Nitrogen-containing compound and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a nitrogen-containing compound and a preparation method therefor and the use thereof. Specifically disclosed in the present invention is a compound as shown in formula I or a pharmaceutically acceptable salt thereof, which has one or more of the following advantages: having good targeting ability and being used for the imaging diagnosis and / or treatment of prostate cancer.

Description

A nitrogen-containing compound and its preparation method and use

[0001] This application claims the benefit of Chinese patent application No. 2024100841208, filed January 19, 2024. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a nitrogen-containing compound and a preparation method and application thereof. Background Art

[0003] Prostate cancer is the second most common type of cancer in men. It is estimated that approximately 1.3 million new cases are diagnosed worldwide each year, with approximately 120,000 cases in China. Prostate-specific membrane antigen-positive, metastatic castration-resistant prostate cancer (PSMA-positive mCRPC) is the terminal stage of prostate cancer progression, with an inadequate response to castration therapy, leading to prostate cancer recurrence and metastasis. Currently, there are few treatment options for this type of patient, with a low 5-year survival rate. Prostate-specific membrane antigen (PSMA) is highly expressed in over 80% of prostate cancer patients. Targeting compounds (ligands) are combined with diagnostic or therapeutic radionuclides to bind to PSMA-expressing prostate cancer cells. The gamma or beta rays emitted when the radioactive diagnostic or therapeutic nuclides decay can image and treat the diseased tissue.

[0004] Given the importance of prostate cancer diagnosis and treatment, there is an urgent need to develop a radioactive compound with good targeting that can be used for prostate cancer imaging diagnosis and / or treatment. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the limitation of the existing art in the diagnosis and treatment of prostate cancer, which is limited in its use. To this end, the present invention provides a nitrogen-containing compound, a preparation method, and its use. The compound of the present invention has one or more of the following advantages: good targeting and can be used for imaging diagnosis and / or treatment of prostate cancer.

[0006] The present invention provides a compound I or a pharmaceutically acceptable salt thereof,

[0007] Among them, A consists of a chelating group and a radionuclide;

[0008] X is (*Position directly connected to L 2 connected);

[0009] n1 is an integer selected from 1 to 20;

[0010] n2 is an integer selected from 1 to 10;

[0011] L 1 and L 2are independently -C1-C6 alkylene-;

[0012] R is In a certain embodiment of the present invention, the compound I is

[0013] Preferably, the compound I is selected from the following structures:

[0014] More preferably, the compound I is selected from the following structures:

[0015] In a certain embodiment of the present invention, in A, the chelating group is a conventional chelating group in the art; preferably, the chelating group is 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl) glutaric acid (DOTA-GA ), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl) glutaric acid (NODA-GA), diethylenetriaminepentaacetic acid (DTPA), N,N′-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid (HBED-CC) or thioacetyltriglycine (MAG3), a structure formed by removing a hydroxyl group from a carboxyl group, for example, a structure formed by removing a hydroxyl group from a carboxyl group of DOTA

[0016] In one embodiment of the present invention, n1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, for example, n1 is an integer from 1 to 10, and for example, n1 is 2.

[0017] In one embodiment of the present invention, n2 is 1, 2, 3, 4, 5, 6, 7, 8 or 9, for example, n2 is an integer from 1 to 5, and for example, n2 is 1.

[0018] In one embodiment of the present invention, L 1 and L 2 In the above, the "-C1-C6 alkylene-" is independently -C1-C3 alkylene-, for example

[0019] In one embodiment of the present invention, L 1 In the above, the "-C1-C6 alkylene-" is

[0020] In one embodiment of the present invention, L 2 In the above, the "-C1-C6 alkylene-" is

[0021] In one embodiment of the present invention, in A, the chelating group chelates with a radionuclide.

[0022] In one embodiment of the present invention, the radionuclide is a diagnostic nuclide or a therapeutic nuclide.

[0023] In a certain embodiment of the present invention, the diagnostic nuclide is 18 F. 68 Ga, 99m Tc or 64 Cu.

[0024] In a certain embodiment of the present invention, the therapeutic nuclide is 177 Lu, 188 Re、 225 Ac, 212 Pb, 211 At or 67 Cu.

[0025] In a certain embodiment of the present invention, the radionuclide is 18 F. 68 Ga, 177 Lu, 99m Tc, 188 Re、 64 Cu, 67 Cu, 225 Ac, 212 Pb or 211 At.

[0026] In one embodiment of the present invention, the valence state of the radionuclide is monovalent, divalent, trivalent or tetravalent, for example, trivalent.

[0027] In one embodiment of the present invention, A is composed of and a radionuclide, wherein the radionuclide is 177 Lu or 68 Ga; preferably, A is composed of and a radioactive nuclide chelate, wherein the radioactive nuclide is 177 Lu or 68 Ga, e.g.

[0028] In a certain embodiment of the present invention, the structure of compound I is

[0029] The present invention also provides a compound II or a pharmaceutically acceptable salt thereof,

[0030] Among them, B is composed of a chelating group and a non-radioactive nuclide;

[0031] The chelating group, X, L 1 、L 2 and R are defined as in any of the previous schemes.

[0032] In one embodiment of the present invention, the non-radioactive nuclide is F, Ga, Lu, Tc, Re, Cu, Cu, Ac, Pb or At.

[0033] In a certain embodiment of the present invention, the compound II is

[0034] The present invention also provides a compound III or a pharmaceutically acceptable salt thereof,

[0035] Wherein, C is a chelating group;

[0036] The chelating group, X, L 1 、L 2 and R are defined as in any of the previous schemes.

[0037] In a certain embodiment of the present invention, the compound III is

[0038] The present invention also provides a pharmaceutical composition comprising a substance D and a pharmaceutical excipient, wherein the substance D is the compound I, compound II, compound III or a pharmaceutically acceptable salt thereof ("it" represents the compound I, compound II or compound III).

[0039] The present invention also provides a kit comprising a substance D and instructions, wherein the substance D is the compound I, compound II, compound III or a pharmaceutically acceptable salt thereof ("it" represents the compound I, compound II or compound III).

[0040] The present invention also provides a use of a substance D in the preparation of a medicament for treating a PSMA-related disease, wherein the substance D is the compound I, compound II, compound III or a pharmaceutically acceptable salt thereof ("it" represents the compound I, compound II or compound III); the PSMA-related disease is preferably prostate cancer, more preferably prostate cancer with high PSMA expression or PSMA-positive mCRPC (prostate-specific membrane antigen-positive, metastatic castration-resistant prostate cancer).

[0041] The present invention also provides a use of the compound I, compound III or a pharmaceutically acceptable salt thereof ("their" represents the compound I or compound III) in the preparation of a drug for treating and / or preventing cancer.

[0042] The cancer is preferably prostate cancer, more preferably prostate cancer with high PSMA expression or PSMA-positive mCRPC (prostate-specific membrane antigen-positive, metastatic castration-resistant prostate cancer).

[0043] The present invention also provides a use of the compound I, compound III or a pharmaceutically acceptable salt thereof ("their" represents the compound I or compound III) in the preparation of an imaging agent.

[0044] The imaging agent is preferably an imaging agent for diagnosing cancer; and the cancer is preferably prostate cancer.

[0045] The present invention also provides a compound IV or a pharmaceutically acceptable salt thereof,

[0046] Among them, L 1 The definition of is as described in the previous scheme.

[0047] In a certain embodiment of the present invention, the compound IV is

[0048] Explanation of terms:

[0049] The term "pharmaceutically acceptable salt" refers to a salt formed by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.

[0050] The term "alkyl" refers to a straight or branched chain alkyl group having a specified number of carbon atoms (e.g., C1 to C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0051] In the present invention, the term "alkylene" refers to a saturated linear or branched divalent hydrocarbon group. 1-6Alkylene refers to an alkylene group having 1 to 6 carbon atoms, and specific examples thereof include methylene, ethylene (e.g., -CH2CH2-, -CH(CH3)-), propylene (e.g., -CH2CH2CH2-, -C(CH3)2-, -CH2CH(CH3)-), butylene (e.g., -CH2CH2CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)CH2-), n-pentylene or n-hexylene.

[0052] In the present invention, the term "alkyleneoxy" refers to -O-alkylene-, wherein alkylene is as defined above.

[0053] In the present invention, the term "alkylenethio" refers to -S-alkylene-, wherein alkylene is as defined above.

[0054] The term "aryl" refers to a group having a specified number of carbon atoms (e.g., C6 to C 10 ) is a cyclic group consisting only of carbon atoms, which is a monocyclic or condensed ring. Aryl includes but is not limited to phenyl or naphthyl.

[0055] The terms "pharmaceutically acceptable excipients" and "pharmaceutical excipients" refer to excipients and additives used in the production of pharmaceuticals and in the preparation of prescriptions. They are all substances contained in pharmaceutical preparations, other than the active ingredient. For details, see the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).

[0056] The term "treat" refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that leads to a disease; or (3) slowing the progression of one or more biological manifestations of a disease.

[0057] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0058] The reagents and raw materials used in the present invention are commercially available.

[0059] The positive progress of the present invention is that the compounds of the present invention have one or more of the following advantages: good targeting and can be used for imaging diagnosis and / or treatment of prostate cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 177 SPECT / CT imaging of Lu-DOTA-Tri-PSMA in mice at 0.5 h;

[0061] Figure 2 177SPECT / CT imaging of Lu-DOTA-Tri-PSMA in mice after 1 hour;

[0062] Figure 3 177 SPECT / CT imaging of Lu-DOTA-Tri-PSMA in mice after 2 hours;

[0063] Figure 4 shows 177 SPECT / CT imaging of Lu-DOTA-Tri-PSMA in mice after 4 hours;

[0064] Figure 5 177 SPECT / CT imaging of Lu-DOTA-Tri-PSMA in mice after 6 hours;

[0065] Figure 6 177 SPECT / CT imaging of Lu-DOTA-Tri-PSMA in mice for 24 hours;

[0066] Figure 7 177 SPECT / CT imaging of Lu-DOTA-Tri-PSMA in mice after 48 hours;

[0067] Figure 8 177 SPECT / CT imaging of Lu-DOTA-Tri-PSMA in mice after 72 hours;

[0068] Figure 9 177 SPECT / CT imaging of Lu-DOTA-Tri-PSMA in mice after 96 hours;

[0069] Figure 10 177 SPECT / CT images of Lu-DOTA-Tri-PSMA in mice after 120 hours. DETAILED DESCRIPTION

[0070] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0071] Example 1 Radionuclide 177 Lu-labeled DOTA-N3

[0072] Preparation of DOTA-N3 solution: DOTA-N3 (Formula 1) was dissolved in 0.5 M acetic acid-sodium acetate buffer solution with a pH of 5.2±0.1, wherein the concentration of DOTA-N3 was 0.2 mg / mL.

[0073] Add 26 μL 177LuCl3 solution (radioactivity of about 18 mCi, solvent is 0.04 mol / L hydrochloric acid) and 150 μL DOTA-N3 solution were mixed and heated at 95 ° C for 15 min to obtain 177 The reaction solution of Lu-DOTA-N3 was 176 μL, and the labeling rate was 87.82% by Radio-HPLC, as shown in Table 1 below; 177 Chromatographic peak corresponding to Lu-DOTA-N3.

[0074] Radio-HPLC detection conditions:

[0075] Chromatographic column: ZORBAX Eclipse Plus C18 (4.6 mm × 250 mm, 5 μm)

[0076] Mobile phase: A: 0.1% TFA in H2O, B: 0.1% TFA in CH3CN

[0077] Gradient: 0-5-10-14-15-17 min, 1-1-10-10-1-1% B

[0078] Flow rate: 1 mL / min

[0079] Wavelength: 220nm

[0080] Column temperature: 30°C

[0081] Table 1

[0082] Example 2 Click Chemistry Reaction

[0083] Synthesis route of PSMA-alkyne:

[0084] Compd1 (1 eq) was dissolved in DMF, and then DIPEA (5 eq) and Compd2 (2 eq) were added in sequence. The mixture was allowed to react at room temperature for 2 hours and monitored by LC-MS. After the raw materials reacted completely, the mixture was concentrated in vacuo, dried, and purified by reverse phase chromatography to obtain the target product PSMA-alkynyl.

[0085] Preparation of PSMA-alkynyl solution: The above-mentioned PSMA-alkynyl was dissolved in DMF, wherein the concentration of PSMA-alkynyl was 0.7 mg / mL.

[0086] Preparation of copper sulfate solution: Dissolve copper sulfate in 0.5 M acetic acid-sodium acetate buffer solution with a pH of 5.2±0.1, wherein the concentration of copper sulfate is 3.2 mg / mL.

[0087] Preparation of sodium ascorbate solution: Sodium ascorbate was dissolved in 0.5 M acetic acid-sodium acetate buffer solution with a pH of 5.2±0.1, wherein the concentration of sodium ascorbate was 17.5 mg / mL.

[0088] 95 μL of PSMA-alkyne solution was mixed with the 177 175 μL of Lu-DOTA-N3 reaction solution, 43 μL of copper sulfate solution, and 45 μL of sodium ascorbate solution were mixed and heated at 40°C for 60 min to obtain 177 358 μL of Lu-DOTA-Tri-PSMA reaction solution was detected by Radio-HPLC under the same analytical conditions. 177 The peak position of Lu-DOTA-Tri-PSMA and the cold reference compound 175 Lu-DOTA-Tri-PSMA (cold reference compound uses non-radioactive raw materials and is 177 Lu-DOTA-Tri-PSMA was prepared by a similar method; the product molecular weight was detected by LC-MS. 175 The theoretical value of Lu-DOTA-Tri-PSMA is consistent; confirmed by Radio-HPLC 175 The peak position of Lu-DOTA-Tri-PSMA is consistent with the peak position of Lu-DOTA-Tri-PSMA. The labeling rate was 72.79% as detected by Radio-HPLC, as shown in Table 2 below; 177 Chromatographic peak corresponding to Lu-DOTA-Tri-PSMA.

[0089] The aforementioned 177 358 μL of the Lu-DOTA-Tri-PSMA reaction solution was diluted to 2 mL with sterile water for injection to prepare the solution to be purified. 2 mL of the solution to be purified was purified by C18 column to obtain the target product with a radiochemical purity of 92.78% ( 177 Lu-DOTA-Tri-PSMA ethanol solution), see Table 3 below, where chromatographic peak 5 is 177 Chromatographic peak corresponding to Lu-DOTA-Tri-PSMA.

[0090] Radio-HPLC detection conditions:

[0091] Chromatographic column: ZORBAX Eclipse Plus C18 (4.6 mm × 250 mm, 5 μm)

[0092] Mobile phase: A: 0.1% TFA in H2O, B: 0.1% TFA in CH3CN

[0093] Gradient: 0-10-20-30-35-38-40-45 min, 1-10-20-40-40-100-1-1% B

[0094] Flow rate: 1 mL / min

[0095] Wavelength: 220nm

[0096] Column temperature: 30°C

[0097] C18 cartridge purification conditions (C18 cartridge model: Waters, Sep-Pak Light-C18 solid phase extraction cartridge):

[0098] Activation of C18 column: First, rinse the C18 column with 5 mL of ethanol, and then rinse with 5 mL of sterile water for injection.

[0099] Purify the product using a C18 column: Pass 2 mL of the aforementioned solution to be purified through a C18 column (i.e., elute it into the C18 column); rinse the C18 column with 1.5 mL of sterile water for injection to remove radioactive impurities; then rinse the C18 column with 0.5 mL of anhydrous ethanol and collect the eluate with a higher concentration to obtain the target product: 177 0.4 mL of Lu-DOTA-Tri-PSMA ethanol solution.

[0100] Table 2

[0101] Table 3

[0102] Example 3 In vitro stability

[0103] 60 μL of the target product obtained in Example 2 was diluted with 1 mL of 0.5 M acetic acid-sodium acetate buffer (pH = 5.2) and placed in a 25°C stability test chamber. The initial radiochemical purity of the target product was 92.78%. After 24 hours, the radiochemical purity of the target product remained essentially unchanged at 92.07%.

[0104] Example 4 Biodistribution

[0105] Preparation of radioactive injection 1: The target product obtained in Example 2 (i.e. 177 The ethanol solution of Lu-DOTA-Tri-PSMA was diluted with 0.5 M acetic acid-sodium acetate buffer at pH 5.2 to a radioactivity concentration of approximately 1 mCi / mL.

[0106] 22Rv1 male tumor-bearing nude mice (Shanghai Junna Medical Technology Co., Ltd., catalog number: NO.202373380) were used, and the aforementioned radioactive injection solution 1 was injected into the mice through the tail vein (about 100 μL, 100 μCi / mouse, 4 mice / group, four groups in total). The animals were killed 0.5 h, 1 h, 4 h and 24 h after injection, and the tissues and organs of interest were dissected and weighed. The radioactive counts were measured using a gamma counter and the ID% / g of the tissues and organs were calculated (calculation formula: ID% / g = tissue count / total count in the injected mouse / tissue weight*100%).

[0107] In this embodiment, 24 hours after administration, 177 The organ distribution of Lu is shown in Table 4 below, which is consistent with the compounds reported in the literature. 177 Compared with Lu-PSMA-617 (Wu, Y.; Zhang, X.; Duan, X.; Yang, X.; Wang, F.; Zhang, J. Optimized Therapeutic 177 Lu-Labeled PSMA-Targeted Ligands with Improved Pharmacokinetic Characteristics for Prostate Cancer.Pharmaceuticals 2022,15,1530), 177 Lu-DOTA-Tri-PSMA showed high PSMA-specific tumor uptake: after 24 h, the initial high uptake in the kidneys was close to complete metabolism (1.58±0.70ID% / g), while the tumor uptake remained high (9.14±3.16ID% / g); other organs, such as the liver (0.07±0.02ID% / g), spleen (0.05±0.02ID% / g) and lung (0.06±0.01ID% / g), showed very low uptake. 177 The favorable pharmacokinetics of Lu-DOTA-Tri-PSMA resulted in a high tumor-to-background ratio (tumor / blood: 304.67; tumor / muscle: 914.00) even after 24 h.

[0108] At different time points after administration, 177 The comparison of Lu uptake in various tissues of 22Rv1 tumor-bearing mice is shown in Table 5 below. 177 Lu is rapidly cleared from all major organs and is specifically taken up by tumor tissue, so the tumor-to-background ratio increases over time.

[0109] Table 4 177 Lu-DOTA-Tri-PSMA177 Comparison of Lu-PSMA-617 uptake in various tissues of 22Rv1 tumor-bearing mice 24 hours after administration

[0110] Table 5 177 Comparison of Lu-DOTA-Tri-PSMA uptake in various tissues of 22Rv1 tumor-bearing mice at different time points after administration (unit: ID% / g)

[0111] Example 5 Small Animal SPECT / CT Imaging

[0112] Preparation of radioactive injection 2: The target product obtained in Example 2 (i.e. 177 The ethanol solution of Lu-DOTA-Tri-PSMA was diluted with 0.5 M acetic acid-sodium acetate buffer at pH 5.2 to a radioactivity concentration of approximately 4.75 mCi / mL.

[0113] 22Rv1 male tumor-bearing nude mice (Shanghai Junna Medical Technology Co., Ltd., Cat. No. 202373380) were used to inject radiolabeled compounds into the nude mice. 177 Lu-DOTA-Tri-PSMA was injected into mice via the tail vein (approximately 120 μL, 600 μCi / mouse, 5 mice in total), and the animals were scanned in vivo at 0.5 h, 1 h, 2 h, 4 h, 6 h, 24 h, 48 h, 72 h, 96 h, and 120 h after injection.

[0114] 177 SPECT / CT imaging of Lu-DOTA-Tri-PSMA showed early accumulation in the bladder and kidney uptake, with rapid background clearance. After 4 hours, kidney accumulation decreased significantly, kidney and bladder accumulation was basically cleared after 6 hours, and kidney and bladder accumulation was completely cleared after 24 hours. 177 Lu-DOTA-Tri-PSMA further accumulated and remained in PSMA-expressing tumors, as shown in Figure 1 ; the corresponding quantitative data are shown in Table 6 below (unit: ID% / mm 3 ):

[0115] Table 6 In vivo scanning data of various organs in SPECT / CT imaging experiments

[0116] Example 6 Treatment Effect

[0117] Take the obtained 177 Lu-DOTA-Tri-PSMA and 177Lu-PSMA-617 was injected into two groups (4 mice / group) of tumor-bearing mice (22Rv1 male nude mice) via the tail vein (injection volume: 100 μL / mouse, injection activity: 1.5 mCi / mouse). Tumor size was measured and volume calculated every other day in a control group (4 mice, not injected with any drug but only with 0.9% NaCl aqueous solution). The therapeutic effects of the two drugs on mice were evaluated by comparing tumor size.

[0118] 177 Lu-DOTA-Tri-PSMA showed good therapeutic effects on cancer mice, especially prostate cancer mice.

[0119] The changes in tumor volume of mice in the experimental group and the control group over time are shown in Table 7 below:

[0120] The volume values ​​in the table above are the average tumor volumes of mice in each group, in mm 3 ;

[0121] “—” indicates that the first test mouse died at that time.

[0122] The changes in body weight of mice in the experimental and control groups over time are shown in Table 8 below:

[0123] The weight values ​​in the above table are the average weights of mice in each group, in g;

[0124] “—” indicates that the first test mouse died at that time.

[0125] The survival of mice in the experimental group and the control group changes over time are shown in Table 9 below:

[0126] Example 7 68 Preparation of Ga-DOTA-Tri-PSMA:

[0127] 1. Synthesis of DOTA-Tri-PSMA

[0128] Compd (1 eq) was dissolved in DMF, and compd2 (1.2 eq) and DIEA (N,N-diisopropylethylamine) (3 eq) were added to the reaction mixture. The reaction was allowed to react at room temperature for 1 hour, and the reaction was monitored by LC-MS. After the reaction was complete, the raw material was concentrated under reduced pressure and then cleaved by adding an appropriate amount of TFA for 5 minutes to remove the tBu protecting group. The product was washed twice with ether, centrifuged, and dried to obtain the crude product compd3 (yield: 32 mg, 70%).

[0129] Compd3 (1 eq) and compd4 (2 eq) were dissolved in EtOH / H2O (1:1). Under nitrogen protection, a CuSO4.5H2O (0.2 eq) aqueous solution was added to the reaction mixture. Finally, a sodium ascorbate (0.2 eq) aqueous solution was added to the reaction mixture. The reaction was allowed to proceed at room temperature for 2.5 hours. LC-MS monitoring indicated that the reaction was complete. The starting materials were concentrated and the reaction was reverse-phase prepared to obtain compd5 (yield: 28 mg, 50%).

[0130] Compd5 (1 eq) was dissolved in DMF, and compd6 (1.5 eq) and DIEA (3 eq) were added to the reaction solution. The reaction was allowed to proceed at room temperature for 2 hours. The reaction was monitored by LC-MS. The reaction was complete. The product was concentrated under reduced pressure and purified by reverse phase to obtain the target product DOTA-Tri-PSMA (Yield: 23 mg, 56%).

[0131] 2. Preparation of 0.5 mg / mL DOTA-Tri-PSMA solution

[0132] Take DOTA-Tri-PSMA, add 2000 μL of deionized water to dilute it, and mix well to obtain a precursor solution.

[0133] 3. 68 Preparation of Ga-labeled compounds

[0134] 1000 μL 68 GaCl3 solution (59.2 MBq) and 150 μL of 1 M NaOAc were mixed, and 100 μL of the aforementioned precursor solution (i.e., 0.5 mg / mL DOTA-Tri-PSMA solution) was added thereto. The mixture was thoroughly mixed and incubated at 95°C for 15 min. After the reaction was complete, the reaction bottle was cooled, sampled, and analyzed by Radio-HPLC.

[0135] 4. Radio-HPLC detection conditions

[0136] Chromatographic column: ZORBAX Eclipse Plus C18 (4.6 mm × 250 mm, 5 μm) Column temperature: 30 °C

[0137] Mobile phase: A: 0.1% TFA in H2O, B: 0.1% TFA in ACN

[0138] Gradient: 0-10-20-22-27-30-35 min, 10-20-40-40-100-10-10% B

[0139] Flow rate: 1 mL / min

[0140] Wavelength: 220nm

[0141] 5. Radio-HPLC test results are shown in Table 10 below

[0142] Table 10

[0143] 6. In vitro stability

[0144] The obtained target product was placed in a 25° C. stability test chamber. The initial radiochemical purity of the target product was 96.62%. After 4.5 hours, the radiochemical purity of the target product remained essentially unchanged at 96.89%.

[0145] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound I or a pharmaceutically acceptable salt thereof, Among them, A is composed of a chelating group and a radionuclide; X is * is the connection position of X and L 2 ; n1 is selected from the integers from 1 to 20; n2 is selected from the integers from 1 to 10; L 1 and L 2 independently is -C1-C6 alkylene-; R is 2. The compound I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) In A, the chelating group is a structure formed by removing the hydroxyl group in one carboxyl group on the basis of the DOTA, NOTA, DOTA-GA, NODA-GA, DTPA, HBED-CC or MAG3 structure; (2) n1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, for example, n1 is an integer from 1 to 10, or n1 is 2; (3) n2 is 1, 2, 3, 4, 5, 6, 7, 8 or 9, for example, n2 is an integer from 1 to 5, or n2 is 1; (4)L 1 and L 2 wherein the "-C1-C6 alkylene-" is independently -C1-C3 alkylene-; (5) In A, the chelating group chelates with the radionuclide; (6) The radionuclide is a diagnostic radionuclide or a therapeutic radionuclide; (7) The radionuclide is 18 F, 68 Ga, 177 Lu, 99m Tc, 188 Re, 64 Cu, 67 Cu, 225 Ac, 212 Pb or 211 At; (8) The valence state of the radionuclide is monovalent, divalent, trivalent or tetravalent; (9) The compound I is 3. The compound I or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that, It satisfies one or more of the following conditions: (1)In A, the chelating group is (2)L 1 in which, the "-C1-C6 alkylene-" is (3)L 2 in which, the "-C1-C6 alkylene-" is (4) The diagnostic radionuclide is 18 F, 68 Ga, 99m Tc or 64 Cu; (5) The therapeutic radionuclide is 177 Lu, 188 Re, 225 Ac, 212 Pb, 211 At, or 67 Cu; (6) The valence state of the radionuclide is trivalent; (7) The compound I is selected from the following structures:

4. The compound I according to claim 3 or a pharmaceutically acceptable salt thereof, characterized in that, It satisfies one or more of the following conditions: (1)A consists of composed of a radionuclide, and the radionuclide is 177 Lu or 68 Ga; preferably, A is composed of composed of a chelate with a radionuclide, wherein the radionuclide is 177 Lu or 68 Ga, for example (2) The compound I is selected from the following structures:

5. The compound I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The structure of the compound I is 6. A compound II or a pharmaceutically acceptable salt thereof, Among them, B is composed of a chelating group and a non-radionuclide; The chelating group, X, L 1 , L 2 and R are as defined in any one of claims 1-4; Preferably, the non-radionuclide is F, Ga, Lu, Tc, Re, Cu, Cu, Ac, Pb or At; Preferably, the compound II is 7. A compound III or a pharmaceutically acceptable salt thereof, Among them, C is a chelating group; The chelating group, X, L 1 , L 2 and R are as defined in any one of claims 1-4; Preferably, the compound III is 8. A pharmaceutical composition comprising substance D and a pharmaceutical excipient, wherein the substance D is Compound I as described in any one of claims 1-5, Compound II as described in claim 6, Compound III as described in claim 7 or a pharmaceutically acceptable salt thereof.

9. A kit comprising substance D and an instruction manual, wherein the substance D is Compound I as described in any one of claims 1-5, Compound II as described in claim 6, Compound III as described in claim 7 or a pharmaceutically acceptable salt thereof.

10. Use of a substance D in the preparation of a drug for treating a disease related to PSMA, wherein the substance D is Compound I as described in any one of claims 1-5, Compound II as described in claim 6, Compound III as described in claim 7 or a pharmaceutically acceptable salt thereof; The disease related to PSMA is preferably prostate cancer, more preferably prostate cancer with high PSMA expression or PSMA-positive mCRPC.

11. Use of Compound I as described in any one of claims 1-5, Compound III as described in claim 7 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing cancer; The cancer is preferably prostate cancer, more preferably prostate cancer with high PSMA expression or PSMA-positive mCRPC.

12. Use of Compound I as described in any one of claims 1-5, Compound III as described in claim 7 or a pharmaceutically acceptable salt thereof in the preparation of an imaging agent; The imaging agent is preferably an imaging agent for diagnosing cancer; the cancer is preferably prostate cancer.

13. A compound IV or a pharmaceutically acceptable salt thereof, Among them, L 1 is defined as described in any one of claims 1-4; The compound IV is preferably

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