FAP-binding compound, metal complex and use thereof

Abstract

The present invention relates to a fibroblast activation protein (FAP)-binding compound and a radioisotope complex thereof. Disclosed are a binding agent containing the FAP-binding compound, and a metal complex, a method of using same, and the use thereof. The FAP-binding compound and the metal complex thereof have a long-acting performance, such that the introduction of radionuclides for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) and radionuclides for clinical treatment are facilitated; therefore, same can be widely applied to imaging or treatment of the expression of fibroblast activation proteins (FAPs).

Description

A FAP binding compound, metal complex and use thereof Technical Field

[0001] The present invention relates to the technical field of radiopharmaceutical chemistry, and in particular to a radioisotope-labeled fibroblast activation protein (FAP) binding compound, a metal complex and uses thereof. Background Art

[0002] The 2020 global cancer data released by the World Health Organization's International Agency for Research on Cancer (IARC) show that in 2020, my country experienced 4.57 million new cancer cases and 3 million cancer deaths, far exceeding other countries. With the rise and development of nuclear medicine, the use of nuclear medicine imaging techniques to detect and accurately identify lesions throughout the body can provide clinicians with better diagnostic information during treatment. Nuclear medicine is the application of nuclear science and technology to the diagnosis and treatment of diseases. Its clinical applications are extensive, including diagnostic imaging for tumors, cardiovascular and cerebrovascular diseases, neurological diseases, and bone diseases; therapeutic applications include thyroid diseases, tumor treatment, and targeted therapies. Specialized drugs that incorporate radionuclides are called nuclear medicines. Molecularly targeted drugs have a well-defined mechanism of action that can effectively discriminate between tumor cells and normal cells. PD-1 inhibitors, currently popular globally, specifically bind to the PD-1 receptor on T cells to relieve the cellular immune suppression of tumors and activate cellular immunity to eliminate tumors. Currently, a variety of targeted drugs are available in China, with indications for solid tumors such as lung cancer, hepatocellular carcinoma, gastric cancer, and breast cancer, as well as hematologic malignancies such as myeloid leukemia. FAP, with its high expression in various malignant tumors, high tumor uptake, and low background in normal tissues, can be used as an effective molecular target for cancer diagnosis and treatment. The development of FAP-specific inhibitors, which bind specifically to FAP, represents a new class of radiopharmaceuticals that can serve as molecularly targeted imaging probes and hold broad clinical application prospects.

[0003] FAP is overexpressed in fibroblasts within the tumor stroma. Tumor-associated fibroblasts are a crucial component of the tumor microenvironment, accounting for up to 90% of the total tumor mass in desmoplastic tumors. They express fibroblast activation protein (FAP) at levels significantly higher than in normal tissue, making FAP a promising molecular target for tumorigenesis. Fibroblast activation protein (FAP) is a type II membrane-bound glycoprotein belonging to the dipeptidyl peptidase 4 family, possessing both dipeptidyl peptidase and endopeptidase activities. Several FAP inhibitors (FAPIs) have been developed as small molecule inhibitors of the enzyme's activity. These FAP inhibitors (FAPIs) have high tumor affinity and high tumor accumulation for FAP on the surface of CAF membranes. They can be used for PET imaging with high sensitivity, facilitating noninvasive early diagnosis, staging, differential diagnosis, and prognostic assessment of FAP-positive diseases, potentially improving clinical diagnostic yield and treatment survival. However, the pharmacokinetic properties of existing FAPIs remain to be improved. For example, DOTA-FAPI-04 is rapidly cleared through the kidneys, limiting its application. Constructing dimer derivatives is a strategy to improve the tumor accumulation and retention time of FAPI, which has great significance in the diagnosis and treatment of tumors. However, studies have shown that the clearance of FAPI is the result of the interaction of multiple processes, and the method to ensure retention time is still inconclusive.

[0004] FDG is currently the most widely used radiotracer in tumor PET imaging, but it also has certain shortcomings. In many cases, nonspecific and physiological uptake of radiotracers by critical organs can reduce diagnostic accuracy. In contrast, FAPI has good development prospects. FAPI is independent of glucose activity and significantly reduces background signals in the brain, liver, oral cavity, nasopharyngeal mucosa, and gastrointestinal tract. FAPI also has significant advantages in detecting primary or metastatic liver lesions, as well as pancreatic cancer, peritoneal cancer, gastric cancer, colon cancer, lung cancer, and ovarian cancer.

[0005] Radionuclide drugs play an important role in cancer diagnosis and treatment. Tumor-targeted radionuclide drugs can release radiation at the tumor site and have achieved good results in the treatment of various cancers.

[0006] There is an urgent need in the art to develop FAP-binding agents with good affinity for tumors and improved pharmacokinetic properties, as well as radioisotope metal complexes that can be used for imaging and / or therapy. Summary of the Invention

[0007] In one aspect, compounds of formula (I) are provided:

[0008] in,

[0009] X1 and X2 are each independently selected from NH, NR, O or S, wherein R is C 1-6 alkyl;

[0010] Each of A1 and A2 is independently selected from C 1-10 Alkylene, NH, -N(C 1-6 alkyl)-, O, S, C(O), C(S), C(O)-C 1-10 Alkylene-NH, NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 Alkyl)-, -N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(O), C(O)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(S), C(S)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(S)-, -C(S)N(C 1- 6-alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene, C 1-10 Alkylene-C(O), a covalent bond, an amino acid, an amino acid sequence, and a polyethylene glycol chain, wherein each alkyl and alkylene group is unsubstituted or substituted with at least one independently selected from R XA Substituents substituted;

[0011] Each of Y1 and Y2 is independently selected from C 1-10 Alkylene, NH, -N(C 1-6 alkyl)-, O, S, C(O), C(S), C(O)-C 1-10 Alkylene-NH, NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 Alkyl)-, -N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(O), C(O)NH-C 1-10Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(S), C(S)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(S)-, -C(S)N(C 1- 6-alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene, C 1-10 Alkylene-C(O), a covalent bond, an amino acid, an amino acid sequence, and a polyethylene glycol chain, wherein each alkyl and alkylene group is unsubstituted or substituted with at least one independently selected from R XY Substituents substituted;

[0012] Z is selected from C 1-10 Alkylene, N, C(O)-C 1-10 Alkylene-NH, NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 Alkyl)-, -N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(O), C(O)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1- 10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(S), C(S)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(S)-, -C(S)N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene, C 1-10 Alkylene-C(O), NH-C 1-10 Alkylene -NH, -NH-C 1-10 Alkylene-N(C1-6 Alkyl)-, -N(C 1-6 alkyl)-C 1-10 Alkylene-NH-, -N(C 1-6 alkyl)-C 1-10 Alkylene-N(C 1-6 alkyl)-, amino acids and amino acid sequences, wherein each alkyl and alkylidene is unsubstituted or substituted by at least one independently selected from R XZ Substituents substituted;

[0013] L is a metal chelating agent;

[0014] R1 and R2 are each independently selected from H, halogen or C 1-6 alkyl;

[0015] Each R XA 、R XY and R XZ Independently selected from halogen, NO2, -CN, C 1-10 Alkyl, -OH, -O(C 1-10 alkyl), -SH, -S(C 1-10 alkyl), -NH2, -NH(C 1-10 Alkyl), -N(C 1-10 Alkyl)2, C(O)C 1-10 Alkyl, -C(O)OH, -C(O)O(C 1-10 alkyl), -C(O)NH2, -C(O)NH(C 1-10 alkyl), -C(O)N(C 1-10 Alkyl)2, -S(O)(C 1-10 Alkyl), -S(O)2(C 1-10 Alkyl), -S(O)2O(C 1-10 alkyl), -S(O)2NH2, -S(O)2NH(C 1-10 alkyl), -S(O)2N(C 1- 10 Alkyl)2, -OC(O)C 1-10 Alkyl, -O(C 1-10 alkyl), -SH, -S(C 1-10 alkyl), -NHC(O)C 1-10 Alkyl, -N(C 1-10 alkyl)C(O)C 1-10 alkyl;

[0016] m1 is an integer selected from 0 to 10;

[0017] m2 is an integer selected from 0 to 10;

[0018] n1 is an integer selected from 0 to 10;

[0019] n2 is an integer selected from 0 to 10.

[0020] In one aspect, a metal complex of a compound of formula (I) is provided, having a structure as shown in formula (II):

[0021] Wherein, M is metal;

[0022] X1, X2, A1, A2, Y1, Y2, Z, L, R1, R2, m1, m2, n1 and n2 are as defined in formula (I).

[0023] In one aspect, a metal complex of a compound of formula (I) is provided, having a structure as shown in formula (II):

[0024] In one embodiment, the compound of formula (I) is a FAP binding compound. In one embodiment, the compound of formula (II) is a metal complex of a FAP binding compound.

[0025] In one aspect, there is provided the use of a compound of formula (II) for the preparation of an imaging agent.

[0026] In one aspect, a pharmaceutical composition is provided, comprising a compound of the present invention and at least one pharmaceutically acceptable carrier.

[0027] In one aspect, provided is use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for treating a disease in which FAP is overexpressed. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG1 is an HPLC spectrum of FAPI-FUSCC-02-DIMER;

[0029] FIG2 is an LC-MS spectrum of FAPI-FUSCC-02-DIMER;

[0030] Figure 3 68 Radioactive HPLC spectrum of Ga-FAPI-FUSCC-02-DIMER;

[0031] Figure 4 shows 68 Radioactive iTLC spectrum of Ga-FAPI-FUSCC-02-DIMER;

[0032] Figure 5 68 Radioactive iTLC spectrum of GaCl3;

[0033] Figure 6 is a mass spectrum of compound 1-3;

[0034] Figure 7 is a mass spectrum of compound 1-5;

[0035] FIG8 is a HPLC spectrum of FAPI-FX-01;

[0036] FIG9 is a mass spectrum of FAPI-FX-01;

[0037] Figure 10 is a mass spectrum of compound 2-3;

[0038] Figure 11 is a mass spectrum of compound 2-5;

[0039] Figure 12 is a mass spectrum of compound 2-7;

[0040] FIG13 is a HPLC spectrum of FAPI-FX-02;

[0041] FIG14 is a mass spectrum of FAPI-FX-02;

[0042] Figure 15 68 Radio-TLC spectrum of Ga-FAPI-FX-01;

[0043] Figure 16 68 Radio-TLC spectrum of Ga-FAPI-FX-02;

[0044] Figure 17 68 Uptake of Ga-FAPI-FUSCC-02-DIMER in HT-1080-FAP cells (n=5);

[0045] Figure 18 68 Ga-FAPI-FUSCC-02-DIMER lipid-water partition coefficient diagram, in the figure " 68 Ga-FAPI02-DIMER" means 68 Ga-FAPI-FUSCC-02-DIMER;

[0046] Figure 19 is 68 Lipid-water partition coefficient of Ga-FAPI-FX-01;

[0047] Figure 20 is 68 The lipid-water partition coefficient of Ga-FAPI-FX-02;

[0048] Figure 21 68 Stability of Ga-FAPI-FUSCC-02-DIMER in PBS and FBS;

[0049] Figure 22 68 The stability of Ga-FAPI-FUSCC-01 in PBS and FBS is shown in the figure. 68 Ga-FUSCC01" means 68 Ga-FAPI-FUSCC-01;

[0050] Figure 23 68 The stability of Ga-FAPI-FUSCC-02 in PBS and FBS is shown in the figure. 68 Ga-FUSCC02" 68 Ga-FAPI-FUSCC-02;

[0051] Figure 24 68 In vivo stability of Ga-FAPI-FUSCC-02-DIMER;

[0052] Figure 25 68 Blood clearance curve of Ga-FAPI-FUSCC-02-DIMER;

[0053] Figure 26 68 Blood clearance curve of Ga-FAPI-FUSCC-01;

[0054] Figure 27 68 Blood clearance curve of Ga-FAPI-FUSCC-02;

[0055] Figure 28 68 PET / CT imaging of HT1080-FAP overexpression tumor model by Ga-FAPI-FUSCC-02-DIMER. 68 Ga-FAPI02-DIMER" means 68 Ga-FAPI-FUSCC-02-DIMER;

[0056] Figure 29 68 Ga-FAPI-FUSCC-01, 68 PET / CT imaging of Ga-FAPI-FUSCC-02 on HT1080-FAP overexpression tumor model. 68 Ga-FUSCC01" means 68 Ga-FAPI-FUSCC-01," 68 Ga-FUSCC02" 68 Ga-FAPI-FUSCC-02.

[0057] Figure 30 68 PET / CT images of Ga-FAPI-FX-01 on the HT1080-FAP overexpression tumor model. DETAILED DESCRIPTION

[0058] The following specific embodiments are provided to illustrate the technical content of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention through the contents disclosed in the specification. The present invention can also be implemented or applied through other different specific embodiments. Those skilled in the art can make various modifications and changes without departing from the spirit of the present invention.

[0059] definition

[0060] Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art. The technology used herein refers to the technology generally understood in the art, including variations and equivalent substitutions that are obvious to those skilled in the art. Although it is believed that the following terms are readily understood by those skilled in the art, the following definitions are set forth to better illustrate the present invention. When a trade name appears herein, it refers to the corresponding commercial product or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0061] When a certain amount, concentration or other numerical value or parameter is described in the form of a range, a preferred range or a preferred upper limit or a preferred lower limit, it should be understood as being equivalent to specifically disclosing any range formed by combining any upper limit or preferred value with any lower limit or preferred value, whether or not the range is explicitly stated. Unless otherwise stated, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range. For example, the expression "C1-C 10 ” or “C 1-10 " covers the range of 1-10 carbon atoms and should be understood to also cover any subranges therein and each point value, for example, C 2-3 、C 2-4 、C 2-5 、C 3-4 、C 3-5 、C 3-6 、C 3-7 、C 1-2 、C 1-3 、C 1-4 、C 1-5 、C 1-6 、C 1-7 、C 1-8 , C1-9, etc., as well as C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 etc. Expression “C1-C6” or “C 1-3” should also be understood in a similar manner. The expression “m1 is an integer selected from 0 to 10” means that m1 is any integer from 0 to 10, for example, m1 can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Other similar expressions such as m2, n1, n2, d, h, g, i, j, k, m and n should also be understood in a similar manner.

[0062] When any variable (such as R XA ) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. For example, the expression “each R XA "Independently selected" means that if there are multiple R XA , then in each case each R XA The options for substituents are independent of each other. Other variables or expressions such as R XY 、R XZ , A1, A2, Y1, Y2, A, X and Y should also be understood in a similar manner.

[0063] Unless the context clearly dictates otherwise, singular forms such as "a," "an," and "the" include plural forms. The expression "one or more" or "at least one" may mean 1, 2, 3, 4, 5, 6, 7, 8, 9 or more. In one embodiment, "at least one" means 1, 2, 3, or 4.

[0064] The term "optional" or "optionally" means that the subsequently described event may or may not occur, and that the description includes instances where said event or circumstance occurs or does not occur.

[0065] The terms "substituted" and "substituted" refer to the replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom with a selected group selected from the indicated group, provided that the normal atomic valence of the designated atom in the current situation is not exceeded and the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. When a substituent is described as absent, it is understood that the substituent may be replaced by one or more hydrogen atoms, provided that the structure results in a stable compound.

[0066] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent. When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such a substituent may be bonded to any ring atom in the substitutable ring.

[0067] The expressions "comprising," "including," "containing," and "having" are open ended and do not exclude additional unrecited elements, steps, or ingredients. The expression "consisting of excludes any elements, steps, or ingredients not specified. The expression "consisting essentially of means that the scope is limited to the specified elements, steps, or ingredients, as well as the optional presence of elements, steps, or ingredients that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the expression "comprising" encompasses the expressions "consisting essentially of" and "consisting of."

[0068] The term "halo" or "halogen" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.

[0069] The term "hydrocarbyl" refers to a monovalent group derived from a hydrocarbon. Examples of hydrocarbyl groups include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, and aryl.

[0070] The term "alkyl" refers to a saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. Alkyl groups include straight-chain alkyl groups and branched-chain alkyl groups. Alkyl groups can contain 1-10 carbon atoms, which are called C 1-10 Alkyl groups, such as C 1-6 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C3 alkyl, C4 alkyl, C 3-6 Alkyl. Non-limiting examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like. Non-limiting examples of branched-chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, and the like.

[0071] A divalent group is a group obtained by removing a hydrogen atom from a carbon atom with free valence electrons of a corresponding monovalent group. A divalent group has two attachment sites to the rest of the molecule, wherein the two attachment sites can be located on the same atom or two different atoms of the divalent group.

[0072] "Alkylene" or "alkylidene" refers to a saturated divalent hydrocarbon group. Alkylene includes straight-chain or branched-chain alkylene. Examples of straight-chain alkylene include, but are not limited to, methylene (-CH2-), -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, and the like. Examples of branched-chain alkylene include, but are not limited to, -CH(CH3)-, -CH(C2H5)-, -CH(CH3)-CH2-, -CH(C3H7)-, -CH(C2H5)-CH2-, -C(CH3)2-CH2-, -(CH(CH3))2-, -CH(CH3)-(CH2)2-, -CH2-CH(CH3)-CH2-, -CH(C4H9)-, -C(CH3)(C3H7)- , -C(C2H5)2-, -CH(C3H7)-CH2-, -CH(C2H5)-CH(CH3)-, -CH(C2H5)-(CH2)2-, -CH2-CH(C2H5)-CH2 -, -C(CH3)2-(CH2)2-, -CH2-C(CH3)2-CH2-, -CH(CH3)-(CH2)3-, -CH2-CH(CH3)-(CH2)2-, -CH(C5H 11 )-, -C(C2H5)(C3H7)-, -C(CH3)(C4H9)-, -CH(C4H9)-CH2-, -C(C2H5)2-CH2-, -C (CH3)(C3H7)-CH2-, -CH(C2H5)-CH(C2H5)-, -CH(CH3)-CH(C3H7)-, -C(CH3)2-C( CH3)2-, -CH(C3H7)-(CH2)2-, -CH2-CH(C3H7)-CH2-, -CH(C2H5)-C(CH3)2-, -C(CH3)2-CH(CH3)-CH2-, -CH(CH3)-C(CH3)2-CH2-, -CH(C2H5)-CH(CH3)-CH2-, -CH( CH3)-CH(C2H5)-CH2-, -CH(CH3)-CH2-CH(C2H5)-, -CH(CH3)-C(CH3)2-CH2-, -(CH(CH3))3-, -C(CH3)2-(CH2)3-, -CH(C2H5)-(CH2)3-, -CH2-CH(C2H5)-(CH2)2-, -CH2-CH(CH3)-CH(CH3)-CH2-, -(CH(CH3))2-(CH2)2-, -CH(CH3)-(CH2)2-CH(CH3)-, -(CH2)2-CH(CH3)-(CH2)2-, -CH2-CH(CH3)-(CH2)3-, -CH(CH3)-(CH2)4-, etc.

[0073] A trivalent group is a group obtained by removing a hydrogen atom from a carbon atom with free valence electrons of a corresponding divalent group. A trivalent group has three attachment sites to the rest of the molecule, wherein the three attachment sites may be located on the same or different atoms of the trivalent group.

[0074] "Alkylidene" refers to a saturated trivalent hydrocarbon group. Alkylidene includes straight-chain or branched-chain alkylidene groups.

[0075] The terms "FAP-binding compound" and "FAP-binding agent" have the same meaning and are used interchangeably, and refer to a compound that has affinity activity for FAP. Affinity activity can also be verified by known methods. Affinity activity can also be detected by known methods, such as proximity scintillation analysis, fluorescence resonance energy transfer, fluorescence polarization detection, fluorescence molecular screening, microthermophoresis, chemiluminescence, surface plasmon resonance, isothermal titration calorimetry, oblique incident light reflectance difference method, and any combination thereof.

[0076] The term "amino acid" refers to naturally occurring, synthetic, and non-natural amino acids, as well as amino acid analogs that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those that are later modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as naturally occurring amino acids, i.e., an alpha carbon bound to a hydrogen, a carboxyl group, an amino group, and an R' group, such as homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. Such analogs have modified R' groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as naturally occurring amino acids. In a particular embodiment, the amino acids are selected from naturally occurring amino acids. In another specific embodiment, the amino acid is selected from glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, serine, tyrosine, cysteine, methionine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, ornithine, citrulline and phenylglycine. In one embodiment, the amino acid is in the L configuration.

[0077] The term "metal complex" refers to a complex formed by a coordination bond between a metal atom or ion and a compound. A "radioisotope metal complex" refers to a metal complex in which the metal is a radioisotope. In a particular embodiment, the radioisotope is any one of Ga-68, Cu-64, Lu-177, Y-90, Y-86, Ac-225, Bi-213, In-111, Cu-67, Pb-212, or Tb-161.

[0078] Chelating agents are multidentate ligands with two or more (e.g., 2 to 15, particularly 4, 6, or 8) coordinating atoms. Chelates are complexes with a cyclic structure formed by the central ion and the multidentate ligand bound by coordination bonds.

[0079] The pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0080] The compounds of the present invention encompass pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites or prodrugs thereof.

[0081] The metal complex of the compound of the present invention encompasses its linkage isomers, coordination isomers and stereoisomers.

[0082] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present invention. For example, the compounds of the present invention may have carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, where "E" represents the preferred substituent on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond according to the Cahn-Ingold-Prelog priority rules, and "Z" represents the preferred substituent on the same side of the carbon-carbon double bond or carbon-nitrogen double bond. The compounds of the present invention may also exist as mixtures of "E" and "Z" isomers. Isomeric forms also include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Purification and isolation of such substances can be achieved by standard techniques known in the art.

[0083] The compounds of the present invention may contain a bond with hindered rotation, so that two separate torsional isomers can be separated. All possible torsional isomers are included within the scope of the present invention. The separation of torsional isomers can be a known method or a method described herein. In one embodiment, chiral chromatography is used to separate torsional isomers, for example, using supercritical CO2 and MEOH as the mobile phase.

[0084] Optically pure enantiomers can be obtained by resolving racemic mixtures according to conventional methods, for example, by forming diastereomeric salts with optically active acids or bases, or by forming covalent diastereomers. Mixtures of diastereomers can be separated into individual diastereomers based on their physical and / or chemical differences by methods known in the art (e.g., by chromatography or fractional crystallization). The optically active enantiomer base or acid is then released from the separated diastereomeric salts. Another method for separating racemic enantiomers can be chiral chromatography (e.g., a chiral HPLC column), and the separated chiral isomers can be subjected to conventional derivatization treatment or not prior to separation, depending on which method can achieve more efficient separation of the chiral isomers. Enzymatic methods can also be used to separate derivatized or underivatized chiral isomers. Similarly, optically pure compounds of the present invention can be obtained by chiral synthesis using optically active starting materials.

[0085] The compounds of the present invention may exist in the form of solvates, wherein the compounds of the present invention contain a solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0086] The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0087] The FAP-binding compounds of the present invention may exist in an isotopically labeled or enriched form, containing one or more atoms having a mass or mass number different from the most common atomic mass found in nature.

[0088] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compounds.

[0089] The present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity but are converted, for example, by hydrolytic cleavage, into compounds of the invention having the desired activity when administered to or onto the body.

[0090] The term "polymorph" or "polymorph" refers to a single polymorph or a mixture of more than one polymorph in any proportion.

[0091] The term "crystalline form" or "crystal" refers to any solid material exhibiting a three-dimensional ordering, in contrast to amorphous solid material, which produces a characteristic X-ray powder diffraction pattern with well-defined peaks.

[0092] The term "amorphous" refers to any solid material that has no order in three dimensions.

[0093] The term "pharmaceutically acceptable" means that it is within the scope of normal medical judgment and will not cause undue toxicity, irritation, allergic response, or the like in contact with the tissues of patients.

[0094] The term "pharmaceutically acceptable carrier" refers to substances that are non-irritating to organisms and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0095] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating or preventing a target disorder, disease, or condition.

[0096] The term "overexpression" refers to an increase compared to normal levels. "Overexpressing FAP" is intended to mean abnormal expression levels of FAP in cells from a diseased area that are higher than normal expression levels in cells of the specific tissue or organ of interest.

[0097] With respect to a drug, pharmaceutical unit, or active ingredient, the terms "effective amount," "therapeutically effective amount," or "prophylactically effective amount" refer to a sufficient amount of the drug or pharmaceutical agent to achieve the desired effect with acceptable side effects. The determination of an effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine testing.

[0098] The term "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from a disease (e.g., a disease described herein) (referred to as a patient) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0099] Compounds of formula (I)

[0100] The present invention satisfies the need for novel specific compounds targeting tumor tissues, and their use as broad-spectrum tumor imaging agents and therapeutic drugs in nuclear medicine; in particular, the present invention provides compounds that differ from the prior art in modification, which were not previously known or suggested, and the novel compounds have better tissue specificity and, in particular, surprisingly longer-lasting in vivo retention properties.

[0101] The technical solution adopted by the present invention to achieve the above-mentioned purpose is: a FAP-binding compound having a structure as shown in formula (I), and pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites and prodrugs of the compound.

[0102] Thus, in one aspect, the present invention provides compounds having the structure of formula (I):

[0103] in,

[0104] X1 and X2 are each independently selected from NH, NR, O or S, wherein R is C 1-6 alkyl;

[0105] Each of A1 and A2 is independently selected from C 1-10 Alkylene, NH, -N(C 1-6 alkyl)-, O, S, C(O), C(S), C(O)-C 1-10 Alkylene-NH, NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 Alkyl)-, -N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(O), C(O)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(S), C(S)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(S)-, -C(S)N(C 1- 6-alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene, C 1-10 Alkylene-C(O), a covalent bond, an amino acid, an amino acid sequence, and a polyethylene glycol chain, wherein each alkyl and alkylene group is unsubstituted or substituted with at least one independently selected from R XA Substituents substituted;

[0106] Each of Y1 and Y2 is independently selected from C 1-10 Alkylene, NH, -N(C1-6 alkyl)-, O, S, C(O), C(S), C(O)-C 1-10 Alkylene-NH, NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 Alkyl)-, -N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(O), C(O)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(S), C(S)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(S)-, -C(S)N(C 1- 6-alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene, C 1-10 Alkylene-C(O), a covalent bond, an amino acid, an amino acid sequence, and a polyethylene glycol chain, wherein each alkyl and alkylene group is unsubstituted or substituted with at least one independently selected from R XY Substituents substituted;

[0107] Z is selected from C 1-10 Alkylene, N, C(O)-C 1-10 Alkylene-NH, NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 Alkyl)-, -N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(O), C(O)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1- 10 Alkylene-C(O)-, C(O)-C 1-10Alkylene-NHC(S), C(S)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(S)-, -C(S)N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene, C 1-10 Alkylene-C(O), NH-C 1-10 Alkylene -NH, -NH-C 1-10 Alkylene-N(C 1-6 Alkyl)-, -N(C 1-6 alkyl)-C 1-10 Alkylene-NH-, -N(C 1-6 alkyl)-C 1-10 Alkylene-N(C 1-6 alkyl)-, amino acids and amino acid sequences, wherein each alkyl and alkylidene is unsubstituted or substituted by at least one independently selected from R XZ Substituents substituted;

[0108] L is a metal chelating agent;

[0109] R1 and R2 are each independently selected from H, halogen or C 1-6 alkyl;

[0110] Each R XA 、R XY and R XZ Independently selected from halogen, NO2, -CN, C 1-10 Alkyl, -OH, -O(C 1-10 alkyl), -SH, -S(C 1-10 alkyl), -NH2, -NH(C 1-10 Alkyl), -N(C 1-10 Alkyl)2, C(O)C 1-10 Alkyl, -C(O)OH, -C(O)O(C 1-10 alkyl), -C(O)NH2, -C(O)NH(C 1-10 alkyl), -C(O)N(C 1-10 Alkyl)2, -S(O)(C 1-10 Alkyl), -S(O)2(C 1-10 Alkyl), -S(O)2O(C 1-10 alkyl), -S(O)2NH2, -S(O)2NH(C 1-10 alkyl), -S(O)2N(C 1- 10 Alkyl)2, -OC(O)C 1-10Alkyl, -O(C 1-10 alkyl), -SH, -S(C 1-10 Alkyl), -NHC(O)C 1-10 Alkyl, -N(C 1-10 alkyl)C(O)C 1-10 alkyl;

[0111] m1 is an integer selected from 0 to 10;

[0112] m2 is an integer selected from 0 to 10;

[0113] n1 is an integer selected from 0 to 10;

[0114] n2 is an integer selected from 0 to 10.

[0115] In one embodiment, the compound of formula (I) is a FAP binding compound. In one embodiment, each R XA 、R XY and R XZ Independently selected from halogen, NO2, -CN, C 1-10 Alkyl, -OH, -O(C 1-10 alkyl), -SH, -S(C 1-10 alkyl), -NH2, -NH(C 1-10 Alkyl) and -N(C 1-10 Alkyl) 2, in particular selected from halogen, NO2, -CN and C 1-10 In one embodiment, the C 1-10 Alkylene is C 1-6 Alkylene, such as C 1-3 In one embodiment, the C 1-10 Alkylene is C 1-6 Alkylene, such as C 1-3 Alkylene, in particular methine or CHCH2. In one embodiment, m1 and m2 are each independently an integer selected from 0 to 5. In one embodiment, n1 and n2 are each independently an integer selected from 0 to 3. In one embodiment, m1 and n1 are not both 0, and m2 and n2 are not both 0.

[0116] In one embodiment, each amino acid sequence in formula (I) is independently an amino acid sequence containing 1-10 amino acids. In one embodiment, each polyethylene glycol chain in formula (I) is independently a polyethylene glycol chain containing 1-10 ethylene glycol structural units. In one embodiment, each ethylene glycol structural unit is independently (C2H4-O) or (O-C2H4). In one embodiment, each polyethylene glycol chain in formula (I) is independently selected from (C2H4-O) d and (O-C2H4)d , d is an integer selected from 1 to 10.

[0117] In one embodiment, X1 and X2 are each independently NH, NR or O, preferably NH or O, especially NH. In one embodiment, R is C 1-6 Alkyl, especially methyl.

[0118] In one embodiment, each of A1 and A2 is independently selected from C 1-10 Alkylene, NH, -N(C 1-6 alkyl)-, O, C(O), C(O)-C 1-10 Alkylene-NH, NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 Alkyl)-, -N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(O), C(O)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene, C 1-10 Alkylene-C(O), a covalent bond, an amino acid, an amino acid sequence, and a polyethylene glycol chain, wherein each alkyl and alkylene group is unsubstituted or substituted with at least one independently selected from R XA In one embodiment, each of A1 and A2 is independently selected from C 1-10 Alkylene, NH, -N(C 1-6 alkyl)-, O, C(O), C(O)-C 1-10 Alkylene-NH, NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 Alkyl)-, -N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(O), C(O)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1-10Alkylene-C(O)-, C(O)-C 1-10 Alkylene, C 1-10 Alkylene-C(O), a covalent bond, and an amino acid, wherein each alkyl and alkylene group is unsubstituted or substituted with at least one independently selected from R XA In a particular embodiment, each alkylene group in A1 and A2 is a methylene group, which is unsubstituted or substituted by at least one independently selected from R XA substituted by a substituent.

[0119] In one embodiment, each of A1 and A2 is independently selected from a covalent bond and an amino acid. In one embodiment, each amino acid in A1 and A2 is independently selected from glycine, alanine, valine, and phenylglycine. In a special embodiment, each amino acid in A1 and A2 is glycine. In a special embodiment, each amino acid in A1 and A2 is independently selected from alanine, valine, and phenylglycine. In one embodiment, each of A1 is independently selected from a covalent bond, Gly, Ala, Phg, and Val. In one embodiment, each of A2 is independently selected from a covalent bond, Gly, and Ala. Wherein, Gly represents glycine, Ala represents alanine, Phg represents phenylglycine, and Val represents valine.

[0120] In one embodiment, (A1) m1 Structure and (A2) m2 The structures are each independently selected from the group consisting of a covalent bond, (Gly) h , Ala, Ala-Phg-Val and Val-Phg-Ala, wherein h is an integer selected from 1 to 10. In one embodiment, h is an integer selected from 1 to 5, in particular 3. In one embodiment, (A1) m1 Structure and (A2) m2 The structure is a covalent bond. In one embodiment, (A1) m1 Structure and (A2) m2 The structure is (Gly) 3. In one embodiment, (A1) m1 The structures are Ala and Ala-Phg-Val. In one embodiment, (A2) m2 The structure is Ala.

[0121] In one embodiment, each of Y1 and Y2 is independently selected from C 1-10 Alkylene, NH, -N(C 1-6 alkyl)-, O, C(O), C(O)-C 1-10 Alkylene-NH, NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C1-6 Alkyl)-, -N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(O), C(O)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene, C 1-10 Alkylene-C(O), a covalent bond, an amino acid, an amino acid sequence, and a polyethylene glycol chain, wherein each alkyl and alkylene group is unsubstituted or substituted with at least one independently selected from R XY substituted by a substituent.

[0122] In one embodiment, each of Y1 and Y2 is independently selected from C 1-10 Alkylene, NH, -N(C 1-6 alkyl)-, O, C(O), C(O)-C 1-10 Alkylene-NH, NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 Alkyl)-, -N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(O), C(O)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene, C 1-10 Alkylene-C(O), covalent bond, amino acid, (C2H4-O) d and (O-C2H4) d , wherein each alkyl and alkylene group is unsubstituted or substituted by at least one independently selected from R XY substituted with a substituent; d is an integer selected from 1 to 10. In one embodiment, d is an integer selected from 3 to 7, in particular 5.

[0123] In a particular embodiment, each alkylene group in Y1 and Y2 is a methylene group which is unsubstituted or substituted with at least one group independently selected from R XYIn one embodiment, each amino acid in Y1 and Y2 is independently selected from glycine, alanine, valine and phenylglycine. In a particular embodiment, each amino acid in Y1 and Y2 is glycine. In a particular embodiment, each amino acid in Y1 and Y2 is independently selected from alanine, valine and phenylglycine. In one embodiment, each Y1 is independently selected from a covalent bond, C 1-10 Alkylene, C(O), C(O)-C 1-10 Alkylene-NH, C(O)-C 1-10 Alkylene, (O-C2H4) d In one embodiment, each Y2 is independently selected from a covalent bond, C 1-10 Alkylene, C(O), NH, (C2H4-O) d and C 1-10 Alkylene-C(O).

[0124] In one embodiment, (Y1) n1 Structure and (Y2) n2 The structures are each independently selected from a covalent bond, C(O)-C 1-10 Alkylene-NH, NH-C 1-10 Alkylene-C(O), C(O)-C 1-10 Alkylene-C(O), C(O)-(C2H4-O) d -C 1-10 Alkylene-NH, NH-C 1-10 Alkylene-(O-C2H4) d -C(O), C(O)-C 1-10 Alkylene-(O-C2H4) d -NH, NH-(C2H4-O) d -C 1-10 Alkylene-C(O), C(O)-C 1-10 Alkylene-(C2H4-O) d -C 1-10 Alkylene-NH, NH-C 1-10 Alkylene-(O-C2H4) d -C 1- 10 Alkylene-C(O), C(O)-C 1-10 Alkylene-(O-C2H4) d -C 1-10 Alkylene-NH and NH-C 1-10 Alkylene-(C2H4-O) d -C 1-10 Alkylene-C(O). In one embodiment, (Y1) n1The structure is selected from covalent bond, C(O)-C 1-10 Alkylene-NH and C(O)-C 1-10 Alkylene-(O-C2H4) d -NH. In one embodiment, (Y2) n2 The structure is selected from covalent bond, C(O)-C 1- 10 Alkylene -C(O) and -NH-(C2H4-O) d -C 1-10 Alkylene-C(O).

[0125] In one embodiment, Z is selected from C 1-10 Alkylene, N, C(O)-C 1-10 Alkylene-NH, NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 Alkyl)-, -N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene-NHC(O), C(O)NH-C 1-10 Alkylene-C(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1-10 Alkylene-C(O)-, C(O)-C 1-10 Alkylene, C 1-10 Alkylene-C(O), NH-C 1-10 Alkylene -NH, -NH-C 1-10 Alkylene-N(C 1-6 Alkyl)-, -N(C 1-6 alkyl)-C 1-10 Alkylene-NH- and -N(C 1-6 alkyl)-C 1-10 Alkylene-N(C 1-6 alkyl), wherein each alkyl and alkylidene is unsubstituted or substituted by at least one independently selected from R XZ In one embodiment, Z is an amino acid. In one embodiment, Z is selected from glutamic acid, aspartic acid, lysine and serine; preferably selected from glutamic acid, aspartic acid and lysine; in particular selected from glutamic acid and lysine.

[0126] In one embodiment, Z is selected from C(O)(CH2) k NH, C(O)(CH2) k NHC(O), C(O)(CH2)k NHC(S), C(O)(CH2) k 、CHNHC(O)(CH2) k 、NH(CH2) k NH, a covalent bond, an amino acid or an amino acid sequence or a polyethylene glycol chain, k is a natural number selected from 1 to 10.

[0127] In one embodiment, L is selected from a metal chelator, wherein the metal chelator contains a ligand portion L0 and optionally further contains a conjugated handle portion Lk that connects L0 to the rest of the molecule. When Lk is present, L can be represented as L0-Lk, wherein L0 is the metal. When Lk is absent, L can be represented as L0. In one embodiment, L0 is selected from a ligand containing 2 to 15 (e.g., 2 to 8, 4 to 8, or 6 to 8) coordinating atoms selected from N and O. In one embodiment, the coordinating atoms in L are selected from N and O. In one embodiment, L0 is selected from DOTA, NOTA, DOTAGA, NETA, HBED-CC, TETA and CB-TE2A, in particular DOTA. In one embodiment, the conjugated handle portion Lk is selected from C 1-10 Alkylene, NH, -N(C 1-6 alkyl)-, O, C(O), C(O)-C 1-10 Alkylene-NH, -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl)-, C(O)-C 1-10 Alkylene-NHC(O), -C(O)-C 1-10 Alkylene-N(C 1-6 alkyl) C(O)-, C(O)-C 1-10 Alkylene, C 1-10 Alkylene-C(O) and C 1-10 Alkylene-C(O)-C 1-10 Alkylene, in particular selected from C(O)-C 1-10 Alkylene and C 1-10 In one embodiment, the conjugated handle portion Lk is selected from C(O)(CH2) g and (CH2) g C(O), g is an integer selected from 0 to 10. In one embodiment, Lk is C(O)(CH2)2. In one embodiment, g is an integer selected from 1 to 5, in particular 2.

[0128] In one embodiment, L is coordinated to M through one or more coordination bonds. In one embodiment, L is coordinated to M through at least 2 (e.g., 2 to 15, particularly 4, 6, or 8) coordination bonds. In one embodiment, L is coordinated to M through 6 coordination bonds.

[0129] In one embodiment, L is selected from DOTA, NOTA, DOTAGA, NETA, HBED-CC, TETA and CB-TE2A. In a particular embodiment, L is selected from DOTA and DOTAGA.

[0130] In one embodiment, R1 and R2 are each independently selected from H and halogen, in particular halogen. In one embodiment, R1 and R2 are F.

[0131] In one embodiment, X1 and X2 are NH; R1 and R2 are F. In one embodiment, each of A1 and A2 is independently selected from a covalent bond, Gly and Ala, Phg and Val; each of Y1 and Y2 is independently selected from a covalent bond, C 1-10 Alkylene, C(O), C(O)-C 1-10 Alkylene-NH, C(O)-C 1-10 Alkylene, (O-C2H4) d 、NH、(C2H4-O) d and C 1-10 Alkylene-C(O), wherein each alkyl and alkylene is unsubstituted or substituted with at least one independently selected from R XY substituted by a substituent; d is an integer selected from 1 to 10. In one embodiment, X1 and X2 are NH, R1 and R2 are both F; A1 is C(O)(CH2) i NH, A2 is C(O)(CH2) i NH or NH(CH2) i C(O), i is a natural number selected from 1 to 6, m1 and m2 are each independently an integer selected from 1 to 5; Y1 is C(O), n1 is an integer selected from 1 to 3; Y2 is C(O)(CH2) j or (CH2) j C(O), j is a natural number selected from 1 to 6, and n2 is an integer selected from 1 to 3. In one embodiment, i is a natural number selected from 1 to 3, m and m2 are each independently an integer selected from 1 to 3; j is a natural number selected from 1 to 3, and n1 and n2 are integers selected from 1 to 3.

[0132] In one embodiment, formula (I) has the structure of formula (I-1):

[0133] wherein X1, X2, A1, A2, Y1, Y2, Z, L, R1, R2, m1, m2, n1 and n2 are as defined in formula (I).

[0134] In one embodiment, the present invention provides a compound selected from the group consisting of:

[0135] Metal complex of formula (II)

[0136] The present invention also discloses a metal complex of the compound of formula (I), which has a structure as shown in formula (II):

[0137] Wherein, M is metal;

[0138] X1, X2, A1, A2, Y1, Y2, Z, L, R1, R2, m1, m2, n1 and n2 are as defined in formula (I).

[0139] In one embodiment, the compound of formula (II) is a metal complex of a FAP binding compound.

[0140] In one embodiment, M is a radioisotope metal.

[0141] In one embodiment, M is any one of Ga, Cu, Lu, Y, Ac, Bi, In, Pb, or Tb.

[0142] In a preferred embodiment, M is any one of Ga-68, Cu-64, Lu-177, Y-90, Y-86, Ac-225, Bi-213, In-111, Cu-67, Pb-212, and Tb- 161. In a particular embodiment, M is Ga-68.

[0143] In one embodiment, In the structure In one embodiment, In the structure It means coordinated through at least 2 (eg, 2 to 15) coordination bonds. In the structure You can also use Replacement also means coordination through one or more coordination bonds.

[0144] In a particular embodiment, L is selected from DOTA and DOTAGA, and M is Ga-68; preferably, L is coordinated to M through 6 coordination bonds.

[0145] In one embodiment, formula (II) has the structure of formula (II-1):

[0146] wherein X1, X2, A1, A2, Y1, Y2, Z, L, R1, R2, m1, m2, n1 and n2 are as defined in formula (II).

[0147] In one embodiment, the present invention provides a metal complex of a compound selected from the group consisting of:

[0148] In one embodiment, the FAP-binding compound of the present invention can also be represented by formula (I'):

[0149] In formula (I'):

[0150] X is NH, NR, O or S, wherein R is C 1-6 alkyl;

[0151] A is selected from C(O), C(O)(CH2) i NH, C(O)(CH2) i NHC(O), C(O)(CH2) i NHC(S), a covalent bond, an amino acid or an amino acid sequence or a polyethylene glycol chain, i is a natural number selected from 1 to 10;

[0152] Y1 and Y2 are each independently selected from C(O), C(O)(CH2) j NH, C(O)(CH2) j NHC(O), C(O)(CH2) j NHC(S), C(O)(CH2) j , a covalent bond, an amino acid or an amino acid sequence or a polyethylene glycol chain, j is a natural number selected from 1 to 10;

[0153] Z is selected from C(O)(CH2) k NH, C(O)(CH2) k NHC(O), C(O)(CH2) k NHC(S), C(O)(CH2) k 、NH(CH2) k NH, a covalent bond, an amino acid or an amino acid sequence or a polyethylene glycol chain, k is a natural number selected from 1 to 10;

[0154] L is a metal chelating agent;

[0155] R1 and R2 are each independently selected from H, halogen or C 1-6 alkyl;

[0156] m is an integer selected from 0 to 10;

[0157] n1 is an integer selected from 0 to 10;

[0158] n2 is an integer selected from 0 to 10.

[0159] Furthermore, in formula (I'), X is NH, R1 and R2 are both F; A is C(O)(CH2) i NH, i is a natural number selected from 1 to 6, m is an integer selected from 1 to 5; Y1 is C(O), n1 is an integer selected from 1 to 3; Y2 is C(O)(CH2) j , j is a natural number selected from 1 to 6, and n2 is an integer selected from 1 to 3.

[0160] Furthermore, in formula (I'), i is a natural number selected from 1 to 3, m is an integer selected from 1 to 3; j is a natural number selected from 1 to 3, and n is an integer selected from 1 to 3.

[0161] Furthermore, in formula (I'), L is selected from DOTA, NOTA, DOTAGA, NETA, HEBD-CC, TETA or CB-TE2A.

[0162] In one embodiment, the metal complex of the FAP-binding compound of the present invention can also be represented by formula (II'):

[0163] In formula (II'), M is a metal;

[0164] X is NH, NR, O or S, wherein R is C 1-6 alkyl;

[0165] A is selected from C(O), C(O)(CH2) i NH, C(O)(CH2) i NHC(O), C(O)(CH2) i NHC(S), a covalent bond, an amino acid or an amino acid sequence or a polyethylene glycol chain, i is a natural number selected from 1 to 10;

[0166] Y1 and Y2 are each independently selected from C(O), C(O)(CH2) j NH, C(O)(CH2) j NHC(O), C(O)(CH2) j NHC(S), C(O)(CH2) j , a covalent bond, an amino acid or an amino acid sequence or a polyethylene glycol chain, j is a natural number selected from 1 to 10;

[0167] Z is selected from C(O)(CH2) k NH, C(O)(CH2) k NHC(O), C(O)(CH2) k NHC(S), C(O)(CH2) k 、NH(CH2) kNH covalent bond, amino acid or amino acid sequence or polyethylene glycol chain, k is a natural number selected from 1 to 10;

[0168] L is a metal chelating agent;

[0169] R1 and R2 are each independently selected from H, halogen or C 1-6 alkyl;

[0170] m is an integer selected from 0 to 10;

[0171] n1 is an integer selected from 0 to 10;

[0172] n2 is an integer selected from 0 to 10.

[0173] Further, in formula (II'), M is a radioisotope metal;

[0174] Further, M is any one of Ga, Cu, Lu, Y, Ac, Bi or In;

[0175] Furthermore, M is any one of Ga-68, Cu-64, Lu-177, Y-90, Y-86, Ac-225, Bi-213, In-111 or Cu-67.

[0176] In one embodiment, the FAP-binding compounds of the present invention can also be represented by formula (I"):

[0177] In formula (I"):

[0178] X is NH, NR, O or S, wherein R is C 1-6 alkyl;

[0179] A is selected from C(O), C(O)(CH2) i NH, C(O)(CH2) i NHC(O), C(O)(CH2) i NHC(S), a covalent bond, an amino acid or an amino acid sequence or a polyethylene glycol chain, i is a natural number selected from 1 to 10;

[0180] Y is selected from C(O), C(O)(CH2) j NH, C(O)(CH2) j NHC(O), C(O)(CH2) j NHC(S), C(O)(CH2) j , a covalent bond, an amino acid or an amino acid sequence or a polyethylene glycol chain, j is a natural number selected from 1 to 10;

[0181] L is a metal chelating agent;

[0182] R1 and R2 are each independently selected from H, halogen or C 1-6 alkyl;

[0183] m is an integer selected from 0 to 10;

[0184] n is an integer selected from 0 to 10.

[0185] Furthermore, in formula (I"), X is NH, R1 and R2 are both F; A is C(O)(CH2) i NH, i is a natural number selected from 1 to 6, m is an integer selected from 1 to 5; Y is C(O)(CH2) j , j is a natural number selected from 1 to 6, and n is an integer selected from 1 to 3.

[0186] Furthermore, in formula (I"), i is a natural number selected from 1 to 3, m is an integer selected from 1 to 3; j is a natural number selected from 1 to 3, and n is an integer selected from 1 to 3.

[0187] Furthermore, in formula (I"), L is selected from DOTA, NOTA, HEBD-CC, TETA or CB-TE2A.

[0188] In one embodiment, the metal complex of the FAP-binding compound of the present invention can also be represented by formula (II"):

[0189] In formula (II"), M is a metal;

[0190] X is NH, NR, O or S, wherein R is C 1-6 alkyl;

[0191] A is selected from C(O), C(O)(CH2) i NH, C(O)(CH2) i NHC(O), C(O)(CH2) i NHC(S), a covalent bond, an amino acid or an amino acid sequence or a polyethylene glycol chain, i is a natural number selected from 1 to 10;

[0192] Y is selected from C(O), C(O)(CH2) j NH, C(O)(CH2) j NHC(O), C(O)(CH2) j NHC(S), C(O)(CH2) j , a covalent bond, an amino acid or an amino acid sequence or a polyethylene glycol chain, j is a natural number selected from 1 to 10;

[0193] L is a metal chelating agent;

[0194] R1 and R2 are each independently selected from H, halogen or C1-6 alkyl;

[0195] m is an integer selected from 0 to 10;

[0196] n is an integer selected from 0 to 10.

[0197] Further, in formula (II"), M is a radioisotope metal;

[0198] Further, M is any one of Ga, Cu, Lu, Y, Ac, Bi or In;

[0199] Furthermore, M is any one of Ga-68, Cu-64, Lu-177, Y-90, Y-86, Ac-225, Bi-213, In-111 or Cu-67.

[0200] In one embodiment, in formula (II') or formula (II"), M is a radioisotope metal.

[0201] In one embodiment, M is any one of Ga, Cu, Lu, Y, Ac, Bi or In.

[0202] In one embodiment, M is any one of Ga-68, Cu-64, Lu-177, Y-90, Y-86, Ac-225, Bi-213, In-111, or Cu-67.

[0203] The present invention also discloses the use of the FAP-binding agent or the metal complex of the FAP-binding agent described above for preparing an imaging agent, wherein cells or tissues are contacted with a compound represented by formula (II') or formula (II"), the compound in the cells or tissues is detected, and the compound in the cells or tissues is imaged.

[0204] Furthermore, the imaging is performed by positron emission tomography (PET).

[0205] Furthermore, the cells or tissues are in vivo or in vitro.

[0206] In one embodiment, the use is for the preparation of an imaging agent for cancer, tumor or neoplasm.

[0207] Furthermore, the use is for preparing an imaging agent for cancer, tumor or neoplasm;

[0208] Furthermore, the cancer includes any one or more of eye cancer, rectal cancer, colon cancer, cervical cancer, prostate cancer, breast cancer, bladder cancer, oral cancer, stomach cancer, liver cancer, pancreatic cancer, lung cancer, uterine cancer, ovarian cancer, testicular cancer, kidney cancer, brain cancer, central nervous system cancer, pharyngeal cancer, skin melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, Kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms' tumor, neuroblastoma, esophageal cancer, laryngeal cancer, lymphoma, neurofibroma, tuberous sclerosis, hemangioma or lymphoma.

[0209] Pharmaceutical compositions and pharmaceutical preparations

[0210] Another object of the present invention is to provide a pharmaceutical composition comprising a FAP-binding compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug thereof, or a metal complex of a FAP-binding compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug thereof, and at least one pharmaceutically acceptable carrier.

[0211] The pharmaceutical compositions of the present invention can be administered in any manner, as long as they achieve the effect of preventing, alleviating, preventing, or treating symptoms in humans or animals. For example, various suitable dosage forms can be prepared depending on the route of administration. For example, they can be administered to patients in the form of conventional formulations. Such conventional formulations include capsules, microcapsules, suppositories, injections, and patches.

[0212] The dosage of the compound administered to a subject can be adjusted to a considerable extent. The dosage can vary depending on the specific route of administration and the needs of the subject and can be subject to the judgment of a healthcare professional.

[0213] Imaging or treatment methods and uses

[0214] According to certain embodiments of the present invention, a FAP-binding compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite, or prodrug thereof, or a metal complex of a FAP-binding compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention can be used for detection or imaging, or for preventing or treating diseases in which FAP is overexpressed.

[0215] Thus, in one aspect, the present invention provides the use of a FAP-binding compound of the invention or a metal complex of a FAP-binding compound of the invention for the preparation of an imaging agent.

[0216] In one embodiment, the method of imaging is to contact a cell or tissue with a metal complex of a FAP-binding compound of the invention and to detect and image the compound within the cell or tissue. In one embodiment, the cell or tissue is in vivo or in vitro.

[0217] The present invention also discloses the use of the FAP binder or the metal complex of the FAP binder described above for preparing an imaging agent, wherein cells or tissues are contacted with a compound represented by formula (II), the compound in the cells or tissues is detected, and the compound in the cells or tissues is imaged.

[0218] In one embodiment, imaging is performed by positron emission tomography (PET) or single photon computed tomography (SPECT), particularly PET.

[0219] In one embodiment, the imaging agent is an imaging agent for cancer, tumor, or neoplasm.

[0220] In yet another aspect, the present invention also provides use of a FAP-binding compound of the invention, or a metal complex of a FAP-binding compound of the invention, or a pharmaceutical composition of the invention, for the preparation of a medicament for treating a disease, disorder, or condition selected from a disease in which FAP is overexpressed, the FAP-binding compound, or the metal complex of a FAP-binding compound, or the pharmaceutical composition, optionally in combination with a second therapeutic agent.

[0221] In another aspect, the present invention provides a FAP-binding compound of the invention or a metal complex of a FAP-binding compound of the invention or a pharmaceutical composition of the invention, optionally in combination with a second therapeutic agent, for use in treating a disease in which FAP is overexpressed.

[0222] In a further aspect, the present invention provides a method of treating a disease in which FAP is overexpressed, comprising administering to a subject in need thereof an effective amount of a FAP-binding compound of the invention, a metal complex of a FAP-binding compound of the invention, or a pharmaceutical composition of the invention, optionally in combination with a second therapeutic agent.

[0223] In one embodiment, the disease in which FAP is overexpressed is cancer, tumor or neoplasm.

[0224] In a preferred embodiment, the cancer includes any one or more of eye cancer, rectal cancer, colon cancer, cervical cancer, prostate cancer, breast cancer, bladder cancer, oral cancer, stomach cancer, liver cancer, pancreatic cancer, lung cancer, uterine cancer, ovarian cancer, testicular cancer, kidney cancer, brain cancer, central nervous system cancer, pharyngeal cancer, skin melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, Kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms' tumor, neuroblastoma, esophageal cancer, laryngeal cancer, lymphoma, neurofibroma, tuberous sclerosis, hemangioma or lymphoma. Beneficial effects

[0225] Advantages and effects of the present invention:

[0226] 1) By modifying the structure of FAP inhibitors, we obtained FAP-binding compounds with higher affinity;

[0227] 2) By modifying the structure of the FAP inhibitor, a FAP-binding compound with excellent long-term efficacy was obtained, that is, the retention time in the tumor was sufficient to meet the requirements.

[0228] The FAP-binding compounds and metal complexes of the FAP-binding compounds of the present invention have excellent tissue specificity and surprisingly long-lasting in vivo retention.

[0229] Example

[0230] The present invention will be further described in detail below with reference to examples, but these examples do not limit the present invention in any way.

[0231] Specific experimental methods not mentioned in the following examples were all carried out according to conventional experimental methods.

[0232] abbreviation

[0233] DOTA: 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid

[0234] NOTA: 1,4,7-triazacyclononane-1,4,7-triacetic acid

[0235] DOTAGA: 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid

[0236] DOTAGA-(COOt-Bu)4: 5-(tert-butoxy)-5-oxo-4-{4,7,10-tris[2-(tert-butoxy)-2-oxoethyl]-1,4,7,10-tetraazacyclododecan-1-yl}pentanoic acid

[0237] NETA: {4-[2-(bis-carboxy-methylamino)-5-(4-nitrophenyl)pentyl]-7-carboxymethyl-triazanonan-1-yl}acetic acid

[0238] HBED-CC: N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid

[0239] TETA: 1,4,8,11-Tetraazacyclotetradecane-1,4,8,11-tetraacetic acid

[0240] CB-TE2A: 2-[4-(Carboxymethyl)-1,4,8,11-tetrazabicyclo[6.6.2]hexadecan-11-yl]acetic acid

[0241] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0242] DIEA, DIPEA: N,N-diisopropylethylamine

[0243] NMM: N-methylmorpholine

[0244] HOBt: Hydroxybenzotriazole

[0245] EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0246] PBS: Phosphate buffered saline

[0247] FBS: Fetal bovine serum

[0248] HBSS: Hanks balanced salt solution

[0249] Instruments, materials and reagents

[0250] LCMS: Agilent 6100

[0251] HPLC: Agilent 1260

[0252] Reversed-phase preparative liquid chromatography: chromatographic column: Agilent 300SB C-18 5 μm 4.6×250 mm; mobile phase: 0-20 min, 18% ACN-38% ACN.

[0253] Gallium Germanium Generator: EZ Gallipharm

[0254] Radio-HPLC: Lablogic Dual Scan-Ram

[0255] Radio-TLC: Lablogic Dual Scan-Ram

[0256] Gamma counter: Zhongke Zhongjia GC1500,

[0257] Gamma counting method: Place the measurement sample in a gamma counter tube, then place the counter tube on the machine to automatically inject the sample and measure the gamma count.

[0258] PET: SIEMENS Micro PET / CT

[0259] PBS: pH 7.4

[0260] Example 1 Preparation of the FAPI-FUSCC-02-DIMER Labeled Precursor

[0261] Synthesis route:

[0262] Synthesis Scheme 1 Schematic diagram of the synthesis of FAPI-FUSCC-02-DIMER labeled precursor

[0263] 1) Synthesis of Compound 1:

[0264] In a 50 mL eggplant-shaped flask, compounds Boc-Glycine (0.175 g), HATU (0.456 g), and DIPEA (0.155 g) were dissolved in 7 mL of anhydrous DMF. The reaction system was stirred at room temperature for 0.5 h, and then (S)-4,4-difluoropyrrolidine-2-carbonitrile hydrochloride (0.132 g, 1 mmol) dissolved in 3 mL of anhydrous DMF was added to the solution. The reaction system was stirred at room temperature overnight. After reaction progress was monitored by TLC, the reaction system was washed with saturated NaHCO₃ solution (2 × 30 mL) and then extracted with EA (3 × 50 mL). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain product 1 as a solid powder (0.15 g, yield: 52%).

[0265] 2) Synthesis of Compound 2:

[0266] In a 50 mL eggplant-shaped flask, compound 1 (0.145 g, 0.5 mmol) was added and dissolved in 10 mL of 4.0 M hydrogen chloride in dioxane. The reaction system was stirred at room temperature for 3 h. After monitoring the reaction progress by TLC, the reaction system was concentrated under reduced pressure. Ether was added for washing. The remaining hydrochloric acid was removed by vacuum filtration to obtain the final product, compound 2 (76 mg, yield: 81%).

[0267] 3) Synthesis of compound 3:

[0268] In a 50 mL eggplant-shaped flask, compound 2 (189 mg), HATU (456 mg), and DIPEA (155 mg) were dissolved in 7 mL of anhydrous DMF. The reaction system was stirred at room temperature for 0.5 h, and then 8-aminoquinoline-4-carboxylic acid (188 mg) dissolved in 3 mL of anhydrous DMF was added to the solution. The reaction system was stirred at room temperature overnight. After reaction progress was monitored by TLC, saturated NaHCO₃ solution (2 × 30 mL) was added to the reaction system for washing, followed by extraction with EA (3 × 50 mL). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain product 3 as a solid powder (150 mg, yield: 42%).

[0269] 4) Synthesis of compound 4:

[0270] In a 50 mL eggplant-shaped flask, compound Boc-GLY-GLY-GLY-OH (120 mg), HATU (190 mg), and DIPEA (65 mg) were dissolved in 7 mL of anhydrous DMF. The reaction system was stirred at room temperature for 0.5 h, and then compound 3 (150 mg) dissolved in 3 mL of anhydrous DMF was added to the solution. The reaction system was stirred at room temperature overnight. After the reaction progress was monitored by TLC, saturated NaHCO₃ solution (2 × 30 mL) was added to the reaction system for washing, followed by extraction with EA (3 × 50 mL). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain solid powder product 4 (96 mg, yield: 38%).

[0271] 5) Synthesis of Compound 5:

[0272] In a 50 mL eggplant-shaped flask, compound 4 (96 mg) was added and dissolved in 10 mL of 4.0 M hydrogen chloride in dioxane. The reaction system was stirred at room temperature for 3 h. After monitoring the reaction progress by TLC, the reaction system was concentrated under reduced pressure. Ether was added for washing. The remaining hydrochloric acid was removed by vacuum filtration to obtain the final product, compound 5 (54 mg, yield: 65%).

[0273] 6) Synthesis of Compound 6:

[0274] In a 50 mL eggplant-shaped flask, the compounds (i.e., BOC-glutamic acid, 12.4 mg), HATU (45.6 mg) and DIPEA (15.5 mg) were dissolved in 7 mL of anhydrous DMF. After the reaction system was stirred at room temperature for 0.5 h, compound 5 (53 mg) dissolved in 3 mL of anhydrous DMF was added to the solution. The reaction system was stirred overnight at room temperature. After the reaction progress was monitored by TLC, saturated NaHCO3 solution (2×30 mL) was added to the reaction system for washing, and then EA (3×50 mL) was added for extraction. The organic phases were combined. The organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a solid powder product 6 (27 mg, yield: 43%).

[0275] 7) Synthesis of Compound 7:

[0276] In a 50 mL eggplant-shaped flask, compound 6 (27 mg) was added and dissolved in 10 mL of 6.0 M hydrochloric acid. The reaction system was stirred at room temperature for 3 h. After the reaction progress was monitored by TLC, the reaction system was concentrated under reduced pressure and washed with diethyl ether. The remaining hydrochloric acid was removed by vacuum filtration to obtain the final product, compound 7 (18.6 mg, yield: 75%).

[0277] 8) Synthesis of Compound 8:

[0278] In a 50 mL eggplant-shaped flask, the compounds (i.e., DOTAGA-(COOt-Bu)4, 11 mg), HATU (7.2 mg) and DIPEA (2.5 mg) were dissolved in 7 mL of anhydrous DMF. After the reaction system was stirred at room temperature for 0.5 h, compound 7 dissolved in 3 mL of anhydrous DMF was added to the solution. The reaction system was stirred at room temperature overnight. After the reaction progress was monitored by TLC, saturated NaHCO3 solution (2×30 mL) was added to the reaction system for washing, and then EA (3×50 mL) was added for extraction. The organic phases were combined. The organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a solid powder product 8 (16 mg, yield: 56%).

[0279] 9) Synthesis of compound 9:

[0280] In a 50 mL eggplant-shaped flask, compound 8 (16 mg) was added and dissolved in 10 mL of 6.0 M hydrochloric acid. The reaction system was stirred at room temperature for 3 h. After the reaction progress was monitored by TLC, the reaction system was concentrated under reduced pressure and washed with diethyl ether. The remaining hydrochloric acid was removed by vacuum filtration to obtain the final product, compound 9 (8.3 mg, yield: 63%).

[0281] The structure of compound 9 was confirmed by HPLC and LC-MS. The relevant spectra are shown in Figures 1 and 2.

[0282] Example 2 Compound 68 Preparation of Ga-FAPI-FUSCC-02-DIMER

[0283] Dissolve the FAPI-FUSCC-02-DIMER labeled precursor in sterile water for injection to prepare a 1 μg / μL precursor solution. Use 0.1M hydrochloric acid to elute through a gallium germanium generator to obtain 68 GaCl3 solution. 40 μL precursor solution, 360 μL 1.5M sodium acetate solution, 4 mL 68 Add GaCl3 solution to the precursor reagent bottle. Heat the solution in the precursor reagent bottle to 100℃ and react for 10 minutes to obtain the final product. 68 The radiochemical purity of Ga-FAPI-FUSCC-02-DIMER was determined by Radio-TLC and Radio-HPLC. The relevant analysis spectra are shown in Figures 3, 4, and 5. The specific reaction route is as follows:

[0284] Example 3 Preparation of Compound FAPI-FX-01

[0285] Synthesis route of FAPI-FX-01:

[0286] 1) Synthesis of Compounds 1-3

[0287] Compound 1-2 (1 eq) was dissolved in 10 mL of DMF, and HATU (1.5 eq) and DIEA (3 eq) were added, followed by compound 3 (1 eq) described in Example 1. The reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction as monitored by LC-MS, the solvent was removed under reduced pressure. 10 mL of TFA was added and the reaction was allowed to proceed for 5 minutes. 100 mL of ether was added, and a large amount of solid precipitated. The mixture was centrifuged and the solvent was removed by filtration. Compound 1-3 was purified by reverse-phase preparative liquid chromatography (yield: 45%).

[0288] LCMS:MS m / z:637.35[M+H] + The spectrum is shown in Figure 6.

[0289] 2) Synthesis of Compounds 1-5

[0290] Compound 1-4 (1 eq) was dissolved in 3 mL of DMF and cooled to 0°C. HOBt (2.5 eq) and EDCI (2.5 eq) were added. The reaction was allowed to proceed at 0°C for 10 minutes. Compound 1-3 (2.5 eq) and NMM (7.5 eq) were added. The cooling device was removed and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete as monitored by LC-MS, the solvent was removed under reduced pressure. 10 mL of TFA was added and the reaction was continued for 5 minutes. 100 mL of ether was added, and a large amount of solid precipitated. The mixture was centrifuged and the solvent was removed by filtration. Compound 1-5 was purified by reverse phase preparative liquid chromatography (yield: 26%).

[0291] LCMS:MS m / z:1384.81[M+H] + The spectrum is shown in Figure 7.

[0292] 3) Synthesis of FAPI-FX-01

[0293] Compound 1-5 (1 eq) was dissolved in 5 mL of DMF, and DIEA (4 eq) and compound 1-6 (2 eq) were added. The reaction was allowed to react overnight at room temperature. After completion of the reaction as monitored by LC-MS, the solvent was removed under reduced pressure. FAPI-FX-01 was purified by reverse-phase preparative liquid chromatography (HPLC) to obtain FAPI-FX-01 (yield: 50%). Purity was determined by HPLC. The spectrum is shown in Figure 8.

[0294] LCMS:MS m / z:886.8[M+2H] + / 2. The spectrum is shown in Figure 9.

[0295] Example 4 Preparation of Compound FAPI-FX-02

[0296] 4.1 Synthesis of Compounds 2-5

[0297] 1) Synthesis of Compound 2-3

[0298] Compound 2-2 (1.1 eq) was dissolved in 5 mL of DMF, and HATU (1.5 eq) and DIEA (3 eq) were added, followed by compound 3 (1 eq) described in Example 1. The reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction as monitored by LC-MS, the solvent was removed under reduced pressure. 10 mL of TFA was added and the reaction continued for 5 minutes. 100 mL of ether was added, and a large amount of solid precipitated. The mixture was centrifuged and the solvent was removed by filtration. Compound 2-3 was purified by reverse-phase preparative liquid chromatography (yield: 58%).

[0299] LCMS:MS m / z:431.22[M+H] + The spectrum is shown in Figure 10.

[0300] 2) Synthesis of Compound 2-5

[0301] Compound 2-3 (1 eq) was dissolved in 3 mL of DMF, and compound 2-4 (1.5 eq) and DIEA (3 eq) were added. The reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction as monitored by LC-MS, the solvent was removed under reduced pressure. Compound 2-5 was purified by reverse phase preparative liquid chromatography (yield: 60%).

[0302] LCMS:MS m / z:545.46[M+H] + The spectrum is shown in Figure 11.

[0303] 4.2 Synthesis of Compounds 2-7

[0304] Compound 2-6 (1 eq, purchased from Tanzhen Bio) was dissolved in 5 mL of DMF, cooled to 0°C, and HOBt (1 eq) and EDCI (1 eq) were added. The reaction was allowed to proceed at 0°C for 10 minutes. Compound 2-3 (1 eq) and NMM (3 eq) were added. The cooling device was removed and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete as monitored by LC-MS, the solvent was removed under reduced pressure. 10 mL of a 4% hydrazine hydrate / DMF solution was added. The reaction was allowed to proceed at room temperature for 10 minutes. The solvent was removed under reduced pressure. Compound 2-7 was purified by reverse-phase preparative liquid chromatography (yield: 28%).

[0305] LCMS:MS m / z:1559.30[M+H] + The spectrum is shown in Figure 12.

[0306] 4.3 Synthesis of FAPI-FX-02

[0307] Compound 2-5 (1 eq) was dissolved in 5 mL of DMF, and HATU (1.5 eq) and DIEA (3 eq) were added, followed by compound 2-7 (1 eq). The reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction as monitored by LC-MS, the solvent was removed under reduced pressure. 10 mL of TFA was added. The reaction was allowed to proceed for 5 minutes. 100 mL of ether was added, and a large amount of solid precipitated. The mixture was centrifuged and the solvent was removed by filtration. FAPI-FX-02 was purified by reverse-phase preparative liquid chromatography (HPLC) to obtain FAPI-FX-02 (yield: 36%). Purity was determined by HPLC. The spectrum is shown in Figure 13.

[0308] LCMS:MS m / z:1861.70[M+H] + The spectrum is shown in Figure 14.

[0309] Example 5 Compound 68 Ga-FAPI-FX-01, compound 68 Preparation of Ga-FAPI-FX-02

[0310] Dissolve FAPI-FX-01 in sterile water for injection to prepare a 1 μg / μL precursor solution. Use 0.1M hydrochloric acid to elute through a gallium germanium generator. 68 GaCl3 solution. 40 μL precursor solution, 360 μL 1.5M sodium acetate solution, 4 mL 68 Add GaCl3 solution to the precursor reagent bottle. Heat the solution in the precursor reagent bottle to 100℃ and react for 10 minutes to obtain the final product. 68 Ga-FAPI-FX-01 was prepared from FAPI-FX-02 using the same method. 68 Ga-FAPI-FX-02. The structure is as follows.

[0311] Determination by Radio-TLC 68 Ga-FAPI-FX-01, 68 The radiochemical purity of Ga-FAPI-FX-02 is shown in Figures 15 and 16.

[0312] Test Example 1 68 Uptake of Ga-FAPI-FUSCC-02-DIMER in HT-1080-FAP cells

[0313] 1.1 Experimental methods:

[0314] (1) Cell plating: HT-1080-FAP cells were plated at 1×10 5 The cells were seeded at a density of 1 / well in a 24-well plate and placed in a cell culture incubator at 37°C and 5% CO2 overnight for attachment.

[0315] (2) Radioactive probe incubation: Aspirate the supernatant and add the freshly prepared 68 Add 500 μL / well of DMEM containing 2 μCi / mL Ga-FAPI-FUSCC-02-DIMER to each well, and place the cell culture plate in a hot chamber incubator for incubation. For the blocking group, add DOTA-FAPI-04 (purchased from Shanghai Jiabiao Biotechnology Co., Ltd.) to the corresponding wells half an hour in advance for incubation, and then add the radioactive medium together with the targeting group.

[0316] (3) Radioactivity measurement: At 0.5, 1, and 2 h, the supernatants in the wells at the corresponding time points were collected into γ-counting tubes, washed three times with pre-cooled PBS, and labeled. The cells were lysed with 1 M NaOH and collected into corresponding γ-counting tubes, and the radioactivity counts in each tube were measured using a γ-counter.

[0317] (4) Attenuation correction: The radioactivity is attenuated and the percentage of the radioactivity taken up by cells to the total radioactivity is calculated;

[0318] (5) Data processing: GraphPad Prism 9.0 was used for graphic analysis.

[0319] 1.2 Experimental results:

[0320] The results of the cell uptake experiment are shown in FIG17 . 68 Ga-FAPI-FUSCC-02-DIMER showed significant uptake in HT-1080-FAP cells, with the uptake being 2.796±0.154% ID / g in the 0.5h group, 2.956±0.167% ID / g in the 1h group, 2.979±0.064% ID / g in the 2h group, and 0.094±0.048% ID / g in the 1h-block group. As time went on, radioactive uptake slowly increased. Cell blocking experiments showed that 68 The cellular uptake of Ga-FAPI-FUSCC-02-DIMER can be blocked by excess DOTA-FAPI-04. 68 Ga-FAPI-FUSCC-02-DIMER mediates its uptake by HT-1080-FAP cells by specifically binding to FAP.

[0321] Test Example 2 68 Ga-FAPI-FUSCC-02-DIMER, 68 Ga-FAPI-FX-01, 68 Ga-FAPI-FX-02 lipid-water partition coefficient experiment

[0322] 2.1 68Ga-FAPI-FUSCC-02-DIMER lipid-water partition coefficient experiment:

[0323] Take 1-2μCi 68 Three parallel experiments were performed, each containing 500 μL of PBS and 500 μL of normal saline, followed by 500 μL of n-octanol. γ-rays were collected from 200 μL of the upper and lower layers of the Ga-FAPI-FUSCC-02-DIMER and the resulting mixture was counted to calculate the LogP and LogD values. The results, shown in Figure 18, demonstrate the excellent hydrophilicity of the Ga-FAPI-FUSCC-02-DIMER.

[0324] 2.2 68 Ga-FAPI-FX-01, 68 Ga-FAPI-FX-02 lipid-water partition coefficient experiment:

[0325] According to the experimental method described in 2.1 above, the 68 Ga-FAPI-FX-01, 68 The LogP and LogD values ​​of Ga-FAPI-FX-02 are shown in Figures 19 and 20, indicating that it has good hydrophilicity.

[0326] Test Example 3 68 In vitro stability study of Ga-FAPI-FUSCC-02-DIMER

[0327] This experiment aims to detect 68 The in vitro stability of Ga-FAPI-FUSCC-02-DIMER is consistent with that reported by the inventors. 68 Ga-FAPI-FUSCC-01 and 68 Ga-FAPI-FUSCC-02 for comparison. 68 Ga-FAPI-FUSCC-01 and 68 The structure and preparation method of Ga-FAPI-FUSCC-02 can be found in CN116375791A, or it can be prepared according to the method described in the examples of this application. 68 Ga-FAPI-FUSCC-01 and 68 The structure of Ga-FAPI-FUSCC-02 is shown in the figure below.

[0328] Take a certain amount 68 Ga-FAPI-FUSCC-02-DIMER was added to PBS and FBS respectively, and its radiochemical purity was determined at different time points to test its stability. The results are shown in Figure 21. After 3 hours, 68 The radiochemical purity of Ga-FAPI-FUSCC-02-DIMER was still greater than 98%, and it maintained good stability.

[0329] For comparison, take a certain amount 68 Ga-FAPI-FUSCC-01 and 68 Ga-FAPI-FUSCC-02 was added to PBS and FBS, and its radiochemical purity was determined at different time points to test its stability. The results are shown in Figures 22 and 23. After 3 hours, 68 Ga-FAPI-FUSCC-01 and 68 The radiochemical purity of Ga-FAPI-FUSCC-02 is still greater than 97%, and it maintains good stability.

[0330] Comprehensive experimental results found 68 Ga-FAPI-FUSCC-02-DIMER Stability and 68 Ga-FAPI-FUSCC-01 and 68 Ga-FAPI-FUSCC-02 is superior.

[0331] Test Example 4 68 In vivo stability study of Ga-FAPI-FUSCC-02-DIMER

[0332] Balb / c nude mice, female, 5-6 weeks old, were provided by Shanghai Lingchang Biotechnology Co., Ltd. 200 μCi / 0.2 mL of 68 Ga-FAPI-FUSCC-02-DIMER was prepared by radio-HPLC to determine its radiochemical purity and stability at different time points. 68 The radiochemical purity of Ga-FAPI-FUSCC-02-DIMER was still greater than 80%, and it maintained good stability.

[0333] Test Example 5 68 Ga-FAPI-FUSCC-02-DIMER hemodynamics experiment

[0334] Balb / c nude mice, female, 5-6 weeks old, were provided by Shanghai Lingchang Biotechnology Co., Ltd. 60 μCi / 0.2 mL of 68 Ga-FAPI-FUSCC-02-DIMER, 68 Ga-FAPI-FUSCC-01 and 68Ga-FAPI-FUSCC-02. At 1, 3, 5, 10, 15, 30, 60, 90, 120, 180, and 240 minutes after injection, the tails were cut and blood was collected using capillary tubes. The radioactivity counts were measured and %ID / g was calculated. The decay curves were fitted using Graphpad Prism 9.0, as shown in Figures 25, 26, and 27. 68 Ga-FAPI-FUSCC-01 has t1 / 2α=1.49min and t1 / 2β=26.91min; 68 Ga-FAPI-FUSCC-02 has t1 / 2α=0.54min and t1 / 2β=28.45min; 68 The results show that the t1 / 2α of Ga-FAPI-FUSCC-02-DIMER is 1.2min and t1 / 2β is 42.3min. 68 The clearance rate of Ga-FAPI-FUSCC-02-DIMER in vivo 68 Ga-FAPI-FUSCC-01 and 68 Ga-FAPI-FUSCC-02 is about 50% slower, thus prolonging its possibility of binding to the tumor and increasing tumor uptake.

[0335] Test Example 6 68 PET Imaging Study of Ga-FAPI-FUSCC-02-DIMER

[0336] SPF grade Balb / c nude mice, female, 6 weeks old, were provided by Shanghai Lingchang Biotechnology Co., Ltd. After two days of acclimatization in the animal room, FAP-transfected HT1080 human fibrosarcoma cells were injected subcutaneously in the right axilla of the nude mice with an injection volume of 0.1 mL (5 × 10 6 cells / mL dispersed in HBSS). Continue to culture for 2-4 weeks after injection until the solid tumor mass grows to 500-600mm 3 For imaging experiments: 100-150 μCi / 0.2 mL was injected via the tail vein 68 Ga-FAPI-FUSCC-02-DIMER, imaging experiments were performed using small animal PET 1 h, 2 h, and 4 h after injection. The imaging images are shown in Figure 28.

[0337] As a comparative experiment, the same tumor model was used 68 Ga-FAPI-FUSCC-01 and 68 Ga-FAPI-FUSCC-02 imaging experiment: Imaging experiments were performed using small animal PET at 0.5 h, 1 h, and 2 h after injection. The imaging images are shown in FIG29 .

[0338] From the PET / CT imaging comparison of the above FAP-positive tumor model, it can be found that 68 The tumor imaging effect of Ga-FAPI-FUSCC-02-DIMER was better than 68 Ga-FAPI-FUSCC-01 and 68 Ga-FAPI-FUSCC-02 has a higher absolute value of tumor uptake and a longer retention time in the tumor, proving that 68 Ga-FAPI-FUSCC-02-DIMER binds better to FAP protein and can better reflect tumor activity.

[0339] Test Example 7 68 Study on PET Imaging of Ga-FAPI-FX-01

[0340] SPF grade Balb / c nude mice, female, 6 weeks old, were provided by Shanghai Regen Biotechnology Co., Ltd. After two days of acclimatization in the animal room, FAP-transfected HT1080 human fibrosarcoma cells were injected subcutaneously in the right axilla of the nude mice with an injection volume of 0.1 mL (5 × 10 6 cells / mL dispersed in HBSS). Continue to culture for 2-4 weeks after injection until the solid tumor mass grows to 500-600mm 3 For imaging experiments: 100-150 μCi / 0.2 mL was injected via the tail vein 68 Ga-FAPI-FX-01, 1h, 2h, 4h after injection, small animal PET imaging experiments were performed, and the imaging images are shown in Figure 30. The results show that 68 Ga-FAPI-FX-01 has good binding to FAP protein, and the uptake in tumor tissue is significantly higher than that in normal tissue.

[0341] The above embodiments are intended only to illustrate the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand the contents of the present invention and implement them accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made based on the essence of the present invention are intended to be covered by the scope of protection of the present invention.

Claims

1. A FAP-binding compound or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug thereof; It is characterized in that, The FAP-binding compound has a structure represented by formula (I): Wherein, X1 and X2 are each independently selected from NH, NR, O or S, where R is C 1-6 alkyl; Each of A1 and A2 is independently selected from C 1-10 alkylene, NH, -N(C 1-6 alkyl)-, O, S, C(O), C(S), C(O)-C 1-10 alkylene-NH, NH-C 1-10 alkylene-C(O), -C(O)-C 1-10 alkylene-N(C 1-6 alkyl)-, -N(C 1-6 alkyl)-C 1-10 alkylene-C(O)-, C(O)-C 1-10 alkylene-NHC(O), C(O)NH-C 1-10 alkylene-C(O), -C(O)-C 1-10 alkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1-10 alkylene-C(O)-, C(O)-C 1-10 alkylene-NHC(S), C(S)NH-C 1-10 alkylene-C(O), -C(O)-C 1-10 alkylene-N(C 1-6 alkyl)C(S)-, -C(S)N(C 1- 6alkyl)-C 1-10 alkylene-C(O)-, C(O)-C 1-10 alkylene, C 1-10 alkylene-C(O), covalent bond, amino acid, amino acid sequence and polyethylene glycol chain, wherein each alkyl and alkylene is unsubstituted or substituted by at least one substituent independently selected from R XA ; Each of Y1 and Y2 is independently selected from C 1-10 alkylene, NH, -N(C 1-6 alkyl)-, O, S, C(O), C(S), C(O)-C 1-10 alkylene-NH, NH-C 1-10 alkylene-C(O), -C(O)-C 1-10 alkylene-N(C 1-6 alkyl)-, -N(C 1-6 alkyl)-C 1-10 alkylene-C(O)-, C(O)-C 1-10 alkylene-NHC(O), C(O)NH-C 1-10 alkylene-C(O), -C(O)-C 1-10 alkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1-10 alkylene-C(O)-, C(O)-C 1-10 alkylene-NHC(S), C(S)NH-C 1-10 alkylene-C(O), -C(O)-C 1-10 alkylene-N(C 1-6 alkyl)C(S)-, -C(S)N(C 1- 6alkyl)-C 1-10 alkylene-C(O)-, C(O)-C 1-10 alkylene, C 1-10 alkylene-C(O), a covalent bond, an amino acid, an amino acid sequence, and a polyethylene glycol chain, wherein each alkyl and alkylene is unsubstituted or substituted by at least one substituent independently selected from R XY ; Z is selected from C 1-10 alkylene, N, C(O)-C 1-10 alkylene-NH, NH-C 1-10 alkylene-C(O), -C(O)-C 1-10 alkylene-N(C 1-6 alkyl)-, -N(C 1-6 alkyl)-C 1-10 alkylene-C(O)-, C(O)-C 1-10 alkylene-NHC(O), C(O)NH-C 1-10 alkylene-C(O), -C(O)-C 1-10 alkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1- 10 alkylene-C(O)-, C(O)-C 1-10 alkylene-NHC(S), C(S)NH-C 1-10 alkylene-C(O), -C(O)-C 1-10 alkylene-N(C 1-6 alkyl)C(S)-, -C(S)N(C 1-6 alkyl)-C 1-10 alkylene-C(O)-, C(O)-C 1-10 alkylene, C 1-10 alkylene-C(O), NH-C 1-10 alkylene-NH, -NH-C 1-10 alkylene-N(C 1-6 alkyl)-, -N(C 1-6 alkyl)-C 1-10 alkylene-NH-, -N(C 1-6 alkyl)-C 1-10 alkylene-N(C 1-6 alkyl)-, amino acids and amino acid sequences, wherein each alkyl and alkylene is unsubstituted or substituted by at least one substituent independently selected from R XZ ; L is a metal chelator; R1 and R2 are each independently selected from H, halogen, or C 1-6 alkyl; Each R XA 、R XY and R XZ are independently selected from halogen, NO2, -CN, C 1-10 alkyl, -OH, -O(C 1-10 alkyl), -SH, -S(C 1-10 alkyl), -NH2, -NH(C 1-10 alkyl), -N(C 1-10 alkyl)2, C(O)C 1-10 alkyl, -C(O)OH, -C(O)O(C 1-10 alkyl), -C(O)NH2, -C(O)NH(C 1-10 alkyl), -C(O)N(C 1-10 alkyl)2, -S(O)(C 1-10 alkyl), -S(O)2(C 1-10 alkyl), -S(O)2O(C 1-10 alkyl), -S(O)2NH2, -S(O)2NH(C 1-10 alkyl), -S(O)2N(C 1- 10 alkyl)2, -OC(O)C 1-10 alkyl, -O(C 1-10 alkyl), -SH, -S(C 1-10 alkyl), -NHC(O)C 1-10 alkyl, -N(C 1-10 alkyl)C(O)C 1-10 alkyl; m1 is an integer selected from 0 to 10; m2 is an integer selected from 0 to 10; n1 is an integer selected from 0 to 10; n2 is an integer selected from 0 to 10.

2. The FAP-binding compound or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug thereof according to claim 1, characterized in that X1 and X2 are NH.

3. The FAP-binding compound or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug thereof according to any one of claims 1 or 2, characterized in that Each of A1 and A2 is independently selected from a covalent bond and an amino acid; preferably, each amino acid in A1 and A2 is independently selected from glycine, alanine, valine and phenylglycine.

4. The FAP-binding compound or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug thereof according to any one of claims 1-3, characterized in that (A1) m1 structures and (A2) m2 structures are each independently selected from a covalent bond, (Gly) h , Ala, Ala-Phg-Val and Val-Phg-Ala, where h is an integer selected from 1 to 10; In particular, h is 3.

5. The FAP-binding compound or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug thereof according to any one of claims 1-4, characterized in that Each of Y1 and Y2 is independently selected from C 1-10 alkylene, NH, -N(C 1-6 alkyl)-, O, C(O), C(O)-C 1-10 alkylene-NH, NH-C 1-10 alkylene-C(O), -C(O)-C 1-10 alkylene-N(C 1-6 alkyl)-, -N(C 1-6 alkyl)-C 1-10 alkylene-C(O)-, C(O)-C 1-10 alkylene-NHC(O), C(O)NH-C 1-10 alkylene-C(O), -C(O)-C 1-10 alkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1-10 alkylene-C(O)-, C(O)-C 1-10 alkylene, C 1- 10 alkylene-C(O), covalent bond, amino acid, (C2H4-O) d and (O-C2H4) d , where each alkyl and alkylene is unsubstituted or substituted by at least one substituent independently selected from R XY ; d is an integer selected from 1 to 10; Preferably, each of Y1 and Y2 is independently selected from a covalent bond, C 1-10 alkylene, C(O), C(O)-C 1-10 alkylene-NH, C(O)-C 1-10 alkylene, (O-C2H4) d , NH, (C2H4-O) d and C 1-10 alkylene-C(O).

6. The FAP-binding compound or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug thereof according to any one of claims 1-5, characterized in that (Y1) n1 Structure and (Y2) n2 Structures are each independently selected from a covalent bond, C(O)-C 1-10 alkylene-NH, NH-C 1-10 alkylene-C(O), C(O)-C 1-10 alkylene-C(O), C(O)-(C2H4-O) d -C 1-10 alkylene-NH, NH-C 1-10 alkylene-(O-C2H4) d -C(O), C(O)-C 1-10 alkylene-(O-C2H4) d -NH, NH-(C2H4-O) d -C 1-10 alkylene-C(O), C(O)-C 1-10 alkylene-(C2H4-O) d -C 1-10 alkylene-NH, NH-C 1-10 alkylene-(O-C2H4) d -C 1-10 alkylene-C(O), C(O)-C 1-10 alkylene-(O-C2H4) d -C 1-10 alkylene-NH and NH-C 1-10 alkylene-(C2H4-O) d -C 1-10 alkylene-C(O); In particular, d is 5.

7. The FAP-binding compound or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug thereof according to any one of claims 1-6, characterized in that Z is an amino acid; Preferably, Z is selected from glutamic acid, aspartic acid, lysine and serine; In particular, Z is selected from glutamic acid and lysine.

8. The FAP-binding compound or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug thereof according to any one of claims 1-7, characterized in that L is selected from DOTA, NOTA, DOTAGA, NETA, HBED-CC, TETA and CB-TE2A; Preferably, L is selected from DOTA and DOTAGA.

9. The FAP-binding compound or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug thereof according to any one of claims 1-8, characterized in that R1 and R2 are each independently selected from H and halogen; Preferably, R1 and R2 are F.

10. The FAP-binding compound or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug thereof according to any one of claims 1-9, characterized in that m1 and m2 are each independently an integer selected from 0 to 5; n1 and n2 are each independently an integer selected from 0 to 3; Preferably, m1 and n1 are not both 0, and m2 and n2 are not both 0.

11. The FAP-binding compound or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug thereof according to any one of claims 1-10, selected from 12. A metal complex of an FAP-binding compound or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug thereof as described in claim 1, It is characterized in that The metal complex has a structure shown in formula (II): wherein M is a metal; X1, X2, A1, A2, Y1, Y2, Z, L, R1, R2, m1, m2, n1 and n2 are as defined in claim 1.

13. The metal complex according to claim 12, characterized in that M is a radioactive isotope metal; Preferably, M is any one of Ga, Cu, Lu, Y, Ac, Bi, In, Pb or Tb; More preferably, M is any one of Ga-68, Cu-64, Lu-177, Y-90, Y-86, Ac-225, Bi-213, In-111, Cu-67, Pb-212 and Tb-161; In particular, M is Ga-68.

14. The metal complex according to claim 12 or 13, selected from 15. A pharmaceutical composition comprising an FAP-binding compound as described in any one of claims 1-11 or a metal complex as described in any one of claims 12-14, and at least one pharmaceutically acceptable carrier.

16. Use of an FAP-binding compound as described in any one of claims 1-11 or a metal complex as described in any one of claims 12-14 for the preparation of an imaging agent.

17. The use according to any one of claims 15 - 16, characterized in that, The imaging is carried out by positron emission tomography (PET).

18. The use according to any one of claims 15-17, characterized in that, The cells or tissues are in vivo or in vitro.

19. The use according to any one of claims 15 to 18, characterized in that, The imaging agent is an imaging agent for cancer, tumor or neoplasm.

20. Use of an FAP-binding compound as described in any one of claims 1-11 or a metal complex as described in any one of claims 12-14 or the pharmaceutical composition of claim 15 for the preparation of a drug for treating a disease, disorder or condition selected from diseases with overexpression of FAP, and the FAP-binding compound or metal complex or pharmaceutical composition is optionally used in combination with a second therapeutic agent.

21. The use according to claim 20, characterized in that, The diseases with overexpression of FAP are cancer, tumor or neoplasm.

22. Use according to claim 19 or 21, characterized in that The cancers include any one or more of eye cancer, rectal cancer, colon cancer, cervical cancer, prostate cancer, breast cancer, bladder cancer, oral cancer, gastric cancer, liver cancer, pancreatic cancer, lung cancer, uterine cancer, ovarian cancer, testicular cancer, kidney cancer, brain cancer, central nervous system cancer, throat cancer, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing sarcoma, Kaposi sarcoma, basal cell carcinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, nephroblastoma, neuroblastoma, esophageal cancer, laryngeal cancer, lymphoma, neurofibroma, tuberous sclerosis, hemangioma or lymphoma.

Images