A nitrogen-containing compound, a method for preparing the same, and a use thereof

Abstract

The application discloses a nitrogen-containing compound and a preparation method and application thereof. The application specifically discloses a compound as shown in formula I or a pharmaceutically acceptable salt thereof, which has one or more advantages of good targeting, and can be used for prostate cancer imaging diagnosis and / or treatment.

Description

Technical Field

[0001] This invention relates to a nitrogen-containing compound, its preparation method, and its uses. Background Technology

[0002] Prostate cancer is the second most common type of cancer in men. Prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer (PSMA-positive mCRPC) represents the final stage of prostate cancer development, characterized by insufficient response to castration therapy, leading to recurrence and metastasis. Currently, treatment options for this group are limited, and the 5-year survival rate is low. Prostate-specific membrane antigen (PSMA) is highly expressed in over 80% of prostate cancer patients. Combining targeted compounds (ligands) with diagnostic or therapeutic radionuclides allows the drug to bind to PSMA-expressing prostate cancer cells. The gamma or beta rays emitted during the decay of the radioactive diagnostic or therapeutic nuclide can then visualize and treat the diseased tissue.

[0003] Given the importance of prostate cancer diagnosis and treatment, there is an urgent need to develop a highly targeted radioactive compound that can be used for imaging diagnosis and / or treatment of prostate cancer. Summary of the Invention

[0004] The technical problem this invention aims to solve is to overcome the deficiency of existing technologies that rely on single compounds for the diagnosis and treatment of prostate cancer. To this end, this invention provides a nitrogen-containing compound, its preparation method, and its uses. The compound of this invention has one or more of the following advantages: good targeting and applicability for imaging diagnosis and / or treatment of prostate cancer.

[0005] This invention provides a compound I or a pharmaceutically acceptable salt thereof.

[0006]

[0007] A consists of a chelating group and a radioactive nuclide;

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

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

[0010] n2 is selected from integers from 1 to 10;

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

[0012] R is

[0013] In one embodiment of the present invention, compound I is

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

[0015] More preferably, compound I is selected from the following structures:

[0016] In one aspect 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), or 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTA-GA). Based on the structures of 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 mercaptoacetyltriglycine (MAG3), a structure is formed by removing a hydroxyl group from a carboxyl group, such as the structure formed by removing a hydroxyl group from a carboxyl group in DOTA.

[0017] 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, or n1 is 2.

[0018] 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, or n2 is 1.

[0019] In one aspect of the present invention, L 1 and L 2 In this context, "-C1-C6 alkylene-" is independently -C1-C3 alkylene-, for example...

[0020] In one aspect of the present invention, L 1 In the text, "-C1-C6 alkylene-" refers to...

[0021] In one aspect of the present invention, L 2 In the text, "-C1-C6 alkylene-" refers to...

[0022] In one embodiment of the present invention, in A, the chelating group is chelated with a radionuclide.

[0023] In one embodiment of the present invention, the radionuclide is a diagnostic radionuclide or a therapeutic radionuclide.

[0024] In one embodiment of the present invention, the diagnostic radionuclide is 18 F, 68 Ga、 99m Tc or 64 Cu.

[0025] In one embodiment of the present invention, the therapeutic radionuclide is 177 Lu、 188 Re、 225 Ac、 212 Pb, 211 At or 67 Cu.

[0026] In one embodiment of the present invention, the radioactive nuclide is 18 F, 68 Ga、 177 Lu、 99m Tc, 188 Re、 64 Cu、 67 Cu、 225 Ac、 212 Pb or 211 At.

[0027] In one aspect of the present invention, the valence state of the radionuclide is monovalent, divalent, trivalent, or tetravalent, for example, trivalent.

[0028] In one embodiment of the present invention, A is... Composed of radioactive nuclides, wherein the radioactive nuclides are 177 Lu or 68 Ga; preferably, A is composed of It is composed of a chelate with a radioactive nuclide, wherein the radioactive nuclide is 177 Lu or 68 Ga, for example

[0029] In one embodiment of the present invention, the structure of compound I is as follows:

[0030]

[0031] The present invention also provides compound II or a pharmaceutically acceptable salt thereof.

[0032]

[0033] B consists of chelating groups and non-radioactive nuclides;

[0034] The chelating groups, X, L 1 L 2 The definitions of R and R are as described in any of the previous schemes.

[0035] In one embodiment of the present invention, the non-radioactive nuclide is F, Ga, Lu, Tc, Re, Cu, Cu, Ac, Pb, or At.

[0036] In one embodiment of the present invention, compound II is

[0037]

[0038] The present invention also provides a compound III or a pharmaceutically acceptable salt thereof.

[0039]

[0040] Wherein, C is a chelating group;

[0041] The chelating groups, X, L 1 L 2 The definitions of R and R are as described in any of the previous schemes.

[0042] In one embodiment of the present invention, compound III is

[0043] The present invention also provides a pharmaceutical composition comprising substance D and a pharmaceutical excipient, wherein substance D is a pharmaceutically acceptable salt of said compound I, compound II, compound III or thereof (“therefore” represents said compound I, compound II or compound III).

[0044] The present invention also provides a kit comprising substance D and instructions, wherein substance D is a pharmaceutically acceptable salt of said compound I, compound II, compound III or thereof (“therefore” represents said compound I, compound II or compound III).

[0045] The present invention also provides the use of substance D in the preparation of a medicament for treating PSMA-related diseases, wherein substance D is compound I, compound II, compound III or a pharmaceutically acceptable salt thereof (“therefore” represents 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).

[0046] The present invention also provides the use of said compound I, compound III or a pharmaceutically acceptable salt thereof (“therefore” represents said compound I or compound III) in the preparation of a medicament for treating and / or preventing cancer.

[0047] 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).

[0048] The present invention also provides the use of said compound I, compound III or a pharmaceutically acceptable salt thereof (“therefore” represents said compound I or compound III) in the preparation of a developer.

[0049] The imaging agent is preferably an imaging agent used for diagnosing cancer; the cancer is preferably prostate cancer.

[0050] The present invention also provides a compound IV or a pharmaceutically acceptable salt thereof.

[0051]

[0052] Among them, L 1 The definition is as described in the previous scheme.

[0053] In one embodiment of the present invention, compound IV is

[0054]

[0055] Terminology Explanation:

[0056] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base. When a 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 a 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.

[0057] The term "alkyl" refers to a straight-chain or branched 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, etc.

[0058] In this invention, the term "alkylene" refers to a saturated straight-chain or branched divalent hydrocarbon group. 1-6Alkylene refers to an alkylene having 1 to 6 carbon atoms, such as 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.

[0059] In this invention, the term "alkeneoxy" refers to -O-alkylene-, wherein the definition of alkylene is as described above.

[0060] In this invention, the term "alkylenethionyl" refers to -S-alkylene-, wherein the definition of alkylene is as described above.

[0061] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6 to C5). 10 Aryl groups are cyclic groups consisting only of carbon atoms, and can be monocyclic or fused-ring. Aryl groups include, but are not limited to, phenyl or naphthyl groups.

[0062] The terms "pharmaceuticalally acceptable excipients" and "pharmaceutical excipients" refer to the excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions. They are all substances included in pharmaceutical preparations, excluding the active ingredient. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009).

[0063] The term “treatment” 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 triggers the disease; or (3) slowing the development of one or more biological manifestations of a disease.

[0064] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0065] The reagents and raw materials used in this invention are all commercially available.

[0066] The positive and progressive effects of this invention are as follows: the compounds of this invention have one or more of the following advantages: good targeting and can be used for imaging diagnosis and / or treatment of prostate cancer. Attached Figure Description

[0067] Figure 1 for 177SPECT / CT images of Lu-DOTA-Tri-PSMA in mice at various time points, corresponding to 0.5h, 1h, 2h, 4h, 6h, 24h, 48h, 72h, 96h, and 120h respectively. Figure 1 The parts a, b, c, d, e, f, g, h, i, and j. Detailed Implementation

[0068] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0069] Example 1 Radionuclide 177 Lu marks DOTA-N3

[0070] DOTA-N3 solution preparation: DOTA-N3 (Formula 1) was prepared by dissolving it in a 0.5M acetate-sodium acetate buffer solution with a pH of 5.2±0.1, wherein the concentration of DOTA-N3 was 0.2 mg / mL.

[0071] 26 μL 177 A mixture of LuCl3 solution (radioactivity approximately 18 mCi, solvent: 0.04 mol / L hydrochloric acid) and 150 μL LOTA-N3 solution was heated at 95 °C for 15 min to obtain a solution containing... 177 The reaction solution of Lu-DOTA-N3 was 176 μL, and the labeling rate was 87.82% as detected by Radio-HPLC (see Table 1 below); among which, chromatographic peak 4 was... 177 The chromatographic peak corresponding to Lu-DOTA-N3.

[0072]

[0073] Radio-HPLC detection conditions:

[0074] Chromatographic column: ZORBAX Eclipse Plus C18 (4.6 mm × 250 mm, 5 μm) Mobile phase: A: 0.1% TFA in H2O, B: 0.1% TFA in CH3CN

[0075] Gradient: 0-5-10-14-15-17min, 1-1-10-10-1-1% B

[0076] Flow rate: 1 mL / min

[0077] Wavelength: 220nm

[0078] Column temperature: 30℃

[0079] Table 1

[0080]

[0081] Example 2 Click Chemical Reaction

[0082] Synthetic route of PSMA-alkynyl group:

[0083]

[0084] Compd1 (1 eq) was dissolved in DMF, and then DIPEA (5 eq) and Compd2 (2 eq) were added sequentially. The mixture was allowed to react at room temperature for 2 hours. The reaction was monitored by LC-MS. After the reaction of the starting materials was complete, the mixture was concentrated under vacuum, dried, and purified by reversed-phase chromatography to obtain the target product PSMA-alkynyl.

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

[0086] Preparation of copper sulfate solution: Copper sulfate was prepared by dissolving it in a 0.5M acetate-sodium acetate buffer solution with a pH of 5.2±0.1, wherein the concentration of copper sulfate was 3.2 mg / mL.

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

[0088] 95 μL of PSMA-alkynyl solution was mixed with the aforementioned... 177 The reaction solution of Lu-DOTA-N3 (175 μL), copper sulfate solution (43 μL), and sodium ascorbate solution (45 μL) were mixed and heated at 40 °C for 60 min to obtain a solution containing... 177 358 μL of the Lu-DOTA-Tri-PSMA reaction solution was analyzed by Radio-HPLC under the same analytical conditions. 177 Peak position of Lu-DOTA-Tri-PSMA and cold reference compound 175 Lu-DOTA-Tri-PSMA (cold reference compound uses non-radioactive raw materials, employing...) 177 It was prepared using a similar method to Lu-DOTA-Tri-PSMA; the molecular weight and molecular weight of the product were determined by LC-MS. 175 The value of Lu-DOTA-Tri-PSMA is consistent with the theoretical value; confirmed by Radio-HPLC detection. 175 The elution positions of Lu-DOTA-Tri-PSMA were consistent. The labeling rate, as determined by Radio-HPLC, was 72.79%, as shown in Table 2 below; among which, chromatographic peak 5 was...177 The 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 purification solution. The 2 mL purification solution was then purified using a C18 column to obtain the target product with a radiochemical purity of 92.78%. 177 The ethanol solution of Lu-DOTA-Tri-PSMA is shown in Table 3 below, where chromatographic peak 5 is... 177 The chromatographic peak corresponding to Lu-DOTA-Tri-PSMA.

[0090]

[0091] Radio-HPLC detection conditions:

[0092] Column: ZORBAX Eclipse Plus C18 (4.6mm × 250mm, 5μm)

[0093] Mobile phase: A: 0.1% TFA in H2O, B: 0.1% TFA in CH3CN

[0094] Gradient: 0-10-20-30-35-38-40-45min, 1-10-20-40-40-100-1-1% B

[0095] Flow rate: 1 mL / min

[0096] Wavelength: 220nm

[0097] Column temperature: 30℃

[0098] C18 column purification conditions (C18 column model: Waters, Sep-Pak Light-C18 solid phase extraction column):

[0099] C18 column activation: First rinse the C18 column with 5 mL of ethanol, then rinse with 5 mL of sterile water for injection.

[0100] C18 column purification: Pass 2 mL of the above-mentioned solution to be purified through a C18 column (i.e., elute onto a C18 column); rinse the C18 column with 1.5 mL of sterile water for injection to remove radioactive impurities; rinse the C18 column with 0.5 mL of anhydrous ethanol, and collect the eluent with the higher concentration to obtain the target product: 177 0.4 mL of an ethanol solution of Lu-DOTA-Tri-PSMA.

[0101] Table 2

[0102]

[0103]

[0104] Table 3

[0105]

[0106] Example 3 In vitro stability

[0107] 60 μL of the target product obtained in Example 2 was diluted with 1 mL of 0.5 M acetate-sodium acetate buffer solution with pH = 5.2 and placed in a stability test chamber at 25 °C. The initial radiochemical purity of the target product was 92.78%, and after 24 h, the radiochemical purity of the target product remained basically unchanged at 92.07%.

[0108] Example 4: Biodistribution

[0109] Preparation of radioactive injection solution 1: The target product obtained in Example 2 (i.e., 177 The ethanol solution of Lu-DOTA-Tri-PSMA was diluted with 0.5M acetate-sodium acetate buffer at pH 5.2 to a radioactive concentration of approximately 1 mCi / mL.

[0110] Male 22Rv1 tumor-bearing nude mice (Shanghai Junna Medical Technology Co., Ltd., catalog number: NO.202373380) were used. The aforementioned radioactive injection solution 1 was injected into the mice via the tail vein (approximately 100 μL, 100 μCi / mouse, 4 mice / group, for a total of four groups). The animals were sacrificed at 0.5 h, 1 h, 4 h and 24 h after injection. The tissues and organs of interest were dissected and weighed. The radioactivity count was measured using a gamma counter and the ID% / g of the tissues and organs was calculated (calculation formula: ID% / g = tissue count / total count in the injected mouse / tissue weight * 100%).

[0111] 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. OptimizedTherapeutic 177 Lu-Labeled PSMA-Targeted Ligands with Improved PharmacokineticCharacteristics for Prostate Cancer.Pharmaceuticals2022,15,1530), 177Lu-DOTA-Tri-PSMA showed high PSMA-specific tumor uptake: after 24 hours, the initial high uptake was almost completely metabolized by the kidneys (1.58±0.70 ID% / g), while tumor uptake remained at a high level (9.14±3.16 ID% / g); other organs, such as the liver (0.07±0.02 ID% / g), spleen (0.05±0.02 ID% / g), and lung (0.06±0.01 ID% / g), showed very low uptake. 177 The favorable pharmacokinetics of Lu-DOTA-Tri-PSMA resulted in a high tumor-to-background ratio even after 24 hours (tumor / blood: 304.67; tumor / muscle: 914.00).

[0112] At different time points after drug administration, 177 Table 5 below shows the comparison of Lu uptake in various tissues of 22Rv1 tumor-bearing mice. It can be seen that... 177 Lu can be rapidly cleared in all major organs and is specifically taken up by tumor tissue, thus the tumor-to-background ratio increases over time.

[0113]

[0114] Table 4 177 Lu-DOTA-Tri-PSMA and 177 Comparison of Lu-PSMA-617 uptake in various tissues of 22Rv1 tumor-bearing mice 24 hours after administration

[0115] <![CDATA[ 177 Lu-DOTA-Tri-PSMA(ID% / g)]]> <![CDATA[ 177 Lu-PSMA-617(ID% / g)]]> Blood 0.03±0.00 0.24±0.11 Heart 0.02±0.00 0.10±0.03 liver 0.07±0.02 0.56±0.14 spleen 0.05±0.02 0.78±0.22 lung 0.06±0.01 0.33±0.10 kidney 1.58±0.70 2.67±1.02 salivary glands 0.04±0.01 0.19±0.05 muscle 0.01±0.00 0.08±0.01 bone 0.03±0.02 0.40±0.13 tumor 9.14±3.16 3.74±0.29 Tumor / blood 304.67 15.58 Tumor / Muscle 914.00 46.75 Tumor / Kidney 5.78 1.40

[0116] Table 5 177 Comparison of Lu-DOTA-Tri-PSMA uptake in various tissues of 22Rvl tumor-bearing mice at different time points after administration (unit: ID% / g)

[0117] 0.5h 1h 4h 24h Blood 3.27±0.09 1.08±0.25 0.16±0.04 0.03±0.00 Heart 1.03±0.32 0.39±0.08 0.06±0.01 0.02±0.00 liver 1.46±0.25 0.74±0.07 0.18±0.06 0.07±0.02 spleen 3.61±0.66 2.11±0.22 0.24±0.14 0.05±0.02 lung 2.98±0.90 1.16±0.28 0.18±0.04 0.06±0.01 kidney 99.49±26.18 64.50±5.38 8.56±2.55 1.58±0.70 salivary glands 1.62±0.44 0.65±0.15 0.15±0.03 0.04±0.01 muscle 0.91±0.22 0.28±0.10 0.08±0.05 0.01±0.00 bone 0.76±0.34 0.30±0.15 0.07±0.02 0.03±0.02 tumor 19.75±3.02 19.00±0.65 14.20±1.45 9.14±3.16 Tumor / blood 6.04 17.59 88.75 304.67 Tumor / Muscle 21.70 67.86 177.50 914.00 Tumor / Kidney 0.20 0.29 1.66 5.78 .

[0118] Example 5: Small Animal SPECT / CT Imaging

[0119] Preparation of radioactive injection solution 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, pH 5.2 acetate-sodium acetate buffer to a radioactive concentration of approximately 4.75 mCi / mL.

[0120] Using male 22Rv1 tumor-bearing nude mice (Shanghai Junna Medical Technology Co., Ltd., catalog number: NO.202373380), radiolabeled compounds were applied. 177Lu-DOTA-Tri-PSMA was injected into mice via the tail vein (approximately 120 μL, 600 μCi / mouse, for a total of 5 mice). In vivo scans of the small animals were performed at 0.5 h, 1 h, 2 h, 4 h, 6 h, 24 h, 48 h, 72 h, 96 h, and 120 h post-injection.

[0121] 177 SPECT / CT imaging of Lu-DOTA-Tri-PSMA showed early enrichment in the bladder and renal uptake, with rapid background clearance. Renal enrichment significantly decreased after 4 hours, and both the kidneys and bladder were largely cleared after 6 hours, with complete clearance after 24 hours. 177 Lu-DOTA-Tri-PSMA further accumulates and remains in PSMA-expressing tumors, see Figure 1 The corresponding quantitative data are shown in Table 6 below (unit: ID% / mm). 3 ):

[0122] Table 6. Vivo scan data of various organs in SPECT / CT imaging experiments.

[0123] 0.5h 1h 2h 4h 6h 24h 48h 72h 96h 120h tumor 3.51E-06 3.29E-06 3.73E-06 3.71E-06 2.87E-06 1.95E-06 3.08E-06 2.05E-06 9.88E-07 8.58E-07 kidney 3.19E-06 3.13E-06 1.59E-06 1.01E-06 6.12E-07 1.44E-07 3.78E-09 8.66E-09 1.12E-11 1.66E-09 bladder 2.85E-04 2.03E-04 1.17E-04 6.43E-06 1.87E-06 1.86E-08 2.35E-08 1.43E-08 9.27E-10 4.43E-15 .

[0124] Example 6 Treatment Effect

[0125] Taken 177 Lu-DOTA-Tri-PSMA and 177 Lu-PSMA-617 was injected via tail vein (injection volume: 100 μL / mouse, injection activity: 1.5 mCi / mouse) into two groups (4 mice / group) of tumor-bearing mice (male 22Rv1 nude mice). The tumor size and volume of the mice were measured every other day along with those of the control group (4 mice, no drug injection, only injection of 0.9% NaCl aqueous solution). The therapeutic effects of the two drugs on mice were evaluated by comparing the tumor size.

[0126] 177 Lu-DOTA-Tri-PSMA showed good therapeutic effects in cancer-stricken mice, especially those with prostate cancer.

[0127] The changes in tumor volume over time in the experimental and control groups of mice are shown in Table 7 below:

[0128]

[0129]

[0130] The volume values ​​in the table above are the average tumor volumes of mice in each group, in mm. 3 ;

[0131] "—" indicates that the first test mouse died at that time.

[0132] The changes in body weight of mice in the experimental and control groups over time are shown in Table 8 below:

[0133]

[0134]

[0135] The weight values ​​in the table above are the average weights of mice in each group, in grams.

[0136] "—" indicates that the first test mouse died at that time.

[0137] The survival rates of mice in the experimental and control groups over time are shown in Table 9 below:

[0138]

[0139] Example 7 68 Preparation of Ga-DOTA-Tri-PSMA:

[0140] 1. Synthesis of DOTA-Tri-PSMA

[0141]

[0142] Compd (1 eq) was dissolved in DMF, and compd2 (1.2 eq) and DIEA (N,N-diisopropylethylamine) (3 eq) were added to the reaction solution. The reaction was carried out at room temperature for 1 hour, and the reaction was monitored by LC-MS. After the starting materials reacted completely, the solution was concentrated under reduced pressure, and then an appropriate amount of TFA was added for cleavage for 5 minutes to remove the tBu protecting group. The solution was washed twice with diethyl ether, centrifuged, dried, and the crude product was used to prepare compd3 (Yield: 32 mg, 70%).

[0143] Compd3 (1 eq) and compd4 (2 eq) were dissolved in EtOH / H2O (1:1). Under N2 protection, CuSO4·5H2O (0.2 eq) aqueous solution was added to the reaction solution, and finally, sodium ascorbate (0.2 eq) aqueous solution was added to the reaction solution. The reaction was carried out at room temperature for 2.5 hours. The reaction was monitored by LC-MS. After the reactants reacted completely, the solution was concentrated and reversed to obtain compd5 (Yield: 28 mg, 50%).

[0144] 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 carried out at room temperature for 2 hours. The reaction was monitored by LC-MS. The reaction of the starting material was completed. The solution was concentrated under reduced pressure and purified by reverse phase to obtain the target product DOTA-Tri-PSMA (Yield: 23 mg, 56%).

[0145] 2. Preparation of 0.5 mg / mL DOTA-Tri-PSMA solution

[0146] Take DOTA-Tri-PSMA, add 2000 μL of deionized water to dilute it, mix well, and you will get the precursor solution.

[0147] 3. 68 Preparation of Ga-labeled compounds

[0148] 1000 μL 68 The GaCl3 solution (59.2 MBq) and 150 μL of 1 M NaOAc were mixed, and then 100 μL of the aforementioned precursor solution (i.e., 0.5 mg / mL DOTA-Tri-PSMA solution) was added. The mixture was thoroughly mixed and incubated at 95 °C for 15 min. After the reaction was completed, the reaction flask was cooled, and a sample was taken for Radio-HPLC analysis.

[0149] 4. Radio-HPLC detection conditions

[0150] Chromatographic column: ZORBAX Eclipse Plus C18 (4.6mm × 250mm, 5μm) Column temperature: 30℃ Mobile phase: A: 0.1% TFA in H2O, B: 0.1% TFA in ACN

[0151] Gradient: 0-10-20-22-27-30-35min, 10-20-40-40-100-10-10% B

[0152] Flow rate: 1 mL / min

[0153] Wavelength: 220nm

[0154] 5. The results of the Radio-HPLC detection are shown in Table 10 below.

[0155] Table 10

[0156]

[0157] 6. In vitro stability

[0158] The obtained target product was placed in a 25℃ 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 basically unchanged at 96.89%.

Claims

1. A compound I or a pharmaceutically acceptable salt thereof, ； in, A is composed of chelating groups and radioactive nuclides; The chelating group is a structure formed by removing a hydroxyl group from a carboxyl group based on the DOTA, NOTA, DOTA-GA or NODA-GA structure. The radioactive nuclide is 18 F, 68 Ga、 177 Lu、 99m Tc, 188 Re、 64 Cu、 67 Cu、 225 Ac、 212 Pb or 211 At; X is or ; For X and L 2 The connection position; n1 is an integer selected from 1 to 20; n2 is selected from integers from 1 to 10; L 1 and L 2 Independently -C1-C6 alkylene-; R is .

2. The compound I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) n1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16; (2) n2 is 1, 2, 3, 4, 5, 6, 7, 8 or 9; (3) L 1 and L 2 In this context, "-C1-C6 alkylene-" is independently -C1-C3 alkylene-; (4) In A, the chelating group is chelated with a radionuclide; (5) Compound I is or .

3. The compound I as described in claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or two of the following conditions: (1) n1 is an integer from 1 to 10; (2) n2 is an integer from 1 to 5.

4. The compound I as described in claim 3, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or two of the following conditions: (1) n1 is 2; (2) n2 is 1.

5. The compound I as claimed in claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) In A, the chelating group is ; (2) L 1 In the text, "-C1-C6 alkylene-" refers to... ; (3) L 2 In the text, "-C1-C6 alkylene-" refers to... or ; (4) Compound I is selected from the following structures: , , or .

6. The compound I as claimed in claim 5, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or two of the following conditions: (1) A is from Composed of radioactive nuclides, wherein the radioactive nuclides are 177 Lu or 68 Ga; (2) Compound I is selected from the following structures: , , or .

7. The compound I as claimed in claim 6, or a pharmaceutically acceptable salt thereof, characterized in that, A by It is composed of a chelate with a radioactive nuclide, wherein the radioactive nuclide is 177 Lu or 68 Ga.

8. The compound I as claimed in claim 7, or a pharmaceutically acceptable salt thereof, characterized in that, A is .

9. The compound I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The structure of compound I is as follows: or .

10. A compound II or a pharmaceutically acceptable salt thereof, ； in, B is composed of chelating groups and non-radioactive nuclides; The chelating groups, X, L 1 L 2 The definition of R is as described in any one of claims 1-9; The non-radioactive nuclides are F, Ga, Lu, Tc, Re, Cu, Cu, Ac, Pb, or At.

11. The compound II of claim 10 or a pharmaceutically acceptable salt thereof, characterized in that, The compound II is: or .

12. A compound III or a pharmaceutically acceptable salt thereof, ； in, C is a chelating group; The chelating groups, X, L 1 L 2 The definition of R is as described in any one of claims 1-9.

13. The compound III of claim 12 or a pharmaceutically acceptable salt thereof, characterized in that, The compound III is: 。 14. A pharmaceutical composition comprising substance D and a pharmaceutical excipient, wherein substance D is compound I as described in any one of claims 1-9, compound II as described in claim 10 or 11, or compound III as described in claim 12 or 13, or a pharmaceutically acceptable salt thereof.

15. A kit comprising substance D and instructions for use, wherein substance D is compound I as claimed in any one of claims 1-9, compound II as claimed in claim 10 or 11, or compound III as claimed in claim 12 or 13, or a pharmaceutically acceptable salt thereof.

16. The use of a substance D in the preparation of a medicament for treating diseases associated with PSMA, wherein the substance D is compound I as described in any one of claims 1-9, compound II as described in claim 10 or 11, compound III as described in claim 12 or 13, or a pharmaceutically acceptable salt thereof; The disease associated with PSMA is prostate cancer.

17. The application as described in claim 16, characterized in that, The prostate cancer referred to is either prostate cancer with high PSMA expression or PSMA-positive mCRPC.

18. The use of compound I as described in any one of claims 1-9, compound III as described in claim 12 or 13, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating and / or preventing cancer.

19. The application as described in claim 18, characterized in that, The cancer in question is prostate cancer.

20. The application as described in claim 19, characterized in that, The prostate cancer referred to is either prostate cancer with high PSMA expression or PSMA-positive mCRPC.

21. The use of compound I as described in any one of claims 1-9, compound III as described in claim 12 or 13, or a pharmaceutically acceptable salt thereof, in the preparation of a developer.

22. The application as described in claim 21, characterized in that, The imaging agent is used for diagnosing cancer.

23. The application as described in claim 22, characterized in that, The cancer in question is prostate cancer.

24. A compound IV or a pharmaceutically acceptable salt thereof, ； in, L 1 The definition is as described in any one of claims 1-6.

25. Compound IV as claimed in claim 24, or a pharmaceutically acceptable salt thereof, characterized in that, The compound IV is: 。

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