Nitrogen-containing compounds as well as preparation method therefor and use thereof

Abstract

Disclosed in the present invention are nitrogen-containing compounds as well as a preparation method therefor and the use thereof. Specifically disclosed in the present invention are compounds shown as formula I or pharmaceutically acceptable salts thereof, which have one or more of the following advantages: accurate targeting of tumor cells, long tumor retention and inhibition time, and capability of being safely used for malignant tumor diagnosis, staging and / or treatment.

Description

A nitrogen-containing compound and its preparation method and use

[0001] This application claims the benefit of Chinese patent application No. 2024100841212 filed on 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] In recent years, radiopharmaceuticals targeting fibroblast activation protein (FAP) have attracted much attention in the field of integrated diagnosis and treatment of malignant tumors. FAP is a protein expressed in the tumor stroma that plays an important role in tumor progression and metastasis and is an important target for tumor diagnosis and treatment. By labeling FAP, radiopharmaceuticals can precisely target tumor cells and surrounding stromal cells in vivo, enabling non-invasive visual diagnosis and internal irradiation treatment of malignant tumors. FAP-2286 shows high affinity for both FAP recombinant protein and FAP expressed on the surface of fibroblasts, and has longer tumor retention and inhibition time than other targeted FAP inhibitors, making it safe for use in the diagnosis, staging, and restaging of malignant tumors.

[0004] Given the importance of diagnosis and treatment of malignant tumors, there is an urgent need to develop a radioactive compound with good targeting, long tumor retention and inhibition time, and can be safely used for diagnosis, staging and / or treatment of malignant tumors. Summary of the Invention

[0005] The technical problem addressed by the present invention is to overcome the limitation of the existing art in the diagnosis and treatment of malignant tumors due to the limited availability of compounds. To this end, the present invention provides a nitrogen-containing compound, a preparation method, and uses thereof. The compounds of the present invention possess one or more of the following advantages: precise tumor cell targeting, prolonged tumor retention and inhibition, and safe use for the diagnosis, staging, and / or treatment of malignant tumors.

[0006] The present invention solves the above technical problems through the following technical solutions.

[0007] The present invention provides a compound I or a pharmaceutically acceptable salt thereof,

[0008] Among them, A consists of a chelating group and a radionuclide;

[0009] X is (*Position directly connected to L 2 connected);

[0010] n1 is an integer selected from 1 to 20;

[0011] n2 is an integer selected from 1 to 10;

[0012] L 1 and L 2 are independently -C1-C6 alkylene-;

[0013] R is

[0014] In a certain embodiment of the present invention, the compound I is

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

[0016] More preferably, the compound I is selected from the following structures:

[0017] 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

[0018] 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.

[0019] 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.

[0020] 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

[0021] In one embodiment of the present invention, L 1 In the above, the "-C1-C6 alkylene-" is

[0022] In one embodiment of the present invention, L 2 In the above, the "-C1-C6 alkylene-" is

[0023] In one embodiment of the present invention, in A, the chelating group chelates with a radionuclide.

[0024] In one embodiment of the present invention, the radionuclide is a diagnostic nuclide or a therapeutic nuclide.

[0025] In a certain embodiment of the present invention, the diagnostic nuclide is 18 F. 68 Ga, 99m Tc or 64 Cu.

[0026] 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.

[0027] 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.

[0028] In one embodiment of the present invention, the valence state of the radionuclide is monovalent, divalent, trivalent or tetravalent, for example, trivalent.

[0029] In one embodiment of the present invention, A is composed of and a radioactive nuclide, wherein the radioactive nuclide 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.

[0030] In a certain embodiment of the present invention, the structure of compound I is

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

[0032] Among them, B is composed of a chelating group and a non-radioactive nuclide;

[0033] The chelating group, X, L 1 , L 2 and R are defined as in any of the previous schemes.

[0034] In one embodiment of the present invention, the non-radioactive nuclide is F, Ga, Lu, Tc, Re, Cu, Cu, Ac, Pb or At.

[0035] In a certain embodiment of the present invention, the compound II is

[0036] The present invention also provides a compound III or a pharmaceutically acceptable salt thereof,

[0037] Wherein, C is a chelating group;

[0038] The chelating group, X, L 1 , L 2 and R are defined as in any of the previous schemes.

[0039] In a certain embodiment of the present invention, the compound III is

[0040] 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).

[0041] 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).

[0042] The present invention also provides a use of a substance D in the preparation of a medicament for treating a disease associated with FAP, wherein the substance D is Compound I, Compound II, Compound III, or a pharmaceutically acceptable salt thereof ("it" represents Compound I, Compound II, or Compound III);

[0043] The FAP-related disease is preferably a cancer with high FAP expression, more preferably pancreatic cancer, breast cancer, ovarian cancer or rectal cancer.

[0044] 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.

[0045] The cancer is preferably a cancer with high FAP expression, more preferably pancreatic cancer, breast cancer, ovarian cancer or rectal cancer.

[0046] 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.

[0047] The imaging agent is preferably an imaging agent for diagnosing cancer; the cancer is preferably a cancer with high FAP expression, such as pancreatic cancer, breast cancer, ovarian cancer or rectal cancer.

[0048] The present invention also provides a compound IV or a pharmaceutically acceptable salt thereof,

[0049] Among them, L 1 The definition of is as described in the previous scheme.

[0050] In a certain embodiment of the present invention, the compound IV is

[0051] Explanation of terms:

[0052] 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.

[0053] 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.

[0054] 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.

[0055] In the present invention, the term "alkyleneoxy" refers to -O-alkylene-, wherein alkylene is as defined above.

[0056] In the present invention, the term "alkylenethio" refers to -S-alkylene-, wherein alkylene is as defined above.

[0057] 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.

[0058] 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).

[0059] 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.

[0060] 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.

[0061] The reagents and raw materials used in the present invention are commercially available.

[0062] The positive progress of the present invention is that the compounds of the present invention have one or more of the following advantages: precise targeting of tumor cells, long-term tumor retention and inhibition, and can be safely used in the diagnosis, staging and treatment of malignant tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 177 SPECT / CT imaging of Lu-DOTA-Tri-FAP2286 in mice after 0.5 h;

[0064] Figure 2177 SPECT / CT imaging of Lu-DOTA-Tri-FAP2286 in mice after 1 hour;

[0065] Figure 3 177 SPECT / CT imaging of Lu-DOTA-Tri-FAP2286 in mice after 2 hours;

[0066] Figure 4 shows 177 SPECT / CT imaging of Lu-DOTA-Tri-FAP2286 in mice after 4 hours;

[0067] Figure 5 177 SPECT / CT imaging of Lu-DOTA-Tri-FAP2286 in mice after 6 hours;

[0068] Figure 6 177 SPECT / CT imaging of Lu-DOTA-Tri-FAP2286 in mice for 24 hours;

[0069] Figure 7 177 SPECT / CT imaging of Lu-DOTA-Tri-FAP2286 in mice after 48 hours;

[0070] Figure 8 177 SPECT / CT images of Lu-DOTA-Tri-FAP2286 in mice after 72 hours. DETAILED DESCRIPTION

[0071] 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.

[0072] Example 1 Radionuclide 177 Lu-labeled DOTA-N3

[0073] 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.

[0074] Add 8 μL 177 LuCl3 solution (radioactivity of about 3.8 mCi, solvent is 0.04 mol / L hydrochloric acid) and 35 μL DOTA-N3 solution were mixed and heated at 95 ° C for 15 min to obtain 177The reaction solution of Lu-DOTA-N3 was 43 μL, and the labeling rate was 87.58% by Radio-HPLC detection, as shown in Table 1 below; wherein the chromatographic peak 4 is 177 Chromatographic peak corresponding to Lu-DOTA-N3.

[0075] Radio-HPLC detection conditions:

[0076] Chromatographic column: ZORBAX Eclipse Plus C18 (4.6 mm × 250 mm, 5 μm)

[0077] Mobile phase: A: 0.1% TFA in H2O, B: 0.1% TFA in CH3CN

[0078] Gradient: 0-5-10-14-15-17 min, 1-1-10-10-1-1% B

[0079] Flow rate: 1 mL / min

[0080] Wavelength: 220nm

[0081] Column temperature: 30℃.

[0082] Table 1

[0083] Example 2 Click Chemistry Reaction

[0084] Synthesis route of FAP2286-alkynyl:

[0085] Compd 1 (1 eq) was dissolved in DMF solvent, TEA was added, and the pH was adjusted to 8.5. Then, 1,3,5-tris(bromomethyl)benzene (1.5 eq) and cysteamine (10 eq) were added to the mixture. The mixture was allowed to react at room temperature for 2 h. The reaction was monitored by LC-MS. After the reaction of the raw material was complete, the mixture was concentrated in vacuo, dried, and purified by reverse phase to obtain Compd2.

[0086] Compd2 (1 eq) was dissolved in DMF, and then DIPEA (5 eq) and compd3 (2 eq) were added in sequence. The mixture was fully reacted at room temperature for 2 hours and monitored by LC-MS. After the raw materials were completely reacted, the mixture was concentrated in vacuo, dried, and purified by reverse phase chromatography to obtain the target product FAP2286-alkynyl.

[0087] Preparation of FAP2286-Alkynyl solution: FAP2286-Alkynyl was dissolved in DMF, wherein the concentration of FAP2286-Alkynyl was 0.7 mg / mL.

[0088] 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.

[0089] 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 15 mg / mL.

[0090] 45 μL of FAP2286-alkyne solution was mixed with the 177 42 μL of Lu-DOTA-N3 reaction solution, 13 μL of copper sulfate solution, and 15 μL of sodium ascorbate solution were mixed and heated at 40°C for 60 min to obtain 177 The reaction solution of Lu-DOTA-Tri-FAP2286 was 115 μL and detected by Radio-HPLC under the same analytical conditions. 177 The peak position of Lu-DOTA-Tri-FAP2286 and the cold reference compound 175 Lu-DOTA-Tri-FAP2286 (cold reference compound uses non-radioactive raw materials and is 177 Lu-DOTA-Tri-FAP2286 was prepared by a similar method; the molecular weight of the product was detected by LC-MS. 175 The theoretical value of Lu-DOTA-Tri-FAP2286 is consistent; confirmed by Radio-HPLC 175 The peak position of Lu-DOTA-Tri-FAP2286 is consistent with the peak position of Lu-DOTA-Tri-FAP2286. The labeling rate was 41.05% by Radio-HPLC, as shown in Table 2 below; 177 Chromatographic peak corresponding to Lu-DOTA-Tri-FAP2286.

[0091] The aforementioned 177 115 μL of the Lu-DOTA-Tri-FAP2286 reaction solution was diluted to 2 mL with sterile water for injection to prepare the purified solution. This 2 mL of the purified solution was purified via a C18 column to obtain a product with a radiochemical purity of 96.31%, as shown in Table 3 below. Peak 6 corresponds to the chromatographic peak of Lu-DOTA-Tri-FAP2286.

[0092] Radio-HPLC detection conditions:

[0093] Chromatographic column: ZORBAX Eclipse Plus C18 (4.6 mm × 250 mm, 5 μm)

[0094] Mobile phase: A: 0.1% TFA in H2O, B: 0.1% TFA in CH3CN

[0095] Gradient: 0-20-22-27-30-35 min, 20-40-40-100-20-20% B

[0096] Flow rate: 1 mL / min

[0097] Wavelength: 220nm

[0098] Column temperature: 30°C

[0099] C18 cartridge purification conditions (C18 cartridge model: Waters, Sep-Pak Light-C18 solid phase extraction cartridge):

[0100] 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.

[0101] 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-FAP2286 ethanol solution.

[0102] Table 2

[0103] Table 3

[0104] Example 3 In vitro stability

[0105] 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 96.31%. After 24 hours, the radiochemical purity of the target product remained essentially unchanged at 95.65%.

[0106] Example 4 Effect Example

[0107] Preparation of radioactive injection: The target product obtained in Example 2 (i.e. 177 Lu-DOTA-Tri-FAP2286 ethanol solution) was diluted with 0.5 M acetic acid-sodium acetate buffer at pH = 5.2.

[0108] (1) Biodistribution studies:

[0109] BxPC-3 pancreatic cancer model mice were used, and the radioactive injection solution was injected into the mice through the tail vein (approximately 100 μCi / mouse, 4 mice / group, a total of four groups). 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%).

[0110] (2) Animal SPECT / CT imaging studies:

[0111] BxPC-3 pancreatic cancer model mice were used, and the radioactive injection solution was injected into the mice through the tail vein (about 600 μCi / mouse, a total of 5 mice). The animals were scanned in vivo at 0.5h, 1h, 2h, 4h, 6h, 24h, 48h, 72h, 96h and 120h after injection.

[0112] 177 Lu-DOTA-Tri-FAP2286 can precisely target tumor cells, and based on its radioactive properties, it can achieve non-invasive visual diagnosis and treatment of tumors.

[0113] (3) Treatment effect

[0114] Take the obtained 177 Lu-DOTA-Tri-FAP2286 and 177 The Lu-FAP-2286 drug was injected into two groups (5 mice / group) of tumor-bearing mice via the tail vein. The tumor size of the mice was measured every other day, and the volume was calculated. By comparing the tumor size, the therapeutic effect of the two drugs on the mice was evaluated.

[0115] 177 Lu-DOTA-Tri-FAP2286 stays in tumor tissue for a long time and has a good inhibitory effect.

[0116] Example 5 Effect Example

[0117] Preparation of radioactive injection: The target product obtained in Example 2 (i.e. 177 Lu-DOTA-Tri-FAP2286 ethanol solution) was diluted with 0.5 M acetic acid-sodium acetate buffer at pH = 5.2.

[0118] (1) Biodistribution studies:

[0119] U87MG glioblastoma model mice were used, and the radioactive injection solution was injected into the mice through the tail vein (approximately 100 μCi / mouse, 4 mice / group, a total of four groups). 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%).

[0120] Table 4 177 Comparison of Lu-DOTA-Tri-FAP2286 uptake in various tissues of U87MG tumor-bearing mice at different time points after administration (unit: ID% / g)

[0121] (2) Animal SPECT / CT imaging studies:

[0122] Using U87MG glioblastoma model mice, radioactive injection solution was injected into the mice through the tail vein (approximately 600 μCi / mouse, a total of 5 mice). Live scans were performed on the animals at 0.5 h, 1 h, 2 h, 4 h, 6 h, 24 h, 48 h, and 72 h after injection. The results are shown in Figures 1-8.

[0123] 177 Lu-DOTA-Tri-FAP2286 can achieve precise targeting of tumor cells, and based on its radioactive properties, it can achieve non-invasive visual diagnosis and treatment of tumors. 177 Lu-DOTA-Tri-FAP2286 is rapidly cleared from the body, especially through bladder excretion.

[0124] (3) Treatment effect

[0125] 177 The structure of Lu-FAP-2286 is as follows:

[0126] Take the obtained 177 Lu-DOTA-Tri-FAP2286 and 177 Lu-FAP-2286 was injected into two groups (4 male U87MG tumor-bearing 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 with a 0.9% NaCl aqueous solution). The therapeutic effects of the two drugs on mice were evaluated by comparing tumor size.

[0127] 177Lu-DOTA-Tri-FAP2286 stays in tumor tissue for a long time and has a good inhibitory effect.

[0128] The changes in tumor volume over time in the experimental and control groups are shown in Table 5 below:

[0129] The volume values ​​in the table above are the average tumor volumes of mice in each group, in mm 3 ;

[0130] “—” indicates that the first test mouse died at that time.

[0131] The changes in body weight of mice in the experimental and control groups over time are shown in Table 6 below:

[0132] The weight values ​​in the above table are the average weights of mice in each group, in g;

[0133] “—” indicates that the first test mouse died at that time.

[0134] The survival of mice in the experimental and control groups over time is shown in Table 7 below:

[0135] According to the experimental results, the compound of the present application 177 Lu-DOTA-Tri-FAP2286 is superior to 177 Lu-FAP-2286.

[0136] In terms of mouse survival rate: 177 In the Lu-DOTA-Tri-FAP2286 group, one mouse died on day 21, two died on day 27, and one mouse survived to the end of the experiment; 177 Two mice in the Lu-FAP2286 group died on the 21st day, and two mice died on the 27th day. At the end of the experiment, no mice survived and all mice died.

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 are -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 in which 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; The compound I as described in (9) 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; Compound (I) is selected from the following structures:

4. 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 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 (4) The compound I is selected from the following structures:

5. The compound I or a pharmaceutically acceptable salt thereof according to claim 1, 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 defined as described 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 FAP, 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 FAP is preferably a cancer with high FAP expression, more preferably pancreatic cancer, breast cancer, ovarian cancer or rectal cancer.

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 a cancer with high FAP expression, more preferably pancreatic cancer, breast cancer, ovarian cancer or rectal cancer.

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 a cancer with high FAP expression, such as pancreatic cancer, breast cancer, ovarian cancer or rectal 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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