WO2025153101A1 - Nitrogen-containing compound and preparation method therefor and use thereof - Google Patents

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

This application claims the priority of Chinese patent application No. 2024100841208 filed on January 19, 2024. This application cites the entire text of the above Chinese patent application.

Technical Field

The invention relates to a nitrogen-containing compound and a preparation method and application thereof.

Background Art

Prostate cancer is the second most common type of cancer in men. It is estimated that there are approximately 1.3 million newly diagnosed cases 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 disease development, with an insufficient response to castration therapy, leading to prostate cancer recurrence and metastasis. Currently, there are few treatment options for this type of patient, and the 5-year survival rate is low. Prostate-specific membrane antigen (PSMA) is highly expressed in more than 80% of prostate cancer patients. Combining targeted compounds (ligands) with diagnostic or therapeutic radionuclides allows the drug to bind to prostate cancer cells expressing PSMA, and the gamma or beta rays emitted when the radioactive diagnostic or therapeutic nuclides decay can image and treat diseased tissues.

In view of 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

The technical problem to be solved by the present invention is to overcome the defect of the single compound for diagnosing and treating prostate cancer in the prior art. To this end, the present invention provides a nitrogen-containing compound and a preparation method and use thereof. 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.

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

Among them, A is composed of a chelating group and a radionuclide;

X is (*The position is directly connected to L ² );

n1 is an integer selected from 1 to 20;

n2 is an integer selected from 1 to 10;

L ¹ and L ² are independently -C ₁ -C ₆ alkylene-;

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

Preferably, the compound I is selected from the following structures:

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

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)pentanedioic 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) structure, the structure formed by removing a hydroxyl group from a carboxyl group, for example, the structure formed by removing a hydroxyl group from a carboxyl group of DOTA

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.

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.

In one embodiment of the present invention, in ^L1 and ^L2 , the " _-C1 - _C6 alkylene-" is independently _-C1 - _C3 alkylene-, for example

In one embodiment of the present invention, in ^L1 , the " _-C1 - _C6 alkylene-" is

In one embodiment of the present invention, in ^L2 , the " _-C1 - _C6 alkylene-" is

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

In a certain embodiment of the present invention, the radionuclide is a diagnostic nuclide or a therapeutic nuclide.

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

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.

In one 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.

In a certain embodiment of the present invention, the valence state of the radionuclide is monovalent, divalent, trivalent or tetravalent, for example, trivalent.

In a certain 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 radionuclide chelate, wherein the radionuclide is ¹⁷⁷ Lu or ⁶⁸ Ga, for example

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

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

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

The chelating group, X, L ¹ , L ² and R are defined as described in any of the previous embodiments.

In a certain embodiment of the present invention, the non-radioactive nuclide is F, Ga, Lu, Tc, Re, Cu, Cu, Ac, Pb or At.

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

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

Wherein, C is a chelating group;

The chelating group, X, L ¹ , L ² and R are defined as described in any of the previous embodiments.

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

The present invention also provides a pharmaceutical composition, which comprises 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).

The present invention also provides a kit, which comprises 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).

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).

The present invention also provides a use of the compound I, compound III or a pharmaceutically acceptable salt thereof ("it" represents the compound I or compound III) 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 (prostate-specific membrane antigen-positive, metastatic castration-resistant prostate cancer).

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

The imaging agent is preferably an imaging agent for diagnosing cancer; the cancer is preferably prostate cancer.

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

Wherein, the definition of ^L1 is as described in any of the previous schemes.

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

Terminology explanation:

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 use by patients) 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.

The term "alkyl" refers to a straight or branched chain alkyl group having a specified number of carbon atoms (e.g., C ₁ to C ₆ ). 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.

In the present invention, the term "alkylene" refers to a saturated straight or branched divalent hydrocarbon group. _C1-6 alkylene 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.

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

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

The term "aryl" refers to a cyclic group consisting only of carbon atoms, having a specified number of carbon atoms (eg, C ₆ to C ₁₀ ), which is a single ring or a condensed ring. Aryl includes, but is not limited to, phenyl or naphthyl.

The terms "pharmaceutically acceptable excipients" and "pharmaceutical excipients" refer to excipients and additives used in the production of drugs and the preparation of prescriptions. They are all substances contained in pharmaceutical preparations except active ingredients. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).

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 initiates a disease; or (3) slowing the progression of one or more biological manifestations of a disease.

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

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

The positive and progressive effects of the present invention are 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

FIG1 is a SPECT/CT image of ¹⁷⁷ Lu-DOTA-Tri-PSMA in mice at 0.5 h;

FIG2 is a SPECT/CT image of ¹⁷⁷ Lu-DOTA-Tri-PSMA in mice for 1 hour;

FIG3 is a SPECT/CT image of ¹⁷⁷ Lu-DOTA-Tri-PSMA in mice for 2 hours;

FIG4 is a SPECT/CT image of ¹⁷⁷ Lu-DOTA-Tri-PSMA in mice for 4 hours;

FIG5 is a SPECT/CT image of ¹⁷⁷ Lu-DOTA-Tri-PSMA in mice for 6 hours;

FIG6 is a SPECT/CT image of ¹⁷⁷ Lu-DOTA-Tri-PSMA in mice for 24 hours;

FIG7 is a SPECT/CT image of ¹⁷⁷ Lu-DOTA-Tri-PSMA in mice at 48 hours;

FIG8 is a SPECT/CT image of ¹⁷⁷ Lu-DOTA-Tri-PSMA in mice at 72 hours;

FIG9 is a SPECT/CT image of ¹⁷⁷ Lu-DOTA-Tri-PSMA in mice at 96 hours;

FIG. 10 is a SPECT/CT image of ¹⁷⁷ Lu-DOTA-Tri-PSMA in mice after 120 hours.

DETAILED DESCRIPTION

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

Example 1 Radionuclide ¹⁷⁷ Lu Labeling DOTA-N ₃

Preparation of DOTA-N ₃ solution: DOTA-N ₃ (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-N ₃ was 0.2 mg/mL.

26 μL of ¹⁷⁷ LuCl ₃ solution (radioactivity of about 18 mCi, solvent is 0.04 mol/L hydrochloric acid) and 150 μL of DOTA-N ₃ solution were mixed, heated at 95°C for 15 min, and 176 μL of reaction solution containing ¹⁷⁷ Lu-DOTA-N ₃ was obtained. The labeling rate detected by Radio-HPLC was 87.82%, as shown in Table 1 below; wherein chromatographic peak 4 is the chromatographic peak corresponding to ¹⁷⁷ Lu-DOTA-N ₃ .

Radio-HPLC detection conditions:

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

Mobile phase: A: 0.1% TFA in H ₂ O, B: 0.1% TFA in CH ₃ CN

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

Flow rate: 1mL/min

Wavelength: 220nm

Column temperature: 30°C

Table 1

Example 2 Click Chemistry Reaction

Synthesis route of PSMA-alkyne:

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

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

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

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.

95 μL of PSMA-alkyne solution was mixed with 175 μL of the reaction solution containing ¹⁷⁷ Lu-DOTA-N ₃ , 43 μL of copper sulfate solution, and 45 μL of sodium ascorbate solution, and heated at 40°C for 60 min to obtain 358 μL of reaction solution containing ¹⁷⁷ Lu-DOTA-Tri-PSMA. Radio-HPLC detection showed that under the same analytical conditions, the peak position of ¹⁷⁷ Lu-DOTA-Tri-PSMA was consistent with the peak position of the cold reference compound ¹⁷⁵ Lu-DOTA-Tri-PSMA (the cold reference compound was prepared using non-radioactive raw materials and a method similar to that of ¹⁷⁷ Lu-DOTA-Tri-PSMA; the molecular weight of the product was consistent with the theoretical value of ¹⁷⁵ Lu-DOTA-Tri-PSMA by LC-MS detection; the peak position of ¹⁷⁵ Lu-DOTA-Tri-PSMA was determined by Radio-HPLC). The labeling rate detected by Radio-HPLC was 72.79%, as shown in Table 2 below; wherein chromatographic peak 5 is the chromatographic peak corresponding to ¹⁷⁷ Lu-DOTA-Tri-PSMA.

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

Radio-HPLC detection conditions:

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

Mobile phase: A: 0.1% TFA in H ₂ O, B: 0.1% TFA in CH ₃ CN

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

Flow rate: 1mL/min

Wavelength: 220nm

Column temperature: 30°C

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

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.

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

Table 2

Table 3

Example 3 In vitro stability

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 basically unchanged at 92.07%.

Example 4 Biodistribution

Preparation of radioactive injection solution 1: The target product obtained in Example 2 (ie, ethanol solution of ¹⁷⁷ Lu-DOTA-Tri-PSMA) was diluted with 0.5 M acetic acid-sodium acetate buffer at pH=5.2 to a radioactivity concentration of about 1 mCi/mL.

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), and the animals were killed at 0.5 h, 1 h, 4 h and 24 h after injection, respectively. The tissues and organs of interest were dissected and weighed, and 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%).

In this embodiment, 24 hours after administration, the organ distribution of ¹⁷⁷ Lu is shown in Table 4 below, compared with the compound ¹⁷⁷ Lu-PSMA-617 reported in the literature (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 ± 0.70 ID% / g), while the tumor uptake remained high (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. The favorable pharmacokinetics of ¹⁷⁷ Lu-DOTA-Tri-PSMA resulted in a high tumor to background ratio after 24 h (tumor/blood: 304.67; tumor/muscle: 914.00).

The comparison of ¹⁷⁷ Lu uptake in various tissues of 22Rv1 tumor-bearing mice at different time points after administration is shown in Table 5 below. It can be seen that ¹⁷⁷ Lu can be quickly cleared in all major organs and is specifically taken up by tumor tissues, so the tumor-to-background ratio increases with time.

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

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

Example 5 Small Animal SPECT/CT Imaging

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

22Rv1 male tumor-bearing nude mice (Shanghai Junna Medical Technology Co., Ltd., catalog number: NO.202373380) were used, and the radiolabeled compound ¹⁷⁷ Lu-DOTA-Tri-PSMA was injected into the mice through the tail vein (about 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.

SPECT/CT imaging of ¹⁷⁷ Lu-DOTA-Tri-PSMA showed early enrichment in the bladder and kidney uptake, rapid background clearance, significant reduction in kidney enrichment after 4 hours, substantial clearance of kidney and bladder after 6 hours, and complete clearance of kidney and bladder after 24 hours. Meanwhile, 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 ):

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

Example 6 Treatment Effect

The prepared ¹⁷⁷ Lu-DOTA-Tri-PSMA and ¹⁷⁷ Lu-PSMA-617 drugs were injected into two groups (4 mice/group) of tumor-bearing mice (22Rv1 male nude mice) through the tail vein (injection volume: 100 μL/mouse, injection activity: 1.5 m Ci/mouse). The tumor size of the mice was measured and the volume was calculated every other day together with the control group (4 mice, not injected with any drugs, only injected with 0.9% NaCl aqueous solution). The therapeutic effects of the two drugs on mice were evaluated by comparing the tumor sizes.

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

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

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

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

The changes in body weight of mice in the experimental group and the control group over time are shown in Table 8 below:

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

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

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

Example 7 Preparation of ⁶⁸ Ga-DOTA-Tri-PSMA:

1. Synthesis of DOTA-Tri-PSMA

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. The raw material was reacted completely, and after being concentrated under reduced pressure, an appropriate amount of TFA was added for 5 minutes to remove the tBu protecting group, and the ether was washed twice, centrifuged, and dried to obtain the crude product compd3 (Yield: 32 mg, 70%)

Compd3 (1 eq) and compd4 (2 eq) were dissolved in EtOH/H ₂ O (1:1). Under N ₂ protection, CuSO ₄ .5H ₂ O (0.2 eq) aqueous solution was added to the reaction solution. Finally, sodium ascorbate (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. The raw material reacted completely, concentrated, and reversed phase was used to obtain compd5 (Yield: 28 mg, 50%).

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 raw material was reacted completely. The reaction was concentrated under reduced pressure and purified by reverse phase to obtain the target product DOTA-Tri-PSMA (Yield: 23 mg, 56%).

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

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

3. Preparation of ⁶⁸ Ga-labeled compounds

1000 μL ⁶⁸ GaCl ₃ solution (59.2 MBq) and 150 μL 1 M NaOAc were mixed, and then 100 μL of the aforementioned precursor solution (ie, 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 completed, the reaction bottle was cooled, and samples were taken for Radio-HPLC analysis.

4. Radio-HPLC detection conditions

Chromatographic column: ZORBAX Eclipse Plus C18 (4.6mm×250mm, 5μm) Column temperature: 30℃

Mobile phase: A: 0.1% TFA in H ₂ O, B: 0.1% TFA in ACN

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

Flow rate: 1mL/min

Wavelength: 220nm

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

Table 10

6. In vitro stability

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%.

Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that these are only examples, and various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the protection scope of the present invention is limited by the appended claims.

Claims (13)

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 between X and ^L2 ; n1 is an integer selected from 1 to 20; n2 is an integer selected from 1 to 10; L ¹ and L ² are independently -C ₁ -C ₆ alkylene-; R is 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 a hydroxyl group from a carboxyl group based on the structure of DOTA, NOTA, DOTA-GA, NODA-GA, DTPA, HBED-CC or MAG3; (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, and for example, 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, and for example, n2 is 1; (4) In ^L1 and ^L2 , 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 nuclide or a therapeutic nuclide; (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 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) In ^L1 , the "-C ₁ -C ₆ alkylene-" is (3) In ^L2 , the " _-C1 - _C6 alkylene-" is (4) The diagnostic nuclide is ¹⁸ F, ⁶⁸ Ga, ^99m Tc or ⁶⁴ Cu; (5) The therapeutic nuclide 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: The compound I or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that it satisfies one or more of the following conditions: (1) A and a radionuclide, wherein the radionuclide is ¹⁷⁷ Lu or ⁶⁸ Ga; preferably, A is composed of and a radionuclide chelate, wherein the radionuclide is ¹⁷⁷ Lu or ⁶⁸ Ga, for example (2) The compound I is selected from the following structures: The compound I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structure of the compound I is

A compound II or a pharmaceutically acceptable salt thereof,
Among them, B is composed of a chelating group and a non-radioactive nuclide; The definitions of the chelating group, X, L ¹ , L ² and R are as described in any one of claims 1 to 4; Preferably, the non-radioactive nuclide is F, Ga, Lu, Tc, Re, Cu, Cu, Ac, Pb or At; Preferably, the compound II is
A compound III or a pharmaceutically acceptable salt thereof,
Wherein, C is a chelating group; The chelating group, X, L ¹ , L ² and R are defined as in any one of claims 1 to 4; Preferably, the compound III is A pharmaceutical composition comprising a substance D and a pharmaceutical excipient, wherein the substance D is the compound I as described in any one of claims 1 to 5, the compound II as described in claim 6, the compound III as described in claim 7, or a pharmaceutically acceptable salt thereof. A kit comprising a substance D and instructions, wherein the substance D is the compound I as described in any one of claims 1 to 5, the compound II as described in claim 6, the compound III as described in claim 7, or a pharmaceutically acceptable salt thereof. A use of a substance D in the preparation of a drug for treating a PSMA-related disease, wherein the substance D is the compound I as described in any one of claims 1 to 5, the compound II as described in claim 6, the compound III as described in claim 7, or a pharmaceutically acceptable salt thereof; The PSMA-related disease is preferably prostate cancer, more preferably prostate cancer with high PSMA expression or PSMA-positive mCRPC. A use of the compound I according to any one of claims 1 to 5, the compound III according to 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. A use of the compound I according to any one of claims 1 to 5, the compound III according to 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. A compound IV or a pharmaceutically acceptable salt thereof,
Wherein, ^L1 is defined as in any one of claims 1 to 4; The compound IV is preferably