was evaporated to remove the organic solvent. The product was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain a yellow oily liquid product b5-2-1-WJ totaling 420 mg with a yield of 72.7%.

[0135] Example 3-2-1

[0136] This example discloses the synthesis of compound b5-2-2-WJ (i.e., in compound b5-2-2, R1=WJ), and the reaction formula is:

[0137]

[0138] Specifically, b5-2-1-WJ (300 mg, 0.399 mmol) was dissolved in methanol (5 ml), and then 5 ml of lithium hydroxide aqueous solution (20 mg / ml) was added, and stirred at room temperature for 10 hours. After the reaction was completed, methanol was removed by rotary evaporation under reduced pressure, and the reaction solution was diluted with water, and the pH was adjusted to 5-6 with 1M hydrochloric acid, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was rotary evaporated to remove the organic solvent, and the product was purified by column chromatography (dichloromethane / methanol=10 / 1) to obtain a total of 187 mg of a white solid crude product b5-2-2-WJ with a yield of 63.6%.

[0139] Example 3-2-2

[0140] This example discloses the synthesis of compound b5-2-4-4-WJ (i.e., in compound b5-2-4, n=4, R1=WJ), and the reaction formula is:

[0141]

[0142] Specifically, b5-2-2-WJ (150 mg, 0.203 mmol) was dissolved in DMF (2 mL), HATU (93 mg, 0.244 mmol) and diisopropylethylamine (32 mg, 0.244 mmol) were added, and the mixture was stirred at room temperature for 30 minutes, and then b5-2-3-4 (112 mg, 0.244 mmol) was added, and the mixture was stirred at room temperature for 8 hours. The reaction solution was poured into ice water, extracted with dichloromethane, and washed with saturated brine 3 times, and the organic phase was collected and dried over anhydrous sodium sulfate overnight. After filtering, the organic solvent was removed by rotary evaporation, and the product was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain a colorless oily liquid product b5-2-4-4-WJ totaling 124 mg, with a yield of 51.7%.

[0143] Example 3-2-3

[0144] This example discloses the synthesis of compound b6-2-4-WJ (i.e., in compound b6, c=0, a=1, b=4, R1=WJ), and the reaction formula is:

[0145]

[0146] b5-2-4-4-WJ (110 mg, 0.093 mmol) was dissolved in dichloromethane (2 ml), and 25% diethanolamine was added to react and stirred overnight at room temperature. After the reaction was completed, the organic solvent was removed by rotary evaporation, and the reaction product was repeatedly washed with n-hexane. The product was purified by column chromatography (dichloromethane / methanol = 8 / 1) to obtain a colorless viscous liquid product b6-2-4-WJ totaling 42 mg, with a yield of 47.2%.

[0147] Example 4-1

[0148] This example discloses the synthesis of compound b8-1-5-BD-WJ (i.e., in compound b8, a=b=e=0, d=1, X=CH3, c=5, R1=WJ), and the reaction formula is:

[0149]

[0150] Specifically, b7-BD (200 mg, 0.425 mmol) was dissolved in DMF (3 mL), EDCI (66 mg, 0.489 mmol), HOBT (94 mg, 0.489 mmol) and TEA (65.9 mg, 0.652 mmol) were added, and stirred at room temperature for 30 minutes, and then b6-1-5-WJ (250 mg, 0.326 mmol) was added, and stirred at room temperature for 10 hours. After the reaction was completed, ice water was added to quench, and the organic phase was extracted with ethyl acetate, and then washed with saturated brine for 3 times. Finally, the organic phase was collected and dried over anhydrous sodium sulfate overnight. After filtering, the organic solvent was removed by rotary evaporation, and the product was purified by column chromatography (dichloromethane / methanol=40 / 1) to obtain a colorless oily liquid product b8-1-5-BD-WJ totaling 190 mg, with a yield of 47.8%.

[0151] Example 4-2

[0152] This example discloses the synthesis of compound b8-1-5-BID-WJ (i.e., in compound b8, a=b=e=0, d=1, X=I, c=5, R1=WJ), and the reaction formula is:

[0153]

[0154] Specifically, b7-BID (248 mg, 0.425 mmol) was dissolved in DMF (3 mL), EDCI (66 mg, 0.489 mmol), HOBT (94 mg, 0.489 mmol) and TEA (66 mg, 0.652 mmol) were added, and the mixture was stirred at room temperature for 30 minutes, and then b6-1-5-WJ (250 mg, 0.326 mmol) was added, and the mixture was stirred at room temperature for 10 hours. After the reaction was completed, ice water was added to quench the mixture, and the organic phase was extracted with ethyl acetate, and then washed with saturated brine for 3 times. Finally, the organic phase was collected and dried over anhydrous sodium sulfate overnight. After filtering, the organic solvent was removed by rotary evaporation, and the product was purified by column chromatography (dichloromethane / methanol=40 / 1) to obtain a colorless oily liquid product b8-1-5-BID-WJ totaling 233 mg, with a yield of 53.6%.

[0155] Example 4-3

[0156] This example discloses the synthesis of compound b8-2-4-PN-WJ (i.e., in compound b8, a=e=1, c=d=0, b=4, R1=WJ), and the reaction formula is:

[0157]

[0158] b7-PN (233 mg, 0.425 mmol) was dissolved in DMF (3 mL), EDCI (66 mg, 0.489 mmol), HOBT (94 mg, 0.489 mmol) and TEA (66 mg, 0.652 mmol) were added, and the mixture was stirred at room temperature for 30 minutes, and then b6-2-4-WJ (269 mg, 0.326 mmol) was added, and the mixture was stirred at room temperature for 10 hours. After the reaction was completed, ice water was added to quench the mixture, and the organic phase was extracted with ethyl acetate, and then washed with saturated brine for 3 times. Finally, the organic phase was collected and dried over anhydrous sodium sulfate overnight. After filtration, the organic solvent was removed by rotary evaporation, and the product was purified by column chromatography (dichloromethane / methanol=35 / 1) to obtain a colorless oily liquid product b8-2-4-PN-WJ totaling 318.2 mg, with a yield of 74.1%.

[0159] Example 4-4

[0160] This example discloses the synthesis of compound b8-2-4-BD-WJ (i.e., in compound b8, a=d=1, X=CH3, b=4, c=e=0, R1=WJ), and the reaction formula is:

[0161]

[0162] Specifically as follows: b7-BD (200 mg, 0.425 mmol) was dissolved in DMF (3 mL), EDCI (66 mg, 0.489 mmol), HOBT (94 mg, 0.489 mmol) and TEA (66 mg, 0.652 mmol) were added, and the mixture was stirred at room temperature for 30 minutes, and then b6-2-4-WJ (269 mg, 0.326 mmol) was added, and the mixture was stirred at room temperature for 10 hours. After the reaction was completed, ice water was added to quench the mixture, and the organic phase was extracted with ethyl acetate, and then washed with saturated brine for 3 times. Finally, the organic phase was collected and dried over anhydrous sodium sulfate overnight. After filtering, the organic solvent was removed by rotary evaporation, and the product was purified by column chromatography (dichloromethane / methanol=35 / 1) to obtain a colorless oily liquid product b8-2-4-BD-WJ totaling 301 mg, with a yield of 65.5%.

[0163] Example 5-1

[0164] This example discloses the synthesis of compound b9-1-5-BD-WJ (i.e., in compound b9, a=b=e=0, d=1, X=CH3, c=5, R1=WJ), and the reaction formula is:

[0165]

[0166] Dissolve 30ul of hydrazine hydrate in anhydrous dichloromethane (1.5mL) and stir evenly, then add b8-1-5-BD-WJ (100mg, 0.082mmol) and stir at room temperature for 1 hour. After completion, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was washed 3 times with saturated brine, collected, and dried over anhydrous sodium sulfate overnight. After filtering to remove the desiccant, the organic solvent was removed by rotary evaporation to obtain 65mg of colorless, transparent, oily crude product b9-1-5-BD-WJ, which was directly used in the next step reaction.

[0167] Example 5-2

[0168] This example discloses the synthesis of compound b9-1-5-BID-WJ (i.e., in compound b9, a=b=e=0, d=1, X=I, c=5, R1=WJ), and the reaction formula is:

[0169]

[0170] Dissolve 30ul of hydrazine hydrate in anhydrous dichloromethane (1.5mL) and stir evenly, then add b8-1-5-BID-WJ (110mg, 0.082mmol) and stir at room temperature for 1 hour. After completion, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was washed with saturated brine 3 times, collected, and dried over anhydrous sodium sulfate overnight. After filtering to remove the desiccant, the organic solvent was removed by rotary evaporation to obtain 58.5mg of colorless, transparent, oily crude product b9-1-5-BID-WJ, which was directly used in the next step reaction.

[0171] Example 5-3

[0172] This example discloses the synthesis of compound b9-2-4-PN-WJ (i.e., in compound b9, a=e=1, c=d=0, b=4, R1=WJ), and the reaction formula is:

[0173]

[0174] Dissolve 30ul of hydrazine hydrate in anhydrous dichloromethane (1.5mL) and stir evenly, then add b8-2-4-PN-WJ (110mg, 0.082mmol) and stir at room temperature for 1 hour. After completion, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was washed 3 times with saturated brine, collected, and dried over anhydrous sodium sulfate overnight. After filtering to remove the desiccant, the organic solvent was removed by rotary evaporation to obtain 52.4mg of colorless, transparent, oily crude product b9-2-4-PN-WJ, which was directly used in the next step reaction.

[0175] Example 5-4

[0176] This example discloses the synthesis of compound b9-2-4-BD-WJ (i.e., in compound b9, a=d=1, X=CH3, b=4, c=e=0, R1=WJ), and the reaction formula is:

[0177]

[0178] Dissolve 30ul of hydrazine hydrate in anhydrous dichloromethane (1.5mL) and stir evenly, then add b8-2-4-BD-WJ (115.5mg, 0.082mmol) and stir at room temperature for 1 hour. After completion, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was washed 3 times with saturated brine, collected, and dried over anhydrous sodium sulfate overnight. After filtering to remove the desiccant, the organic solvent was removed by rotary evaporation to obtain 56.8mg of colorless, transparent, oily crude product b9-2-4-BD-WJ, which was directly used in the next step reaction.

[0179] Example 6-1

[0180] This example discloses the synthesis of compound b11-1-5-BD-WJ-DOTA (i.e., in compound b11, a=b=e=0, d=1, X=CH3, c=5, R1=WJ, R2=DOTA), and the reaction formula is:

[0181]

[0182] b10-DOTA (45 mg, 0.096 mmol) was dissolved in acetonitrile (2 mL), and NHS (13.2 mg, 0.115 mmol), HBTU (41.8 mg, 0.110 mmol) and diisopropylethylamine (19 mg, 0.147 mmol) were added. After stirring at room temperature for 30 minutes, b9-1-5-BD-WJ (77.4 mg, 0.074 mmol) was added, and stirred at room temperature for 10 hours. The reaction solution was poured into ice water, extracted with dichloromethane, washed with saturated brine 3 times, and the organic phase was collected and dried over anhydrous sodium sulfate overnight. After filtering to remove the desiccant, the organic solvent was removed by rotary evaporation, and the product was directly used for the next step reaction.

[0183] Example 6-2

[0184] This example discloses the synthesis of compound b11-1-5-BID-WJ-DOTA (i.e., in compound b11, a=b=e=0, d=1, X=I, c=5, R1=WJ, R2=DOTA), and the reaction formula is:

[0185]

[0186] b10-DOTA (45 mg, 0.096 mmol) was dissolved in acetonitrile (2 mL), and NHS (13.2 mg, 0.115 mmol), HBTU (41.8 mg, 0.110 mmol) and diisopropylethylamine (19 mg, 0.147 mmol) were added. After stirring at room temperature for 30 minutes, b9-1-5-BID-WJ (87 mg, 0.074 mmol) was added, and stirred at room temperature for 10 hours. The reaction solution was poured into ice water, extracted with dichloromethane, washed with saturated brine 3 times, and the organic phase was collected and dried over anhydrous sodium sulfate overnight. After filtering to remove the desiccant, the organic solvent was removed by rotary evaporation, and the product was directly used for the next step reaction.

[0187] Example 6-3

[0188] This example discloses the synthesis of compound b11-1-5-BD-WJ-DOTAGA (i.e., in compound b11, a=b=e=0, d=1, c=5, R1=WJ, R2=DOTAGA), and the reaction formula is:

[0189]

[0190] b10-DOTAGA (67.3 mg, 0.096 mmol) was dissolved in acetonitrile (2 mL), and NHS (13.2 mg, 0.115 mmol), HBTU (41.8 mg, 0.110 mmol) and diisopropylethylamine (19 mg, 0.147 mmol) were added. After stirring at room temperature for 30 minutes, b9-1-5-BD-WJ (78 mg, 0.074 mmol) was added and stirred at room temperature for 10 hours. The reaction solution was poured into ice water, extracted with dichloromethane, washed with saturated brine 3 times, and the organic phase was collected and dried over anhydrous sodium sulfate overnight. After filtering to remove the desiccant, the organic solvent was removed by rotary evaporation, and the product was directly used in the next step reaction.

[0191] Example 6-4

[0192] This example discloses the synthesis of compound b11-2-4-PN-WJ-DOTA (i.e., in compound b11, a=e=1, c=d=0, b=4, R1=WJ, R2=DOTA), and the reaction formula is:

[0193]

[0194] b10-DOTA (45 mg, 0.096 mmol) was dissolved in acetonitrile (2 mL), and NHS (13.2 mg, 0.115 mmol), HBTU (41.8 mg, 0.110 mmol) and diisopropylethylamine (19 mg, 0.147 mmol) were added. After stirring at room temperature for 30 minutes, b9-2-4-PN-WJ (85.5 mg, 0.074 mmol) was added. After stirring at room temperature for 10 hours, the reaction solution was poured into ice water, extracted with dichloromethane, washed with saturated brine 3 times, and the organic phase was collected and dried over anhydrous sodium sulfate overnight. After filtering to remove the desiccant, the organic solvent was removed by rotary evaporation, and the product was directly used for the next step reaction.

[0195] Example 6-5

[0196] This example discloses the synthesis of compound b11-2-4-BD-WJ-DOTA (i.e., in compound b11, a=d=1, X=CH3, b=4, c=e=0, R1=WJ, R2=DOTA), and the reaction formula is:

[0197]

[0198] b10-DOTA (45 mg, 0.096 mmol) was dissolved in acetonitrile (2 mL), and NHS (13.2 mg, 0.115 mmol), HBTU (41.8 mg, 0.110 mmol) and diisopropylethylamine (19 mg, 0.147 mmol) were added. After stirring at room temperature for 30 minutes, b9-2-4-BD-WJ (92.1 mg, 0.074 mmol) was added, and stirred at room temperature for 10 hours. The reaction solution was poured into ice water, extracted with dichloromethane, washed with saturated brine 3 times, and the organic phase was collected and dried over anhydrous sodium sulfate overnight. After filtering to remove the desiccant, the organic solvent was removed by rotary evaporation, and the product was directly used in the next step reaction.

[0199] Example 7-1

[0200] This embodiment discloses the synthesis of compound formula Ⅰ-1-5-BD-WJ-DOTA (i.e., in compound formula Ⅰ, a=b=e=0, d=1, X=CH3, c=5, R1=WJ, R2=DOTA), and the reaction formula is:

[0201]

[0202] b11-1-5-BD-WJ-DOTA (25.8 mg, 0.016 mmol) was dissolved in a mixed solvent of dichloromethane (0.5 ml) and trifluoroacetic acid (0.5 ml), and the reaction solution was stirred at room temperature for 12 hours. The organic solvent and trifluoroacetic acid were removed by rotary evaporation under reduced pressure, and the product was dissolved in methanol again, and extracted with ether to obtain a crude product, which was then separated and purified by preparative high performance liquid chromatography to obtain the product formula Ⅰ-1-5-BD-WJ-DOTA, a total of 3.4 mg, yield: 16.7%.

[0203] The compound of formula I-1-5-BD-WJ-DOTA was subjected to LC-MS analysis, and its mass spectrum is shown in the attached Figure 1 shown.

[0204] The mass spectrometer was an Agilent 1200 series 6120 model, electrospray protonation (ESI), and the HPLC conditions were: Waters XBridge C18 column (150 mm x 4.6 mm x 3.5 μm), flow rate: 1.0 ml / min, column temperature: 40°C, and a gradient of acetonitrile (0.05% TFA): water (0.05%), wherein acetonitrile increased from 5% to 100% in 10 minutes, and isocratic elution was performed at 100% for 10 minutes.

[0205] Example 7-2

[0206] This example discloses the synthesis of compound formula I-1-5-BID-WJ-DOTA (i.e., in compound formula I, a=b=e=0, d=1, X=I, c=5, R1=WJ, R2=DOTA), and the reaction formula is:

[0207]

[0208] b11-1-5-BID-WJ-DOTA (27.5 mg, 0.016 mmol) was dissolved in a mixed solvent of dichloromethane (0.5 ml) and trifluoroacetic acid (0.5 ml), and the reaction solution was stirred at room temperature for 12 hours. The organic solvent and trifluoroacetic acid were removed by rotary evaporation under reduced pressure, and the product was dissolved in methanol again, and extracted with ether to obtain a crude product, which was then separated and purified by preparative high performance liquid chromatography to obtain the product formula Ⅰ-1-5-BID-WJ-DOTA, a total of 4.2 mg, yield: 19%.

[0209] Example 7-3

[0210] This example discloses the synthesis of compound formula Ⅰ-1-5-BD-WJ-DOTAGA (i.e., in compound formula Ⅰ, a=b=e=0, d=1, c=5, R1=WJ, R2=DOTAGA), and the reaction formula is:

[0211]

[0212] b11-1-5-BD-WJ-DOTAGA (27.8 mg, 0.016 mmol) was dissolved in a mixed solvent of dichloromethane (0.5 ml) and trifluoroacetic acid (0.5 ml), and the reaction solution was stirred at room temperature for 12 hours. The organic solvent and trifluoroacetic acid were removed by rotary evaporation under reduced pressure, and the product was dissolved in methanol again, and extracted with ether to obtain a crude product, which was then separated and purified by preparative high performance liquid chromatography to obtain the product formula Ⅰ-1-5-BD-WJ-DOTAGA, a total of 4.9 mg, yield: 22.8%.

[0213] Example 7-4

[0214] This embodiment discloses the synthesis of compound I-2-4-BD-WJ-DOTA (i.e., in compound I, a=d=1, X=CH3, b=4, c=e=0, R1=WJ, R2=DOTA), and the reaction formula is:

[0215]

[0216] b11-2-4-BD-WJ-DOTA (28.8 mg, 0.016 mmol) was dissolved in a mixed solvent of dichloromethane (0.5 ml) and trifluoroacetic acid (0.5 ml), and the reaction solution was stirred at room temperature for 12 hours. The organic solvent and trifluoroacetic acid were removed by rotary evaporation under reduced pressure, and the product was dissolved in methanol again, and extracted with ether to obtain a crude product, which was then separated and purified by preparative high performance liquid chromatography to obtain the product formula I-2-4-BD-WJ-DOTA, a total of 4.4 mg, yield: 18.8%.

[0217] The compound of formula I-2-4-BD-WJ-DOTA was subjected to LC-MS analysis, and its mass spectrum is shown in the attached Figure 2 shown.

[0218] The mass spectrometer was an Agilent 1200 series 6120 model, electrospray protonation (ESI), and the HPLC conditions were: Waters XBridge C18 column (150 mm x 4.6 mm x 3.5 μm), flow rate: 1.0 ml / min, column temperature: 40°C, and a gradient of acetonitrile (0.05% TFA): water (0.05%), wherein acetonitrile increased from 5% to 100% in 10 minutes, and isocratic elution was performed at 100% for 10 minutes.

[0219] Example 7-5

[0220] This example discloses the synthesis of compound formula I-2-4-PN-WJ-DOTA (i.e., in compound formula I, a=e=1, c=d=0, b=4, R1=WJ, R2=DOTA), and the reaction formula is:

[0221]

[0222] b11-2-4-PN-WJ-DOTA (27.5 mg, 0.016 mmol) was dissolved in a mixed solvent of dichloromethane (0.5 ml) and trifluoroacetic acid (0.5 ml), and the reaction solution was stirred at room temperature for 12 hours. The organic solvent and trifluoroacetic acid were removed by rotary evaporation under reduced pressure, and the product was dissolved in methanol again, and extracted with ether to obtain a crude product, which was then separated and purified by preparative high performance liquid chromatography to obtain the product formula I-2-4-PN-WJ-DOTA, a total of 5.5 mg, yield: 22.3%.

[0223] Formula I-2-4-PN-WJ-DOTA was subjected to LC-MS analysis, and its mass spectrum is shown in the attached Figure 3 shown.

[0224] The mass spectrometer was an Agilent 1200 series 6120 model, electrospray protonation (ESI), and the HPLC conditions were: Waters XBridge C18 column (150 mm x 4.6 mm x 3.5 μm), flow rate: 1.0 ml / min, column temperature: 40°C, and a gradient of acetonitrile (0.05% TFA): water (0.05%), wherein acetonitrile increased from 5% to 100% in 10 minutes, and isocratic elution was performed at 100% for 10 minutes.

[0225] Example 8

[0226] This embodiment discloses 68 Ga-labeled compounds 68 Ga-Formula II-1-5-BD-WJ-DOTA, 68 Ga-formula II-1-5-BD-WJ-DOTAGA, 68 Ga-Formula II-1-5-BID-WJ-DOTA, 68 Ga-Formula II-2-4-BD-WJ-DOTA, 68 Preparation of Ga-formula II-2-4-PN-WJ-DOTA, the reaction formula is:

[0227]

[0228]

[0229] The specific method is as follows: NaAc / HAc buffer solution (pH = 4.2, 1 mL) and 0.85% saline (1 mL) were mixed at room temperature, and then Formula I-5-BD-WJ-DOTA (10 μL, 10 μg) was added, and then mixed and then added 68 GaCl3 high-purity hydrochloric acid solution (5mCi, 2mL, 0.05mol / L) was heated to 90°C for 15 minutes, passed through a C18 lighting reverse phase column, washed with saline and collected as waste liquid. The reverse phase column was then washed with 50% medical alcohol (1mL), washed with 0.85% saline (5mL), the alcohol wash and saline wash were collected, and the retention time and radiochemical purity were measured by high performance liquid chromatography (acetonitrile / water, acetonitrile 10% to 90% within 15 minutes, water and acetonitrile both contained 0.1% trifluoroacetic acid), the product radioactive peak retention time was 9.688min, and the labeling rate was 98.95%.

[0230] 68 Ga-formula II-1-5-BD-WJ-DOTAGA, 68 Ga-Formula II-1-5-BID-WJ-DOTA, 68 Ga-Formula II-2-4-BD-WJ-DOTA, 68 Preparation method of Ga-formula II-2-4-PN-WJ-DOTA and 68 Ga-formula II-1-5-BD-WJ-DOTA is the same. 68 Ga--Formula II-1-5-BD-WJ-DOTAGA labeling rate is 99.32%, 68 The labeling rate of Ga-formula II-1-5-BID-WJ-DOTA was 98.98%, 68 The labeling rate of Ga-formula II-2-4-BD-WJ-DOTA was 98.74%. 68 The labeling rate of Ga-formula II-2-4-PN-WJ-DOTA was 99.11%.

[0231] The formula I-1-5-BD-WJ-DOTA, formula I-1-5-BID-WJ-DOTA, formula I-1-5-BD-WJ-DOTAGA, formula I-2-4-PN-WJ-DOTA and formula I-2-4-BD-WJ-DOTA used in this embodiment are prepared according to the methods of Examples 7-1, 7-2, 7-3, 7-4 and 7-5, respectively.

[0232] The formula prepared in this embodiment 68 The radioactive HPLC chromatogram of Ga-formula II-1-5-BD-WJ-DOTA is shown in the attached figure. Figure 4 The formula prepared in this embodiment is 68The radioactive HPLC chromatogram of Ga-formula II-2-4-BD-WJ-DOTA is shown in the attached figure. Figure 5 shown.

[0233] The formula prepared in this embodiment 68 The radioactive HPLC chromatogram of Ga-formula II-2-4-PN-WJ-DOTA is shown in the attached figure. Figure 6 shown.

[0234] HPLC conditions were: Angilent C18 column (250 mm x 4.6 mm x 3.5 μm), flow rate: 1.0 ml / min, column temperature: room temperature. The gradient was acetonitrile (0.1% TFA): water (0.1% TFA), where acetonitrile increased from 10% to 90% in 15 minutes, and eluted isocratically at 90% for 10 minutes.

[0235] Example 9

[0236] This embodiment discloses 177 LuCl3 labeled compound of formula II 177 Lu-Formula II-1-5-BD-WJ-DOTA, 177 Lu-style

[0237] Ⅱ-1-5-BD-WJ-DOTAGA, 177 Lu-Formula II-1-5-BID-WJ-DOTA, 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 Lu-style

[0238] Ⅱ-2-4-PN-WJ-DOTA preparation, the reaction formula is:

[0239]

[0240]

[0241] Specifically, NaAc / HAc buffer solution (pH = 4.6, 1 mL) was mixed with 0.85% saline (1 mL) at room temperature, and then the precursor I-1-5-BD-WJ-DOTA (20 μL, 20 μg) was added, mixed, and then added 177LuCl3 high-purity hydrochloric acid solution (5 μL, 0.04 mol / L high-purity hydrochloric acid, specific activity 1 mCi / μL), heated to 90°C for 15 minutes, passed through C18 lighting reverse phase column, washed with saline and collected as waste liquid. Then wash the reverse phase column with 50% medical alcohol (0.2 mL), wash with 0.85% physiological saline (2 mL), collect the alcohol solution and washing liquid, measure its high performance liquid chromatography (acetonitrile / water, acetonitrile 10% to 90% within 15 minutes, water and acetonitrile both contain 0.1% trifluoroacetic acid), the product radioactive peak retention time is 7.69 min, labeling rate: 98.29%.

[0242] 177 Lu-Formula II-1-5-BD-WJ-DOTAGA, 177 Lu-Formula II-1-5-BID-WJ-DOTA, 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 Preparation method of Lu-formula II-2-4-PN-WJ-DOTA and 177 Lu-Formula II-1-5-BD-WJ-DOTA is the same, 177 Lu--Formula II-1-5-BD-WJ-DOTAGA labeling rate is 99.13%, 177 The labeling rate of Lu-Formula II-1-5-BID-WJ-DOTA was 98.74%, 177 The labeling rate of Lu-Formula II-2-4-BD-WJ-DOTA was 97.94%, 177 The labeling rate of Lu-Formula II-2-4-PN-WJ-DOTA was 99.09%.

[0243] The formula I-1-5-BD-WJ-DOTA, formula I-1-5-BID-WJ-DOTA, formula I-1-5-BD-WJ-DOTAGA, formula I-2-4-PN-WJ-DOTA, and formula I-2-4-BD-WJ-DOTA used in this embodiment are prepared according to the methods of Examples 7-1, 7-2, 7-3, 7-4, and 7-5, respectively. 177 The radioactive HPLC chromatogram of Lu-Formula II-1-5-BD-WJ-DOTA is shown in the attached figure. Figure 7 The formula prepared in this embodiment is 177 The radioactive HPLC chromatogram of Lu-Formula II-2-4-BD-WJ-DOTA is shown in the attached figure. Figure 8 shown.

[0244] The formula prepared in this embodiment 177 The radioactive HPLC chromatogram of Lu-Formula II-2-4-PN-WJ-DOTA is shown in the attached figure. Fig. 9HPLC conditions were: Angilent C18 column (250 mm x 4.6 mm x 3.5 μm), flow rate: 1.0 ml / min, column temperature: room temperature. The gradient was acetonitrile (0.1% TFA): water (0.1% TFA), where acetonitrile increased from 10% to 90% in 15 minutes, and eluted isocratically at 90% for 10 minutes.

[0245] Example 10

[0246] This embodiment discloses 225 Ac-labeled compound of formula II 225 Ac-Formula II-1-5-BD-WJ-DOTA, 225 Ac-type

[0247] Ⅱ-1-5-BD-WJ-DOTAGA, 225 Preparation of Ac-Formula II-1-5-BID-WJ-DOTA, the reaction formula is:

[0248]

[0249] Add 0.1M Tris buffer (pH 9.0, 1.0 mL) to a 5 mL EP tube, and then add 225 Ac hydrochloric acid solution 0.1mL 0.3MBq) and formula I-1-5-BD-WJ-DOTA (20μL, 20μg). After preheating to 85°C in a metal bath, place the above reaction system in a metal heating bath and heat at 85°C for 5 minutes. Stop heating and add 2mL of sterile water for injection to the reaction solution. Pass through a C18 micro separation column, and wash the column with 5mL of sterile water for injection, and collect it as waste liquid. The C18 column is then rinsed with 0.5mL 50% medical alcohol, and then washed with 2mL of sterile water for injection. The alcohol washing liquid and 2mL of sterile water for injection are collected as the product. Take 10μL of the product liquid and use thin layer chromatography (TLC) to detect the radiochemical purity. The labeling rate is 98.55%.

[0250] 225 Ac-Formula II-1-5-BD-WJ-DOTAGA, 225 Preparation method of Ac-formula II-1-5-BID-WJ-DOTA and 225 Ac-Formula II-1-5-BD-WJ-DOTA is the same, 225 The labeling rate of Ac-Formula II-1-5-BD-WJ-DOTAGA was 98.79%. 225 The labeling rate of Ac-Formula II-1-5-BID-WJ-DOTA was 99.02%.

[0251] The formula I-1-5-BD-WJ-DOTA, formula I-1-5-BID-WJ-DOTA and formula I-1-5-BD-WJ-DOTAGA used in this embodiment are prepared according to the methods of Examples 7-1, 7-2 and 7-3, respectively.

[0252] Embodiment 11

[0253] This embodiment discloses 64 Cu-labeled compound of formula II 64 Cu-Formula II-1-5-BD-WJ-DOTA, 64 Cu-Formula II-1-5-BD-WJ-DOTAGA, 64 Preparation of Cu-Formula II-1-5-BID-WJ-DOTA, the reaction formula is:

[0254]

[0255]

[0256] The specific steps are as follows: add 1.0M NaAc / HAc buffer (pH 4.4, 1.0mL) to a 5mL EP tube, then add the purified 64 CuCl2 solution (1mL, 3.8MBq) and formula I-1-5-BD-WJ-DOTA (20μL, 20μg). After preheating to 85℃ in a metal bath, place the above reaction system in a metal heating bath and heat at 85℃ for 10 minutes. Stop heating and add 2mL of sterile water for injection to the reaction solution. Pass through a C18 micro column, wash the column with 5mL of sterile water for injection, and collect as waste liquid. The C18 column is then rinsed with 0.5mL50% medical alcohol, and then washed with 2mL of sterile water for injection. The alcohol washing liquid and 2mL of sterile water for injection are collected as the product. 10μL of the product liquid is extracted and the radiochemical purity is determined by radioactive high performance liquid chromatography. The labeling rate is 97.56%.

[0257] 64 Cu-Formula II-1-5-BD-WJ-DOTAGA, 64 Preparation method of Cu-formula II-1-5-BID-WJ-DOTA and 64 Cu-Formula II-1-5-BD-WJ-DOTA, 64 The labeling rate of Cu-Formula II-1-5-BD-WJ-DOTAGA was 98.99%. 64 The labeling rate of Cu-Formula II-1-5-BID-WJ-DOTA was 98.61%.

[0258] The formula I-1-5-BD-WJ-DOTA, formula I-1-5-BID-WJ-DOTA, and formula I-1-5-BD-WJ-DOTAGA used in this example were prepared according to the methods of Examples 7-1, 7-2, and 7-3, respectively.

[0259] This test example discloses 68 Ga-labeled compound of formula II 68 Ga-Formula II-1-5-BD-WJ-DOTA, 68 Ga-Formula II-2-4-BD-WJ-DOTA, 68 The PBS stability test of Ga-formula II-2-4-PN-WJ-DOTA is as follows:

[0260] Take 20 μL of marker in parallel 68 Ga-Formula II-1-5-BD-WJ-DOTA was dissolved in 3 vials of 180 μL PBS buffer and incubated at 37°C for 30 min, 60 min, and 120 min. Samples were taken at each time point, and the changes in the retention time of the sample radiation peak were determined by high performance liquid chromatography.

[0261] Same method determination 68 Ga-Formula II-2-4-BD-WJ-DOTA, 68 Stability of Ga-Formula II-2-4-PN-WJ-DOTA in PBS.

[0262] Test Results: Sample 68 The radiochemical purity of Ga-Formula II-1-5-BD-WJ-DOTA was 99.7% at 30 minutes and 99.23% after 2 hours. 68 The radiochemical purity of Ga-formula II-2-4-BD-WJ-DOTA was 99.58% at 30 minutes. 68 The radiochemical purity of Ga-formula II-2-4-PN-WJ-DOTA was 99.47% at 30 minutes. After 2 hours, both still maintained high radiochemical purity, 98.51% and 97.7%, respectively. 68 Ga-Formula II-1-5-BD-WJ-DOTA, 68 Ga-Formula II-2-4-BD-WJ-DOTA, 68 The Ga-formula II-2-4-PN-WJ-DOTA label has good stability in PBS.

[0263] Table 1 68 Ga-Formula II-1-5-BD-WJ-DOTA, 68 Ga-Formula II-2-4-BD-WJ-DOTA, 68PBS stability experimental results of Ga-formula II-2-4-PN-WJ-DOTA

[0264] time 30min 60min 120min <![CDATA[ 68 The radiochemical purity of Ga-formula II-1-5-BD-WJ-DOTA]]> 99.7％±1.2％ 99.35％±0.9％ 99.23％±1.4％ <![CDATA[ 68 The radiochemical purity of Ga-formula II-2-4-BD-WJ-DOTA]]> 99.58％±0.69％ 99.23％±0.58％ 98.51％±0.19％ <![CDATA[ 68 The radiochemical purity of Ga-formula II-2-4-PN-WJ-DOTA]]> 99.47％±0.15％ 98.57％±0.14％ 97.70％±0.98％

[0265] Test Example 2

[0266] This test example discloses 68 Ga-labeled compound of formula II 68 Ga-Formula II-1-5-BD-WJ-DOTA, 68 Ga-Formula II-2-4-BD-WJ-DOTA, 68 The fetal bovine serum stability test of Ga-formula II-2-4-PN-WJ-DOTA is as follows:

[0267] Take 200 μL of fetal bovine serum in parallel into three 2 mL EP tubes, and then add radiochemically pure > 99% 68 100 μL of Ga-formula II-1-5-BD-WJ-DOTA marker (specific activity: 0.5 μci / μL) was incubated at 37°C for 30 min, 60 min, and 120 min. At each time point, acetonitrile equal to the amount of serum was added to the sample, shaken and precipitated, and after centrifugation, 20 μL of the supernatant was taken and the radiochemical purity of the sample was detected by radioactive high performance liquid chromatography.

[0268] Same method determination 68 Ga-Formula II-2-4-BD-WJ-DOTA, 68 Stability of Ga-formula II-2-4-PN-WJ-DOTA in fetal bovine serum.

[0269] Test Results: Sample 68 The radiochemical purity of Ga-formula II-1-5-BD-WJ-DOTA was 98.16% at 30 minutes and remained 97.50% after 2 hours. 68 The radiochemical purity of Ga-formula II-2-4-BD-WJ-DOTA was 97.87% at 30 minutes. 68 The radiochemical purity of Ga-formula II-2-4-PN-WJ-DOTA was 98.59% at 30 minutes; after 2 hours, both still maintained high radiochemical purity, 96.48% and 93.07% respectively. 68 Ga-Formula II-1-5-BD-WJ-DOTA, 68 Ga-Formula II-2-4-BD-WJ-DOTA, 68 The Ga-formula II-2-4-PN-WJ-DOTA marker has good stability in fetal bovine serum.

[0270] The radioactive HPLC chromatogram of its stability in fetal bovine serum (120 min) is shown in the attached figure. Fig.10 , 11 and 12.

[0271] Table 2 68 Ga-Formula II-1-5-BD-WJ-DOTA, 68 Ga-Formula II-2-4-BD-WJ-DOTA, 68 Results of fetal bovine serum stability test of Ga-formula II-2-4-PN-WJ-DOTA

[0272] time 30min 60min 120min <![CDATA[ 68 The radiochemical purity of Ga-formula II-1-5-BD-WJ-DOTA]]> 98.16％±0.7％ 98.43％±0.9％ 97.50％±1.2％ <![CDATA[ 68 The radiochemical purity of Ga-formula II-2-4-BD-WJ-DOTA]]> 97.87％±1.47％ 96.86％±1.18％ 96.48％±1.06％ <![CDATA[ 68 The radiochemical purity of Ga-formula II-2-4-PN-WJ-DOTA]]> 98.59％±0.45％ 96.77％±1.47％ 93.07％±1.73％

[0273] Test Example 3

[0274] This test example discloses 225 Ac-labeled compound of formula II 225 The PBS stability test of Ac-Formula II-1-5-BD-WJ-DOTA is as follows:

[0275] In parallel, take 20 μL of the labeled compound of formula II 225 Ac-Formula II-1-5-BD-WJ-DOTA was dissolved in 3 vials of 80 μL PBS buffer and incubated at 37°C for 30 min, 60 min, and 120 min. Samples were taken at each time point, and changes in the retention time of the sample radiation peak were determined by thin layer chromatography.

[0276] Test Results: Sample 225 The radiochemical purity of Ac-Formula II-1-5-BD-WJ-DOTA was 98.50% at 30 minutes, and after 2 hours, it still maintained 98.01% radiochemical purity. 225 The Ac-Formula II-1-5-BD-WJ-DOTA marker has good stability in PBS.

[0277] Table 3 225 PBS stability test results of Ac-Formula II-1-5-BD-WJ-DOTA

[0278] time 30min 60min 120min <![CDATA[ 225 Ac-Formula II-1-5-BD-WJ-DOTA radiochemical purity]]> 98.50％±0.8％ 99.20％±1.4％ 98.01％±0.9％

[0279] Test Example 4

[0280] This test example discloses 225 Ac-labeled compound of formula II 225 The fetal bovine serum stability test of Ac-Formula II-1-5-BD-WJ-DOTA is as follows:

[0281] Take 100 μL of fetal bovine serum and 2 mL of three EP tubes in parallel, and then add radiochemically pure > 99% markers.225 Ac-Formula II-1-5-BD-WJ-DOTA 100 μL, incubate at 37°C for 30 min, 60 min, 120 min. At each time point, add acetonitrile equal to the amount of serum to the sample, shake and precipitate, centrifuge, take the supernatant and spot it on thin layer chromatography paper, and use thin layer chromatography to detect the radiochemical purity of the sample.

[0282] Test Results: Sample 225 The radiochemical purity of Ac-Formula II-1-5-BD-WJ-DOTA was 98.17% at 30 minutes, and after 2 hours, it still maintained a radiochemical purity of 95.39%. 225 The Ac-Formula II-1-5-BD-WJ-DOTA marker has good stability in fetal bovine serum.

[0283] Table 4 225 Results of fetal bovine serum stability test of Ac-Formula II-1-5-BD-WJ-DOTA

[0284] time 30min 60min 120min <![CDATA[ 225 Ac-Formula II-1-5-BD-WJ-DOTA radiochemical purity]]> 98.17％±0.6％ 98.09％±0.3％ 95.39％±0.8％

[0285] Test Example 5

[0286] This test example discloses 64 Cu-labeled compound of formula II 64 The PBS stability test of Cu-Formula II-1-5-BD-WJ-DOTA is as follows:

[0287] Take 20 μL of marker in parallel 64 Cu-Formula II-1-5-BD-WJ-DOTA was dissolved in 3 vials of 180 μL PBS buffer and incubated at 37°C for 30 min, 60 min, and 120 min. Samples were taken at each time point, and the changes in the retention time of the sample radiation peak were determined by HPLC.

[0288] Test results: The radiochemical purity of the sample was 98.7% after 30 minutes, and it remained 97.62% after 2 hours. 64 The Cu-Formula II-1-5-BD-WJ-DOTA label has good stability in PBS.

[0289] Table 5 64 PBS stability test results of Cu-Formula II-1-5-BD-WJ-DOTA

[0290] time 30min 60min 120min <![CDATA[ 64 Radiochemical purity of Cu-Formula II-1-5-BD-WJ-DOTA]]> 98.7％±0.5％ 98.1％±1.1％ 97.62％±1.6％

[0291] Test Example 6

[0292] This test example discloses 64 Cu-labeled compound of formula II64 The fetal bovine serum stability test of Cu-Formula II-1-5-BD-WJ-DOTA is as follows:

[0293] Take 200 μL of fetal bovine serum and 3 2mL EP tubes in parallel, add 100 μL of radiochemically pure >99% marker, and incubate at 37°C for 30min, 60min, and 120min. Add acetonitrile equal to the serum to the sample at each time point, shake and precipitate, centrifuge, take 20 μL of the supernatant, and use radioactive high performance liquid chromatography to detect the radiochemical purity of the sample.

[0294] Test results: The radiochemical purity of the sample was 98.5% after 30 minutes, and it remained 96.7% after 2 hours. 64 The Cu-formula II-1-5-BD-WJ-DOTA marker has good stability in fetal bovine serum.

[0295] Table 6 64 Results of the fetal bovine serum stability test of Cu-Formula II-1-5-BD-WJ-DOTA

[0296] time 30min 60min 120min <![CDATA[ 64 Radiochemical purity of Cu-Formula II-1-5-BD-WJ-DOTA]]> 98.5％±1.9％ 97.9％±1.3％ 96.7％±2.1％

[0297] Test Example 7

[0298] This test example discloses 177 Lu-labeled compound of formula II 177 Lu-Formula II-1-5-BD-WJ-DOTA, 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 The PBS stability test of Lu-Formula II-2-4-PN-WJ-DOTA is as follows:

[0299] Take 20 μL of marker 177 Lu-Formula II-1-5-BD-WJ-DOTA was dissolved in 180 μL of PBS buffer and incubated at 37° C. for 1 h, 4 h, and 24 h. Samples were taken at each time point, and the changes in the radioactive peaks of the samples were determined by high performance liquid chromatography.

[0300] Same method determination 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 Stability of Lu-Formula II-2-4-PN-WJ-DOTA in PBS.

[0301] Test Results: Sample 177 The radiochemical purity of Lu-Formula II-1-5-BD-WJ-DOTA was 98.50% in 1 hour, and after 24 hours, it still maintained 96.54% radiochemical purity. 177The radiochemical purity of Lu-Formula II-2-4-BD-WJ-DOTA in 1h was 98.84%. 177 The radiochemical purity of Lu-Formula II-2-4-PN-WJ-DOTA was 98.82% in 1 hour; after 24 hours, both still maintained high radiochemical purity, 96.17% and 97.9% respectively. 177 Lu-Formula II-1-5-BD-WJ-DOTA, 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 The Lu-Formula II-2-4-PN-WJ-DOTA marker has good stability in PBS.

[0302] Table 7 177 Lu-Formula II-1-5-BD-WJ-DOTA, 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 PBS stability test results of Lu-Formula II-2-4-PN-WJ-DOTA

[0303] time 1h 4h 24h <![CDATA[ 177 Lu-Formula II-1-5-BD-WJ-DOTA radiochemical purity]]> 98.50％±1.5％ 98.29％±1.1％ 96.54％±0.6％ <![CDATA[ 177 Lu-Formula II-2-4-BD-WJ-DOTA radiochemical purity]]> 98.84％±1.2％ 97.79％±2.19％ 96.17％±1.24％ <![CDATA[ 177 Lu-Formula II-2-4-PN-WJ-DOTA radiochemical purity]]> 98.82％±1.87％ 98.47％±3.61％ 97.9％±0.51％

[0304] Test Example 8

[0305] This test example discloses 177 Lu-labeled compound of formula II 177 Lu-Formula II-1-5-BD-WJ-DOTA, 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 The fetal bovine serum stability test of Lu-Formula II-2-4-PN-WJ-DOTA is as follows:

[0306] Take 100 μL of fetal bovine serum and 3 2mL EP tubes in parallel, then add 100 μL of radiochemically pure >99% marker, and incubate at 37°C for 1h, 4h, and 24h. At each time point, add acetonitrile equal to the serum to the sample, shake and precipitate, centrifuge, take 20 μL of the supernatant, and use radioactive high performance liquid chromatography to detect the radiochemical purity of the sample.

[0307] Same method determination 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 Stability of Lu-Formula II-2-4-PN-WJ-DOTA in fetal bovine serum.

[0308] Test Results: Sample 177 The radiochemical purity of Lu-Formula II-1-5-BD-WJ-DOTA was 92.68% in 1 hour, and after 24 hours, it still maintained 88.15% radiochemical purity. 177The radiochemical purity of Lu-Formula II-2-4-BD-WJ-DOTA in 1h was 96.4%. 177 The radiochemical purity of Lu-Formula II-2-4-PN-WJ-DOTA was 98.7% in 1 hour; after 24 hours, both still maintained high radiochemical purity, 90.85% and 94.78% respectively. 177 Lu-Formula II-1-5-BD-WJ-DOTA, 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 The Lu-formula II-2-4-PN-WJ-DOTA marker has good stability in fetal bovine serum.

[0309] Table 8 177 Lu-Formula II-1-5-BD-WJ-DOTA, 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 Results of stability test of Lu-Formula II-2-4-PN-WJ-DOTA in fetal bovine serum

[0310] time 1h 4h 24h <![CDATA[ 177 Lu-Formula II-1-5-BD-WJ-DOTA radiochemical purity]]> 92.68％±1.2％ 90.06％±0.9％ 88.15％±1.2％ <![CDATA[ 177 Lu-Formula II-2-4-BD-WJ-DOTA radiochemical purity]]> 96.4％±2.03％ 94.5％±1.38％ 90.85％±2.03％ <![CDATA[ 177 Lu-Formula II-2-4-PN-WJ-DOTA radiochemical purity]]> 98.7％±1.07％ 97.9％±1.56％ 94.78％±0.82％

[0311] Test Example 9

[0312] This test example discloses 68 Ga-Formula II-1-5-BD-WJ-DOTA, 68 Ga-Formula II-2-4-BD-WJ-DOTA and 68 Ga-formula II-2-4-PN-WJ-DOTA LNCaP animal model PET / CT imaging experiment, specifically:

[0313] LNCaP cells were implanted in the axilla of the left forelimb of NOD / SCID mice and kept in an SPF animal room for about 4 weeks. The tumor mass was about 0.8 cm in diameter. About 100 μL of a high-radiochemical purity drug (radiochemical purity> 98.5%) was injected through the tail vein. Imaging was performed at 10 minutes, 30 minutes, 60 minutes and 120 minutes.

[0314] The imaging results are attached. Fig.13 ( 68 Ga-formula II-1-5-BD-WJ-DOTA), attached Fig.14 ( 68 Ga-formula II-2-4-BD-WJ-DOTA) and attached Fig.15 ( 68 Ga-Formula II-2-4-PN-WJ-DOTA).

[0315] The results show that: 68 Ga-Formula II-1-5-BD-WJ-DOTA,68 Ga-Formula II-2-4-BD-WJ-DOTA and 68 Ga-formula II-2-4-PN-WJ-DOTA showed rapid accumulation in PSMA-positive LNCaP tumors at 10 min, and all images showed a clean background at 120 min. 68 The tumor uptake of Ga-formula II-1-5-BD-WJ-DOTA was higher than that of other radioligands, and its cardiac uptake was most obvious at 10 min, followed by rapid clearance and close to background value after 30 min. In addition, in addition to tumors, only kidneys and bladders could significantly take up these radioligands, indicating that these drugs are excreted into the body through the kidneys.

[0316] Test Example 10

[0317] This test example discloses 177 Lu-Formula II-1-5-BD-WJ-DOTA, 177 Lu-Formula II-2-4-PN-WJ-DOTA and 177 SPECT / CT imaging experiment of LNCaP animal model with Lu-formula II-2-4-PN-WJ-DOTA, specifically:

[0318] LNCaP cells were implanted in the axilla of the left forelimb of NOD / SCID mice and kept in an SPF animal room for about 4 weeks. The tumor mass was about 0.8 cm in diameter. About 100 μL of a high-radiochemical purity drug (radiochemical purity> 98.5%) was injected through the tail vein. Imaging was performed at 1 hour, 4 hours, 24 hours, 48 ​​hours and 96 hours. The imaging results are shown in the attached Fig.16 ( 177 Lu-Formula II-1-5-BD-WJ-DOTA), attached Fig.17 ( 177 Lu-Formula II-2-4-BD-WJ-DOTA) and attached Fig.18 ( 177 Lu-Formula II-2-4-PN-WJ-DOTA).

[0319] The results show that: 177 Lu-Formula II-1-5-BD-WJ-DOTA, 177 Lu-Formula II-2-4-PN-WJ-DOTA and 177 Lu-Formula II-2-4-PN-WJ-DOTA maintained a good tumor-to-background ratio over 96 hours. The tumor showed a clear radioactive signal at 1 hour, while the rest of the radioactivity accumulated in the kidney and bladder. 177 Lu-Formula II-2-4-PN-WJ-DOTA and 177The uptake of Lu-Formula II-2-4-PN-WJ-DOTA in the tumor reached a peak at 4 hours and then gradually decreased with the passage of time. 177 The peak time of tumor uptake of Lu-Formula II-1-5-BD-WJ-DOTA is about 48 hours after injection. 177 Lu-Formula II-1-5-BD-WJ-DOTA, 177 Lu-Formula II-2-4-PN-WJ-DOTA and 177 Lu-Formula II-2-4-PN-WJ-DOTA all showed rapid clearance.

[0320] Test Example 11

[0321] This test example discloses the pharmacodynamic test of the compound of the present invention.

[0322] The drugs used in this test example are as follows:

[0323] 177 Lu-Formula II-1-5-BD-WJ-DOTA was prepared according to the method of Example 9.

[0324] 177 Lu-Formula II-2-4-BD-WJ-DOTA was prepared according to the method of Example 9.

[0325] 177 Lu-Formula II-2-4-PN-WJ-DOTA, prepared according to the method of Example 9. Positive control drug:

[0326] 177 Lu-PSMA-617 (Aladdin, 25 mg), which became the first radioligand approved by the FDA for internal radiotherapy of prostate cancer in 2022, prolongs progression-free survival and overall survival in patients with PSMA-positive metastatic castration-resistant prostate cancer.

[0327] 177 Lu-Flu-1: This compound is a compound in the applicant's prior application, patent publication number CN115010629A "Prostate-specific membrane antigen inhibitor, its radionuclide marker, preparation method and application" 177 Lu-Formula II-1-SP-W0-DOTA, the compounds involved in this patent are all modified on the basis of the molecular structure of this compound, and therefore serve as control drugs for efficacy studies.

[0328] Negative control: saline

[0329] The specific experimental steps are as follows:

[0330] LNCaP cells were implanted in the axilla of the left forelimb of NOD / SCID mice and kept in an SPF animal room. When the average tumor volume of LNCaP tumor-bearing mice reached about 250±25mm 3 In vivo distribution and radioligand therapy studies were performed.

[0331] 1. Distribution in vivo: Male mice carrying LNCaP tumors with an average body weight of approximately 20 ± 5 g were injected with 2.5 MBq of the corresponding radioligand via the tail vein. Mice were sacrificed at 1, 4, 24, 48, and 96 h after injection, blood was drawn, and organs of interest were quickly collected, blotted, and weighed. Radioactivity was detected using a γ counter, and biodistribution results were calculated as a percentage of injected dose per gram (% ID / g). Each time point consisted of at least 4 mice.

[0332] 2. Treatment: Tumor-bearing mice were randomly divided into 16 groups (7 mice in each group), specifically:

[0333] Normal saline group;

[0334] 177 Three dose groups of Lu-PSMA-617: 37MBq, 18.5MBq, and 7.4MBq;

[0335] 177 Three dose groups of Lu-Flu-1: 37MBq, 18.5MBq, and 7.4MBq;

[0336] 177 Three dose groups of Lu-BWD: 37MBq, 18.5MBq, and 7.4MBq;

[0337] 177 three dose groups of Lu-P4-BWD: 37MBq, 18.5MBq, and 7.4MBq;

[0338] 177 Three dose groups of Lu-P4-PND: 37MBq, 18.5MBq and 7.4MBq.

[0339] Individual tumor size (mm 3 ) is calculated as: (length × width 2 ) / 2. The tumor volume and body weight of all mice were monitored every two days. Once the body weight loss reached 40% or the tumor volume exceeded 1500mm 3 , the mice were euthanized.

[0340] result:

[0341] 1. Distribution in the body

[0342] The distribution of each group of drugs in vivo is shown in the attached Fig.19, as shown in 20,21,22,23.

[0343] From the above results, we can know that: 177 Lu-Formula II-1-5-BD-WJ-DOTA, 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 Lu-Formula II-2-4-PN-WJ-DOTA, 177 Lu-PSMA-617, 177 Lu-Flu-1 was observed to have high tumor radioactivity 1 h after injection and reached a peak at 4 h, after which the tumor uptake value gradually decreased, but overall maintained high tumor uptake within 96 h. 177 Compared with Lu-PSMA-617: 177 Lu-Formula II-1-5-BD-WJ-DOTA and 177 Lu-Formula II-2-4-BD-WJ-DOTA showed faster tumor targeting absorption in the early stage, within 48 hours, 177 The tumor uptake value of Lu-Formula II-1-5-BD-WJ-DOTA was significantly higher than 177 Lu-PSMA-617, up to 96 hours, 177 The tumor uptake of Lu-Formula II-1-5-BD-WJ-DOTA was only slightly lower than 177 Lu-PSMA-617; 177 Lu-Formula II-2-4-BD-WJ-DOTA has a higher tumor uptake value within 24 hours than 177 Lu-PSMA-617, at subsequent time points slightly lower 177 Lu-PSMA-617; 177 Lu-Formula II-2-4-PN-WJ-DOTA was lower than 177 Lu-PSMA-617. 177 Compared with Lu-Flu-1, 177 Lu-Formula II-1-5-BD-WJ-DOTA and 177 Lu-Formula II-2-4-BD-WJ-DOTA exhibited higher tumor uptake and longer retention at all time points; 177 Lu-Formula II-2-4-PN-WJ-DOTA shows the same 177 Lu-Flu-1 showed comparable tumor uptake, but was lower at subsequent time points 177 Lu-Flu-1.

[0344] For renal uptake, the results showed that the renal pathway was the major excretion route for all radioligands. High renal radioactivity was observed 1 hour after intravenous injection and then gradually decreased.177 Lu-Flu-1 177 Lu-Type II-1-5-BD-WJ-DOTA 177 Lu-Type II-2-4-BD-WJ-DOTA initially showed relatively high renal uptake, but these values were much lower than 177 Lu-PSMA-617. 177 Both Lu-Type II-1-5-BD-WJ-DOTA and 177 Lu-Type II-2-4-BD-WJ-DOTA had higher renal uptake at 1 hour than 177 Lu-Flu-1, and then decreased to the same level. 177 Lu-Type II-2-4-PN-WJ-DOTA showed relatively low renal uptake from the beginning, and the uptake values were much lower than 177 Lu-Flu-1. After 96 hours of injection, the radioactive accumulation of all drugs in the kidneys decreased to a relatively low level.

[0345] In addition, after 4 hours of injection, the accumulation levels of all radioligands in key organs such as the heart were relatively low. The salivary gland is one of the most critical organs in PSMA-targeted radioligand therapy, and the accumulation activity was negligible for all the radioligands studied. Similarly, the accumulation activity in normal organs and tissues such as the liver, muscle, and blood with relatively low %ID / g values was negligible.

[0346] These results indicate that 177 Lu-Type II-2-4-PN-WJ-DOTA showed both low renal uptake and the lowest tumor uptake. 177 Both Lu-Type II-1-5-BD-WJ-DOTA and 177 Lu-Type II-2-4-BD-WJ-DOTA had higher tumor uptake than 177 Lu-Flu-1, and at the same time had rapid renal clearance, demonstrating excellent therapeutic potential. In particular, 177 Lu-Type II-1-5-BD-WJ-DOTA showed faster and higher tumor uptake and lower renal uptake than 177 Lu-PSMA-617. Therefore, 177 Lu-Type II-1-5-BD-WJ-DOTA has similar or even potentially better therapeutic potential than 177 Lu-PSMA-617.

[0347] 2. Treatment data

[0348] The treatment data for each dose group are shown in the appendix Figure 24-26 as follows.

[0349] Among them, the appendix Fig.24The overall trend graph of tumor volume change (A) and body weight change trend graph (B) of each group of animals at a dose of 37MBq; the trend graph of individual tumor change in each treatment group at the corresponding dose (C-H).

[0350] Attached Fig.25 The overall trend graph of tumor volume change (A) and body weight change trend graph (B) of each group of animals at a dose of 18.5MBq; the trend graph of individual tumor change in each treatment group at the corresponding dose (C-H).

[0351] Attached Fig.26 The overall trend graph of tumor volume change (A) and body weight change trend graph (B) of each group of animals at a dose of 7.4MBq; the trend graph of individual tumor change in each treatment group at the corresponding dose (C-H).

[0352] The above results show that the weight of mice in all treatment groups decreased slightly, but when the tumor volume was controlled, the weight loss was reduced and even returned to normal levels, such as 177 37 MBq of Lu-Formula II-1-5-BD-WJ-DOTA. Overall, the body weight of all treated mice remained above 65% of their initial body weight throughout the treatment period.

[0353] All mice in the saline group had rapidly growing tumors, with tumor volumes exceeding 1500 mm within 30 days. 3 Compared with the control group, a single dose of 37MBq, 18.5MBq or 7.4MBq 177 Lu-PSMA-617, 177 Lu-Flu-1, 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 Lu-Formula II-2-4-PN-WJ-DOTA and 177 The Lu-Formula II-1-5-BD-WJ-DOTA treatment groups all showed significant tumor growth inhibition or delay.

[0354] 37MBq and 18.5MBq dose groups: During the 60-day treatment cycle, 177 Lu-PSMA-617, 177 Lu-Flu-1, 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 Lu-Formula II-2-4-PN-WJ-DOTA and 177 The Lu-Formula II-1-5-BD-WJ-DOTA treatment group significantly inhibited tumor growth, and the tumor volume decreased to about 50 mm 3 There was no significant difference in the effectiveness of each drug in the two dose groups.177 Lu-Formula II-1-5-BD-WJ-DOTA has the best effect in inhibiting or reducing tumors in mice while restoring body weight, which is better than 177 Lu-PSMA-617 and 177 Lu-Flu-1; 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 Lu-Formula II-2-4-PN-WJ-DOTA is better in weight recovery 177 Lu-PSMA-617 and 177 Lu-Flu-1 was slightly worse. In the 18.5MBq dose group, 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 Lu-Formula II-2-4-PN-WJ-DOTA and 177 Lu-Formula II-1-5-BD-WJ-DOTA has better effect on restoring body weight in mice than 177 Lu-PSMA-617 and 177 Lu-Flu-1.

[0355] 7.4MBq dose group: 177 Lu-PSMA-617, 177 Lu-Flu-1, 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 Lu-Formula II-2-4-PN-WJ-DOTA significantly reduced the inhibitory effect on tumors, showing a short-term tumor inhibition in tumors, followed by a trend of tumor volume increase. 177 Lu-Formula II-2-4-BD-WJ-DOTA, 177 The tumor volume of the Lu-Formula II-2-4-PN-WJ-DOTA group decreased within 20 days and then increased. 177 Lu-PSMA-617, 177 Tumors in the Lu-Flu-1 group were suppressed within 30 days and then increased in size. 177 Lu-Formula II-1-5-BD-WJ-DOTA still maintained significant tumor inhibition, and the tumor volume decreased to about 50 mm during the treatment cycle. 3 Even smaller. At this dose, 177 Lu-Formula II-1-5-BD-WJ-DOTA had the best therapeutic effect in PSMA-positive LNCaP tumor-bearing mice.

[0356] Based on the above data, 177 Lu-Formula II-1-5-BD-WJ-DOTA has the best therapeutic effect while maintaining body weight, indicating 177The therapeutic effect of Lu-formula II-1-5-BD-WJ-DOTA in PSMA-positive LNCaP tumor-bearing mice was better than that of 177 Lu-PSMA-617 and 177 Lu-Flu-1.

[0357] In summary, the present invention prepares novel macrocyclic polyamine carboxylic acid short peptide compound I for the first time through two routes. The preparation conditions of the compound are mild, the chemical reaction type is simple, and the physical and chemical properties of the prepared compound are stable. The labeling method used by the radioactive nuclide label formula II is simple and efficient, the reaction conditions are controllable, the product labeling rate and radiochemical purity are high, and can reach more than 99%. In the stability test, the labeled product has good stability in both PBS and FBS. Formula I can be used with diagnostic nuclides 68 Ga, 64 Cu, 18 F and other combinations form imaging agents for targeted diagnosis, and can also be used by beta-particle emitters 177 Lu, 225 Ac and other labels for tumor nuclide targeting 68 Ga, 64 Cu, internal radiation therapy.

[0358] When Formula I adopts 68 Ga and 64 When radionuclide labels such as Cu are used for targeted diagnosis, in vivo PET / CT imaging studies have found that 68 Ga-formula II and 64 Cu-Formula II has good tumor uptake in the LNCaP tumor model, with a high ratio of tumor to kidney, muscle and other organs. It has good imaging performance in the LNCaP tumor model and has the potential to become a new generation of prostate cancer imaging and guidance imaging agent.

[0359] When Formula I adopts 177 Lu and 225 Ac radionuclide labeling is used for tumor radionuclide targeted internal irradiation therapy. 177 Lu-Formula II and 225 Ac-Formula II showed excellent 24-hour PBS and serum stability in physicochemical properties and in vitro and in vivo properties studies. SPECT imaging and biodistribution studies showed that the marker was mainly excreted via the renal pathway. In the LNCaP model, the drug exhibited high affinity binding to PSMA on LNCaP, which to a certain extent improved tumor absorption and therapeutic effects, and is worthy of further study in intra-prostate cancer radiotherapy.

[0360] The embodiments described above are part of the embodiments of the present invention, rather than all of the embodiments. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention claimed for protection, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Claims

1. A prostate specific membrane antigen inhibitor as shown in formula I, R 1 ＝ R 2 ＝ A＝ B＝ C＝ D= Wherein X is alkyl or halogen; E＝ in: When a=b=e=0, d=1, c=an integer from 1 to 8; When c=e=0, a=d=1, b=an integer from 1 to 8; When c=d=0, a=e=1, b=an integer from 1 to 8.

2. The prostate-specific membrane antigen inhibitor according to claim 1, It is characterized in that X is a C1-C4 alkyl or halogen; preferably, the halogen is I; Preferably, the alkyl group is methyl.

3. The radioactive label of the prostate specific membrane antigen inhibitor according to claim 1 or 2, It is characterized in that Its structure is shown in Formula II: R 3 ＝ Where M is the radionuclide; R 1 The definitions of A, B, C, D, E, X, a, b, c, d, and e are the same as those in claim 1.

4. The radioactive label of the prostate specific membrane antigen inhibitor according to claim 3, It is characterized in that When R 3 =DOTA-M, M= 68 Ga, 177 Lu, 225 Ac or 64 Cu; When R 3 =DOTAGA-M, M= 68 Ga, 177 Lu, 225 Ac or 64 Cu; When R 3 =NOTA-M, M= 68 Ga or 18 F; When R 3 =DATA-M, M= 68 Ga, 177 Lu, 225 Ac or 64 Cu; When R 3 =DATAM-C, C = 68 Ga, 177 Lu, 225 Ac or 64 Cu; When R 3 =HBED-CC-M, M= 68 Ga.

5. A method for preparing a compound of formula I according to claim 1 or 2, It is characterized in that The following steps are involved: Step 1. Compound b6 reacts with b7 to generate compound b8 through nucleophilic substitution reaction; Step 2. Compound b8 is deprotected to generate compound b9; Step 3. Compound b9 and b10 undergo peptide coupling reaction to generate compound b11; Step 4. Removing the protecting group from compound b11 to generate compound I; The reaction route is as follows: Among them, R 1 , R 2 The definitions of A, B, C, D, E, X, a, b, c, d, and e are the same as those in claim 1.

6. A method for preparing a compound of formula (I) according to claim 5, It is characterized in that In the step 1, compound b6 and compound b7 are coupled to generate compound b8 in the presence of a basic solvent and a condensing agent; preferably, the molar ratio of compound b7 to compound b6 is 1.0 to 2.0; or / and in said step 2, compound b8 is subjected to reduction reaction with a reducing agent in a solvent to generate compound b9; or / and in step 3, compound b9 and compound b10 are subjected to a coupling reaction in the presence of a basic solvent and a condensing agent to generate compound b11; preferably, the molar ratio of compound b9 to compound b10 is 1.0 to 2.0; Or / and in step 4, compound b11 is subjected to a deprotection reaction under acidic solvent conditions to generate compound of formula I; Preferably, the base in step 1 and step 3 comprises at least one of triethylamine, diethylamine, diethanolamine, pyridine, diisopropylamine, ethylenediamine, and cyclohexylamine; further preferably, the molar ratio of the base to b6 or b9 is 1.0 to 5.0; Preferably, the condensing agent used in the coupling reaction in step 1 and step 3 includes at least one of HATU, HBTU, HOBT, DCC, and EDCI; The solvent in steps 1 to 4 is an aprotic polar solvent, and more preferably, includes at least one of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, and acetonitrile; The reaction temperature of step 1 to step 4 is 0 to 60° C., and the reaction time is 1 to 24 hours.

7. A method for preparing a compound of formula (I) according to claim 5, It is characterized in that The preparation method of compound 6 comprises the following steps: S1-1. Compound b1 and b2-1 undergo a Mannich reaction to generate compound b3-1; S1-2. Compound b3-1 undergoes a nucleophilic substitution reaction with b4 to generate compound b5-1; S1-3. Compound b5-1 undergoes azide reduction reaction to generate compound b6; The reaction route is: Among them, R 1 , A, B, C, a, b, c, are all defined as in claim 1, and n is an integer from 1 to 6; Preferably, in S1-1, compound b1, compound b2-1 and CH 3 BNNa undergoes a Mannich reaction in an organic solvent to generate compound b3-1; preferably, the molar ratio of compound b1 to compound b2-1 is 1.0 to 3.0; preferably, compound b1 and CH 3 The molar ratio of BNNa is 1.0 to 3.0; preferably, the organic solvent used in S1-1 is a polar solvent; further preferably, it includes any one or more of dimethylformamide, methanol, ethanol, water, formic acid, acetic acid, and hydrochloric acid; preferably, the reaction temperature in S1-1 is 0 to 80°C, and the reaction time is 4 to 24 hours; Preferably, in S1-2, compound b3-1 reacts with b4 in a basic organic solvent to generate compound b5-1 by nucleophilic substitution reaction; preferably, the molar ratio of compound b3-17 to compound b4 is 1.0 to 3.5; preferably, the base is one or more of triethylamine, diethylamine, diethanolamine, pyridine, diisopropylamine, ethylenediamine, and cyclohexylamine, and the molar ratio thereof to compound b3-1 is 1.0 to 5.0; preferably, the organic solvent in S1-2 is an aprotic polar solvent, and further preferably, includes any one or more of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, and acetonitrile; preferably, the reaction temperature of S1-2 is 0-60°C, and the reaction time is 4 to 48 hours; Preferably, in S1-3, compound b5-1 is reduced with a reducing agent in an alkaline organic solvent to generate b6; preferably, the reducing agent is Pd / C and hydrogen or triphenylphosphine, the amount of Pd / C is 1.25-20.50% of the molar number of compound b5-1, the amount of hydrogen is 1.0-20.0% of the molar number of compound b5-1, and the molar ratio of triphenylphosphine to compound b5-1 is 1.0-5.0; preferably, the organic solvent is a polar solvent; further preferably, it includes any one or more of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile, water, methanol, and ethanol; preferably, the reaction temperature of S1-3 is 0-90°C, and the reaction time is 1-20 hours.

8. A method for preparing a compound of formula (I) according to claim 5, It is characterized in that The preparation method of compound 6 comprises the following steps: S2-1. Compound b1 and b2-2 undergo a Mannich reaction to generate compound b3-2; S2-2. Compound b3-2 undergoes a nucleophilic substitution reaction with b4 to generate compound b5-2-1; S2-3. Compound b5-2-1 is deprotected to generate compound b5-2-2; S2-4. Compound b5-2-2 undergoes peptide coupling reaction with b5-2-3 to generate compound b5-2-4; S2-5. Compound b5-2-4 is deprotected to generate compound b6; The reaction route is as follows: Among them, R 1 , A, B, C, a, b, c, are all defined as in claim 1, and n is an integer from 1 to 6; Preferably, in S2-1, compound b1, compound b2-2 and NaBH 4 Mannich reaction in an organic solvent to generate compound b3-2; preferably, the molar ratio of compound b1 to compound b2-2 is 1.0 to 3.0; preferably, compound b1 and NaBH 4 The molar ratio of is 1.0 to 3.0; preferably, the organic solvent is a polar organic solvent; further preferably, it includes any one or more of dimethylformamide, methanol, ethanol, water, formic acid, acetic acid, and hydrochloric acid; preferably, the reaction temperature of S2-1 is 0 to 80°C, and the reaction time is 4 to 24 hours; Preferably, in S2-2, compound b3-2 reacts with b4 in a basic organic solvent to generate compound b5-2-1 by nucleophilic substitution reaction; preferably, the molar ratio of compound b3-2 to compound b4 is 1.0 to 3.5; preferably, the base is one or more of triethylamine, diethylamine, diethanolamine, pyridine, diisopropylamine, ethylenediamine, and cyclohexylamine, and the molar ratio thereof to compound b3-2 is 1.0 to 5.0; preferably, the organic solvent in S2-2 is an aprotic polar solvent; further preferably, it includes any one or more of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, and acetonitrile; preferably, the reaction temperature in S2-2 is 0-60°C, and the reaction time is 4 to 48 hours; Preferably, in S2-3, compound b5-2-1 is deprotected under alkaline solvent conditions to generate compound b5-2-2; preferably, the base is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide, and the molar ratio thereof to compound b5-2-1 is 1.0 to 5.0; preferably, the solvent is a protonic polar solvent, and further preferably, includes any one or more of water, methanol, ethanol, isopropanol, and n-butanol; preferably, the reaction temperature in S2-3 is 0 to 90° C., and the reaction time is 1 to 20 hours; Preferably, in S2-4, compound b5-2-2 and compound b5-2-3 are coupled to generate compound b5-2-4 in the presence of an alkaline solvent and a condensing agent; preferably, the molar ratio of compound b5-2-3 to compound b5-2-2 is 1.0 to 3.0; preferably, the base is one or more of triethylamine, diethylamine, diethanolamine, pyridine, diisopropylamine, ethylenediamine, and cyclohexylamine, and the molar ratio of the base to compound b5-2-2 is 1.0 to 3.

0. 5.0; preferably, the coupling agent used is one or more of HATU, HBTU, HOBT, DCC, EDCI, and the molar ratio thereof to compound b5-2-2 is 1.0 to 5.0; preferably, the solvent is an aprotic polar solvent, and further preferably, includes any one or more of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, and acetonitrile; preferably, the reaction temperature of S2-4 is 0 to 60° C., and the reaction time is 1 to 24 hours; Preferably, in S2-5, compound b5-2-4 is deprotected under alkaline solvent conditions to generate compound b6; preferably, the base is one or more of triethylamine, diethylamine, diethanolamine, pyridine, diisopropylamine, ethylenediamine, and cyclohexylamine, and the molar ratio thereof to compound b5-2-4 is 1.0 to 5.0; preferably, the solvent is a non-protonic polar solvent, and further preferably, includes any one or more of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, and acetonitrile; preferably, the reaction temperature of S2-5 is 0 to 90°C, and the reaction time is 1 to 24 hours.

9. The method for preparing a radioactive label of a prostate specific membrane antigen inhibitor according to claim 3 or 4, It is characterized in that The compound of formula I reacts with a radioactive metal salt to generate a radioactive labeled compound of formula I, the reaction formula of which is: Where R 1 , R 2、 R 3、 The definitions of A, B, C, D, E, a, b, c, d, and e are the same as those in claim 3.

10. Use of the radioactive label of the compound of formula I according to claim 1 or 2 or the prostate specific membrane antigen inhibitor according to claim 3 or 4 in the preparation of diagnostic reagents / drugs and / or therapeutic drugs for prostate cancer.

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