Long-acting FAP binder, metal complex, and use thereof

Abstract

A fibroblast activation protein (FAP) binding compound and a radioisotope complex thereof. Also disclosed is an FAP binder. Also disclosed are a metal complex of the FAP binder, a use method therefor, and a use thereof. The FAP binder and the metal complex thereof have a novel chemical structure, making it easier to introduce radionuclides for clinical treatment; the present invention can be widely used in radioactive targeted therapy for FAP expression.

Description

Long-acting fap binders, metal complexes and uses thereof TECHNICAL FIELD

[0001] The present application relates to the field of radiopharmaceutical chemistry, in particular to a radioisotope labeled fibroblast activation protein (FAP) binder, metal complex and uses thereof. BACKGROUND

[0002] Cancer is one of the major causes of public health safety, and it is causing an increasingly heavy burden on the global health system. Every year, there are more than 10 million people dying from cancer, accounting for one sixth of the global death toll. According to the cancer prediction data released by the WHO IARC Cancer Agency in 2024, it is estimated that the number of people dying from cancer worldwide will exceed 180 million by 2050, an increase of about 90% compared with the number of people in 2020, and the number of new cancer patients worldwide will reach 35 million, an increase of 81.4% compared with 2020. Global environmental problems and dietary problems are the reasons for the increase in this prediction index. Therefore, it is urgent to promote global anti-cancer treatment actions to solve the increasingly heavy health burden. With the rise and development of nuclear medicine, the use of nuclear medicine imaging technology can detect lesions in the whole body early and accurately, providing better diagnostic reference for clinicians in treatment. Nuclear medicine is a discipline that applies nuclear science and technology to the diagnosis and treatment of diseases, and its clinical applications are very wide, including diagnostic applications such as tumor, cardiovascular, brain, and skeletal imaging diagnosis; therapeutic applications include thyroid disease, tumor treatment, and targeted therapy. Through the combination of special drugs of radionuclides, it is called nuclear medicine. Cancer-associated fibroblasts (CAFs) are an important component of tumor stroma, which stimulates hypoxia or activates oxidative stress to release growth factors. CAFs highly express surface markers such as fibroblast activation protein (FAP), which plays a key role in tumor occurrence, development, metastasis, and treatment resistance. FAP is a type II transmembrane serine protease belonging to the prolyl oligopeptidase family, which is highly expressed on the surface of 90% of epithelial tumor CAFs and some sarcoma cells (fibrosarcoma, leiomyosarcoma, osteosarcoma, etc.). It is also highly expressed in diseases characterized by interstitial tissue activation, such as infectious, inflammatory, fibrotic diseases, and healing wounds, while it is not expressed or expressed at low levels in normal tissues and benign tumor stroma. Molecular targeted drugs are drugs with a clear mechanism of action, and this mechanism has good differentiation between tumor cells and normal cells. FAP has the characteristics of high expression in various malignant tumors, high tumor uptake, and low normal tissue background, which can be used as an effective molecular target for tumor diagnosis and treatment. The development of FAP-specific inhibitors (FAPI), which only specifically bind to FAP, is a new class of radiopharmaceuticals that can be used as molecular targeted diagnostic and therapeutic probes, and has broad application prospects in clinical practice. Some FAP inhibitors (FAPI) have been developed, which are small molecule enzyme activity inhibitors.FAP inhibitors (FAPI) have high affinity and high tumor accumulation for FAP on the surface of CAF membrane, which can be used for PET imaging, has high sensitivity, and is conducive to the non-invasive early diagnosis, staging, differential diagnosis and prognosis evaluation of FAP expression positive diseases, and can promote the improvement of clinical diagnosis rate and treatment survival rate, but still needs to overcome the defects of low affinity, short tumor retention time and insufficient specificity for treatment.

[0003] Based on the high specific uptake of FAPI in tumors, the diagnosis and treatment integration targeting FAP has gradually become a new direction of current research. Targeted radioligand therapy can produce significant effects on tumor cells by combining targeted compounds with therapeutic radionuclides. When the drug binds to FAP-expressing fibroblasts, beta rays are generated by radionuclide decay, thereby killing tumor cells. This innovative therapy has less damage to surrounding healthy tissue cells and has a highly selective tumor-killing effect. At present, FAPI is mainly labeled with therapeutic radionuclides such as 177 Lu、 90 Y、 188 Re、 225 Ac, and the structure of FAPI is further optimized to improve the selectivity and retention time of tumors. 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 and can be used to design tumor-targeted internal irradiation therapy targeting FAP. However, research shows that the clearance of FAPI is the result of the interaction of multiple processes, and there is no definitive method to ensure retention time. On the other hand, repeated treatment with FAPI labeled with short half-life radionuclides such as 188 Re、 213 Bi may be a new research idea, which can significantly improve tumor-specific uptake and retention while maintaining rapid clearance of non-target organs in the body, and shows good tumor inhibition effect. The diagnosis and treatment integration FAPI probe has a very promising role in promoting the application of clinical tumor treatment. SUMMARY

[0004] In one aspect, a compound of Formula (I) is provided:

[0005] wherein,

[0006] X1and X2are each independently selected from NH, NR, O, or S, wherein R is C 1-6 alkyl;

[0007] each A1and A2is independently selected from C 1-10 alkylene, NH, -N(C 1-6 alkyl)-, O, S, C(O), C(S), C(O)-C 1-10alkylene-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 with at least one substituent independently selected from R XA ;

[0008] each Y1and Y2is each 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 1-10alkylene-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 with at least one substituent independently selected from R XY

[0009] Z is selected from C 1-10 hypoalkylene, N, C(O)-C 1-10 hypoalkylene-NH, NH-C 1-10 hypoalkylene-C(O), -C(O)-C 1-10 hypoalkylene-N(C 1-6 alkyl)-, -N(C 1-6 alkyl)-C 1-10 hypoalkylene-C(O)-, C(O)-C 1-10 hypoalkylene-NHC(O), C(O)NH-C 1-10 hypoalkylene-C(O), -C(O)-C 1-10 hypoalkylene-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1- 10 hypoalkylene-C(O)-, C(O)-C 1-10 hypoalkylene-NHC(S), C(S)NH-C 1-10 hypoalkylene-C(O), -C(O)-C 1-10 hypoalkylene-N(C 1-6 alkyl)C(S)-, -C(S)N(C 1-6 alkyl)-C 1-10 hypoalkylene-C(O)-, C(O)-C 1-10 hypoalkylene, C 1-10 hypoalkylene-C(O), NH-C 1-10 hypoalkylene-NH, -NH-C 1-10 hypoalkylene-N(C 1-6 alkyl)-, -N(C 1-6 alkyl)-C 1-10 hypoalkylene-NH-, -N(C 1-6 alkyl)-C 1-10 hypoalkylene-N(C 1-6 alkyl)-, amino acid, and amino acid sequence, wherein each alkyl and hypoalkylene is unsubstituted or substituted with at least one substituent independently selected from R​XZ Substituents substituted;

[0010] L is a metal chelating agent;

[0011] R1 and R2 are each independently selected from H, halogen or C 1-6 alkyl;

[0012] 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;

[0013] m1 is an integer selected from 0 to 10;

[0014] m2 is an integer selected from 0 to 10;

[0015] n1 is an integer selected from 0 to 10;

[0016] n2 is an integer selected from 0 to 10.

[0017] In one aspect, a metal complex of a compound of formula (I) is provided, having a structure as shown in formula (II):

[0018] Wherein, M is metal;

[0019] X1, X2, A1, A2, Y1, Y2, Z, L, R1, R2, m1, m2, n1 and n2 are as defined in formula (I).

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

[0021] In one embodiment, the compound of formula (I) is a FAP binding agent. In one embodiment, the compound of formula (II) is a metal complex of a FAP binding agent.

[0022] In one aspect, there is provided a use of the compound of formula (II) for the manufacture of an imaging agent or theranostic probe.

[0023] In one aspect, there is provided a pharmaceutical composition comprising a compound of the present application, and at least one pharmaceutically acceptable carrier.

[0024] In one aspect, there is provided a use of a compound of the present application or a pharmaceutical composition of the present application for the manufacture of a medicament for treating a disease with FAP overexpression. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 is the MS spectrum of intermediate compound A3;

[0026] Figure 2 is the MS spectrum of intermediate compound A5;

[0027] Figure 3 is the HPLC spectrum of FAPI-FUSCC-02-DIMER;

[0028] Figure 4 is the LC-MS spectrum of FAPI-FUSCC-02-DIMER;

[0029] Figure 5 is 177 the radio-HPLC spectrum of Lu-FAPI-FUSCC-02-DIMER;

[0030] Figure 6 is 177 the radio-iTLC spectrum of Lu-FAPI-FUSCC-02-DIMER;

[0031] Figure 7 is 177 the radio-iTLC spectrum of Lu-FAPI-FUSCC-02-DIMER;

[0032] Figure 8 is 177 the stability profile of Lu-FAPI-FUSCC-02-DIMER in normal saline;

[0033] Figure 9 is the MS spectrum of compound 4-2;

[0034] Figure 10 is a MS spectrum of compound 4-3;

[0035] Figure 11 is a FAPI-FX-01 HPLC spectrum;

[0036] Figure 12 is a FAPI-FX-01 HPLC spectrum;

[0037] Figure 13 is a MS spectrum of compound 5-2;

[0038] Figure 14 is a MS spectrum of compound 5-3;

[0039] Figure 15 is a MS spectrum of compound 5-6;

[0040] Figure 16 is a FAPI-FX-02 HPLC spectrum;

[0041] Figure 17 is a FAPI-FX-02 MS spectrum;

[0042] Figure 18 is a MS spectrum of compound 6-1;

[0043] Figure 19 is a MS spectrum of compound 6-2;

[0044] Figure 20 is a FAPI-FX-03 HPLC spectrum;

[0045] Figure 21 is a FAPI-FX-03 MS spectrum;

[0046] Figure 22 is a MS spectrum of compound 7-1;

[0047] Figure 23 is a MS spectrum of compound 7-2;

[0048] Figure 24 is a MS spectrum of compound 7-3;

[0049] Figure 25 is a FAPI-FX-04 HPLC spectrum;

[0050] Figure 26 is a FAPI-FX-04 MS spectrum;

[0051] Figure 27 is a MS spectrum of compound 8-1;

[0052] Figure 28 is a MS spectrum of compound 8-2;

[0053] Figure 29 is a MS spectrum of compound 8-3;

[0054] Figure 30 is a FAPI-FX-05 HPLC spectrum;

[0055] Figure 31 is a FAPI-FX-05 MS spectrum;

[0056] Figure 32 is a MS spectrum of compound 9-1;

[0057] Figure 33 is a MS spectrum of compound 9-2;

[0058] Figure 34 is a HPLC spectrum of FAPI-FX-06;

[0059] Figure 35 is a mass spectrum of FAPI-FX-06;

[0060] Figure 36 is a MS spectrum of compound 10-1;

[0061] Figure 37 is a MS spectrum of compound 10-2;

[0062] Figure 38 is a HPLC spectrum of FAPI-FX-07;

[0063] Figure 39 is a mass spectrum of FAPI-FX-07;

[0064] Figure 40 is a MS spectrum of compound 11-1;

[0065] Figure 41 is a MS spectrum of compound 11-2;

[0066] Figure 42 is a MS spectrum of compound 11-3;

[0067] Figure 43 is a MS spectrum of compound 11-4;

[0068] Figure 44 is a HPLC spectrum of FAPI-FX-08;

[0069] Figure 45 is a mass spectrum of FAPI-FX-08;

[0070] Figure 46 is a MS spectrum of compound 12-2;

[0071] Figure 47 is a MS spectrum of compound 12-3;

[0072] Figure 48 is a MS spectrum of compound 12-4;

[0073] Figure 49 is a HPLC spectrum of FAPI-FX-09;

[0074] Figure 50 is a mass spectrum of FAPI-FX-09;

[0075] Figures 51 to 59 are, in this order, 68 Ga-FAPI-FX-01, 68 Ga-FAPI-FX-02, 68 Ga-FAPI-FX-03, 68 Ga-FAPI-FX-04, 68 Ga-FAPI-FX-05, 68 Ga-FAPI-FX-06, 68Ga-FAPI-FX-07, 68 Ga-FAPI-FX-08, 68 Ga-FAPI-FX-09;

[0076] Figures 60 to 63 are, in sequence, Radio-TLC chromatograms of 177 Lu-FAPI-FX-02, 177 Lu-FAPI-FX-06, 177 Lu-FAPI-FX-07, 177 Lu-FAPI-FX-08;

[0077] Figures 64 to 72 are, in sequence, Radio-TLC chromatograms of 68 Ga-FAPI-FX-01, 68 Ga-FAPI-FX-02, 68 Ga-FAPI-FX-03, 68 Ga-FAPI-FX-04, 68 Ga-FAPI-FX-05, 68 Ga-FAPI-FX-06, 68 Ga-FAPI-FX-07, 68 Ga-FAPI-FX-08, 68 Ga-FAPI-FX-09;

[0078] Figures 73 to 81 are, in sequence, LogP plots of 68 Ga-FAPI-FX-01, 68 Ga-FAPI-FX-02, 68 Ga-FAPI-FX-03, 68 Ga-FAPI-FX-04, 68 Ga-FAPI-FX-05, 68 Ga-FAPI-FX-06, 68 Ga-FAPI-FX-07, 68 Ga-FAPI-FX-08, 68 Ga-FAPI-FX-09 in HT-1080-FAP cells;

[0079] Figures 82 to 85 are, in sequence, Uptake of 177 Lu-FAPI-FX-02, 177 Lu-FAPI-FX-06, 177 Lu-FAPI-FX-07, 177 Lu-FAPI-FX-08 in HT-1080-FAP cells;

[0080] Figure 86 168 Micro-PET / CT images of Ga-FAPI-FX-01 at 1, 2, and 4 hours after inoculation into the HT-1080-FAP tumor-bearing mouse model, as well as semi-quantitative analysis of tumor regions of interest in Micro-PET / CT images;

[0081] Figure 87 68 Micro-PET / CT images of Ga-FAPI-FX-07 at 1, 2, and 4 hours after inoculation into the HT-1080-FAP tumor-bearing mouse model, as well as semi-quantitative analysis of tumor regions of interest in Micro-PET / CT images;

[0082] Figure 88 is 177 SPECT / CT imaging of Lu-FAPI-FUSCC-02-DIMER in the HT1080-FAP overexpressing tumor model for monitoring treatment;

[0083] Figure 89 177 Micro-SPECT / CT imaging of Lu-FAPI-FX-07 (n=3);

[0084] Figure 90 is 177 Tumor volume curve of Lu-FAPI-FUSCC-02-DIMER in the HT1080-FAP overexpression tumor model;

[0085] Figure 91 is 177 The therapeutic weight curve of Lu-FAPI-FUSCC-02-DIMER on HT1080-FAP overexpression tumor model;

[0086] Figure 92 177 Radioactive HPLC spectrum of Lu-FAPI-FUSCC-02;

[0087] Figure 93 177 SPECT / CT imaging of Lu-FAPI-FUSCC-02 therapy monitoring in HT1080-FAP overexpressing tumor models;

[0088] Figure 94 is 177 Tumor volume curve of Lu-FAPI-FUSCC-02 in the HT1080-FAP overexpression tumor model;

[0089] Figure 95 177 The body weight curve of Lu-FAPI-FUSCC-02 in the HT1080-FAP overexpression tumor model. DETAILED DESCRIPTION

[0090] The embodiments of the present application are described in detail below with reference to the accompanying drawings.

[0091] The following describes the embodiments of the present application through specific examples, and those skilled in the art can easily understand other advantages and effects of the present application from the contents disclosed in this specification. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. The present application can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present application. It should be noted that, in the absence of conflict, the features in the following embodiments and embodiments can be combined with each other. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without making creative work are within the scope of protection of this application.

[0092] definition

[0093] 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.

[0094] 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 、C 1-9, and C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 The 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.

[0095] When any variable (e.g., R XA ) occurs more than one time in a compound or substituent, its XA each occurrence is independent. For example, the expression "each R XA is independently selected from" means that if there are multiple R XA substituents, each occurrence of each R XY substituent is independently selected from the options listed. Other variables or expressions such as R XZ , A1, A2, Y1, Y2, A, X, and Y should also be understood in a similar manner.

[0096] "one" or "this" or "that" or the like, includes a plural unless the context clearly dictates otherwise. The expressions "one or more" or "at least one" can mean 1, 2, 3, 4, 5, 6, 7, 8, 9, or more. In one embodiment, "at least one" means 1, 2, 3, or 4.

[0097] The term "optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0098] The terms "substituted" and "substitution" mean the replacement of one or more (e.g., one, two, three, or four) hydrogens on the designated atom with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that 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 substitution is described as not occurring, it is understood that the substitution group can be one or more hydrogen atoms, provided that the structure results in a stable compound.

[0099] Unless otherwise indicated, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent. When a bond to a substituent is shown as a dashed line, then such substituent can be bonded to any of the available ring members in the ring to which it is shown to be bonded.

[0100] 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."

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] "Alkylene" or "alkylidene" refers to a saturated divalent hydrocarbon radical. Alkylene groups include straight chain or branched chain alkylene groups. Examples of straight chain alkylene groups 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 groups 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)-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-, and the like.

[0106] A trivalent group refers to a group obtained by removing one hydrogen atom from a carbon atom having a free valence electron of a corresponding divalent group. A trivalent group has three attachment sites to the rest of the molecule, wherein the three attachment sites can be on the same or different atoms of the trivalent group.

[0107] An "alkylidyne" refers to a saturated trivalent hydrocarbon group. Alkylidynes include straight chain or branched chain alkylidynes.

[0108] The terms "FAP binding compound" and "FAP binding agent" have the same meaning and are used interchangeably and refer to a compound having an affinity activity for FAP. Affinity activity can also be verified by known methods. Affinity activity can also be detected by selecting known methods, such as proximity ligation assay, fluorescence resonance energy transfer, fluorescence polarization detection, fluorescence molecular beacons, microscale thermophoresis, chemiluminescence, surface plasmon resonance, isothermal titration calorimetry, oblique-incidence reflectance difference, and any combination thereof.

[0109] The term "amino acid" refers to naturally occurring, synthetic and non-natural amino acids, as well as amino acid analogs that function in a similar manner as naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those modified later, such as hydroxyproline, gamma-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds having the same basic chemical structure as naturally occurring amino acids, i.e., an alpha carbon bonded to a hydrogen, a carboxyl, an amino, and an R' group, such as homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. Such analogs have a modified R' group (e.g., norleucine) or a modified peptide backbone, but retain the same basic chemical structure as naturally occurring amino acids. In a particular embodiment, the amino acid is selected from the group consisting of 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 an embodiment, the amino acid is in the L-configuration.

[0110] The term "metal complex" refers to a complex formed by a metal atom or ion and a compound through a coordinate bond. 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 Lu-177, Y-90, Ac-225, Bi-213, and Re-188.

[0111] Chelating agents are polydentate ligands having two or more (e.g., 2 to 15, particularly 4, 6, or 8) coordinating atoms. Chelates are complexes having cyclic structures formed by the combination of a central ion and a polydentate ligand through coordinate bonds.

[0112] Pharmaceutically acceptable salts of the compounds of the present application include both acid and base addition salts. Methods for preparing pharmaceutically acceptable salts of the compounds of the present application are known to those of skill in the art.

[0113] The compounds of the present application encompass pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopically enriched compounds, metabolites, or prodrugs thereof.

[0114] Metal complexes of the compounds of the present application encompass linkage isomers, coordination isomers, and stereoisomers thereof.

[0115] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds. For example, the compounds of the present application can exist in either the E or Z conformation about carbon-carbon double bonds or carbon-nitrogen double bonds, where "E" represents the more substituted groups being 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 more substituted groups being on the same side of the carbon-carbon double bond or carbon-nitrogen double bond. The compounds of the present application can also exist as mixtures of the "E" and "Z" isomers. Isomeric forms also include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, as well as racemic mixtures and other mixtures of the enantiomers or diastereomers, all of which are intended to be within the scope of the present application. Purification and separation of such materials can be achieved by standard techniques known in the art.

[0116] Optically pure enantiomers can be obtained from racemic mixtures according to conventional procedures, for example by forming diastereomeric salts with an optically active acid, or base, or by resorting to covalent diastereomeric derivatives. Mixtures of diastereomers can be separated by methods known in the art, for example by chromatography or fractional crystallization based on the differences in solubility of the individual diastereomers. The optically active bases or acids are then liberated from the separated diastereomeric salts. Another method of separating racemic enantiomers is by chiral chromatography (for example chiral HPLC columns), the separated chiral isomers can or can not be derivatized prior to separation, depending on which method allows for more efficient separation of the chiral isomers. Enzymatic methods can also be used to separate derivatized or non-derivatized chiral isomers. Likewise, optically pure compounds of the present application can be obtained by chiral synthesis using optically pure starting materials.

[0117] The compounds of the present application can exist as solvates, wherein the compounds of the present application contain a solvent as an integral component in the crystal lattice of the compound, in particular, for example, water, methanol or ethanol. The amount of solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts.

[0118] The present application also encompasses all possible crystalline forms or polymorphs of the compounds of the present application, which can be a single polymorph or a mixture of more than one polymorph in any ratio.

[0119] The FAP binding compounds of the present application can exist in isotopically-labeled or enriched forms, comprising one or more atoms differing from the most abundant atomic mass and mass number in nature.

[0120] Metabolites of the compounds of the present application, i.e., substances formed in the body after administration of the compounds of the present application, are also within the scope of the present application. Such products can result, for example, from oxidation, reduction, hydrolysis, am idation, deam idation, esterification, enzymatic cleavage, and the like.

[0121] The present application further includes within its scope prodrugs of the compounds of the present application, which are certain derivatives of the compounds of the present application that have less or no pharmacological activity as such but, when administered into or onto the body, are converted into the compounds of the present application having the desired activity, for example, by hydrolytic cleavage.

[0122] The term "polymorph" or "polymorphs" refers to a single polymorph or a mixture of more than one polymorph in any ratio.

[0123] The term "crystal form" or "crystal" refers to any solid material that exhibits a three-dimensional order, in contrast to amorphous solid material, which produces a characteristic X-ray powder diffraction pattern with well-defined peaks.

[0124] The term "amorphous" refers to any solid substance without ordering in three dimensions.

[0125] The term "pharmaceutically acceptable" means, within the scope of sound medical judgment, that the material is not biologically or otherwise undesirable, i.e., with respect to irritation, allergic response, the formation of immune responses, and the like.

[0126] The term "pharmaceutically acceptable carrier" means a material that is not biologically or otherwise undesirable, i.e., with respect to irritation, allergic response, the formation of immune responses, and the like, and does not abrogate the biological activity and properties of the active compound. Pharmaceutically acceptable carriers include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, tablet-disintegrating agents, stabilizers, solvents, or emulsifiers.

[0127] The term "active ingredient," "therapeutic agent," "active substance," or "active agent" refers to a chemical entity that is effective in treating or preventing a disorder, disease, or condition of interest.

[0128] The term "overexpressed" refers to an increase compared to normal levels. "Overexpression of FAP" is intended to mean an abnormal level of FAP in cells from a disease area that is higher than the normal level of expression in cells of the relevant particular tissue or organ.

[0129] The term "effective amount," "therapeutically effective amount," or "prophylactically effective amount" with respect to a drug, pharmaceutical unit, or active ingredient means a sufficient amount of the drug or agent to provide a desired effect, with acceptable side effects. Determination of an effective amount is within the ordinary skill in the art and will depend on the age and general condition of the individual, as well as the particular active substance, and can be determined by routine testing.

[0130] The term "individual" includes a human or non-human animal. Exemplary human individuals include a human individual (referred to as a patient) who has a disease, such as a disease described herein, or a normal individual. "Non-human animals" in the present application include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles) and mammals (e.g., non-human primates, livestock and / or domestic animals, e.g., sheep, dogs, cats, cows, pigs, etc.).

[0131] Compounds of formula (I)

[0132] The present application satisfies the need for new specific compounds for tumor tissue, and their use in nuclear medicine as broad-spectrum tumor treatment drugs; in particular, the present application provides compounds that differ from the prior art in terms of modification, which were previously unknown or not suggested. The new compounds have better tissue specificity, longer in vivo retention properties.

[0133] The technical scheme adopted by the present application to achieve the above-mentioned purpose is: a FAP binding agent, having a structure as shown in formula (I), and pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites and prodrugs of the compound.

[0134] Therefore, in one aspect, the present application provides a compound having the structure of formula (I):

[0135] wherein,

[0136] X1and X2are each independently selected from NH, NR, O and S, wherein R is C 1-6 alkyl;

[0137] each A1and A2is 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 with at least one substituent independently selected from R XA ;

[0138] each Y1and Y2is 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;

[0139] 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;

[0140] L is a metal chelating agent;

[0141] R1 and R2 are each independently selected from H, halogen or C 1-6 alkyl;

[0142] 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;

[0143] m1 is an integer selected from 0 to 10;

[0144] m2 is an integer selected from 0 to 10;

[0145] n1 is an integer selected from 0 to 10;

[0146] n2 is an integer selected from 0 to 10.

[0147] In one embodiment, the compound of formula (I) is a FAP binding agent.

[0148] In one embodiment, each R XA , R XY and R XZ is 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 one embodiment, each R XA , R XY and R XZ is independently selected from halogen, NO2, -CN and C 1-10 alkyl, in particular from halogen and C 1-10 alkyl.

[0149] In one embodiment, the C 1-10 alkylene is C 1-6 alkylene, for example C 1-3 alkylene, in particular methylene or ethylene. In one embodiment, the C 1-10 hypoalkylene is C 1-6 hypoalkylene, for example C 1-3 hypoalkylene, in particular hypomethyl or CHCH2.

[0150] In one embodiment, m1 and m2 are each independently an integer selected from 0 to 5, in particular 3. In one embodiment, n1 and n2 are each independently an integer selected from 0 to 3. In one embodiment, m1 and n1 are not simultaneously 0 and m2 and n2 are not simultaneously 0.

[0151] In an embodiment, each amino acid sequence in formula (I) is independently an amino acid sequence comprising 1 to 10 amino acids.

[0152] In an embodiment, each polyethylene glycol chain in formula (I) is independently a polyethylene glycol chain comprising 1 to 10 ethylene glycol building blocks.

[0153] In an embodiment, each ethylene glycol building block is independently (C2H4-O) or (O-C2H4).

[0154] In an embodiment, each polyethylene glycol chain in formula (I) is independently selected from the group consisting of (C2H4-O) d and (O-C2H4) d , d is an integer selected from 1 to 10.

[0155] In an embodiment, X1and X2are each independently NH, NR or O. In an embodiment, R is C 1- 6alkyl, in particular methyl. In an embodiment, X1and X2are NH. In an embodiment, X1and X2are O.

[0156] In an embodiment, each A1and A2is independently selected from the group consisting of 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 is unsubstituted or substituted with at least one substituent independently selected from R XA .

[0157] In an embodiment, each A1and A2is independently selected from the group consisting of C 1-10 alkylene, NH, -N(C1-6 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, and an amino acid, wherein each alkyl and alkylene is unsubstituted or substituted with at least one substituent independently selected from R XA .

[0158] In a particular embodiment, each alkylene in A1and A2is methylene, which is unsubstituted or substituted with at least one substituent independently selected from R XA . In an embodiment, each A1and A2is each independently a covalent bond. In an embodiment, each A1and A2is each independently selected from a covalent bond and an amino acid. In an embodiment, each amino acid in A1and A2is each independently selected from glycine, aspartic acid, glutamine, alanine, valine, and phenylglycine. In a particular embodiment, each amino acid in A1and A2is each independently selected from alanine, valine, and phenylglycine. In a particular embodiment, each amino acid in A1and A2is each independently selected from glycine, aspartic acid, and glutamine. In a particular embodiment, each amino acid in A1and A2is glycine.

[0159] In an embodiment, each A1is each independently selected from a covalent bond, Gly, Asp, Gln, Ala, Phg, and Val. In an embodiment, each A2is each independently selected from a covalent bond, Gly, Asp, Gln, and Ala. Wherein, Gly represents glycine, Asp represents aspartic acid, Gln represents glutamine, Ala represents alanine, Phg represents phenylglycine, and Val represents valine.

[0160] In an embodiment, (A1) m1 structure and (A2) m2The structures are each independently selected from a covalent bond, (Gly) h , Ala, Gly-Asp-Gln, Gln-Asp-Gly, Ala-Phg-Val and Val-Phg-Ala, wherein h is an integer selected from 1 to 10. In one embodiment, (A1) m1 Structure and (A2) m2 The structures are each independently selected from the group consisting of a covalent bond and (Gly) h , wherein h is an integer selected from 1 to 10. wherein Gly represents glycine. In one embodiment, h is an integer selected from 1 to 5. In a particular embodiment, h is 1. In a particular embodiment, h is 3. In a particular embodiment, h is 5. 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. In one embodiment, (A1) m1 Structure and (A2) m2 The structure is (Gly) 3. In one embodiment, (A1) m1 Structure and (A2) m2 The structure is (Gly) 5. In one embodiment, (A1) m1 The structure is Gly-Asp-Gln. In one embodiment, (A2) m2 The structure is Gln-Asp-Gly. In one embodiment, (A1) m1 The structure is selected from Ala and Ala-Phg-Val. In one embodiment, (A2) m2 The structure is Ala.

[0161] 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(C1-6 alkyl)-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 with at least one substituent independently selected from R XY

[0162] In one embodiment, each Y1and Y2is each 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 is unsubstituted or substituted with at least one substituent independently selected from R XY d is an integer selected from 1 to 10. In one embodiment, d is an integer selected from 3 to 7, in particular 5.

[0163] In a particular embodiment, each alkylene in Y1and Y2is methylene, which is unsubstituted or substituted with at least one substituent independently selected from R XY ​substituted. In one embodiment, each Y1and Y2is each independently a covalent bond. In one embodiment, each Y1and Y2is each independently selected from a covalent bond and an amino acid. In one embodiment, each amino acid in Y1and Y2is each independently selected from glycine, aspartic acid, glutamine, alanine, valine, and phenylglycine. In a particular embodiment, each amino acid in Y1and Y2is each independently selected from alanine, valine, and phenylglycine. In a particular embodiment, each amino acid in Y1and Y2is each independently selected from glycine, aspartic acid, and glutamine. In a particular embodiment, each amino acid in Y1and Y2is glycine. In one embodiment, each Y1and Y2is each independently selected from a covalent bond, C 1-10 alkylene, C(O), C(S), NH, (C2H4-O) d , (O-C2H4) d , C(O)-C 1-10 alkylene-NH, NH-C 1-10 alkylene-C(O), C(O)-C 1-10 alkylene, and C 1-10 alkylene-C(O).

[0164] In one embodiment, each Y1is each independently selected from a covalent bond, C 1-10 alkylene, C(O), C(S), C(O)-C 1-10 alkylene-NH, C(O)-C 1-10 alkylene, (O-C2H4) d , and NH.

[0165] In one embodiment, each Y2is each independently selected from a covalent bond, C 1-10 alkylene, C(O), C(S), NH, (C2H4-O) d , and C 1-10 alkylene-C(O).

[0166] In one embodiment, (Y1) n1 structure and (Y2) n2 structure is each independently selected from a covalent bond, C(O)-C 1-10 alkylene-NH, -C 1-10 alkylene-NH-C(O)-C 1-10 alkylene-NH-, -NH-C 1-10 alkylene-C(O)-NH-C 1-10 alkylene-, NH-C 1-10 alkylene-C(O), -NH-C 1-10 alkylene-C(O)-NH-C 1-10 alkylene-, C(O)-C1-10 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, NH-C 1-10 Alkylene-(C2H4-O) d -C 1-10 Alkylene-C(O), -C 1-10 Alkylene-NH-, -NH-C 1-10 Alkylene-, -C(S)-NH-C 1-10 Alkylene-NH- and -NH-C 1-10 Alkylene-NH-C(S)-.

[0167] In one embodiment, (Y1) n1 The structure is selected from covalent bond, C(O)-C 1-10 Alkylene-NH, C(O)-C 1-10 Alkylene-(O-C2H4) d -NH, C(O)-C 1-10 Alkylene-C(O), -C 1-10 Alkylene-NH-C(O)-C 1-10 Alkylene-NH- and -C(S)-NH-C 1-10 Alkylene-NH-.

[0168] In one embodiment, (Y1) n1 The structure is selected from the group consisting of a covalent bond, C(O)-(CH2)3-NH, C(O)-CH2-(O-C2H4)5-NH, C(O)-(CH2)3-C(O), -(CH2)2-NH-C(O)-CH2-NH- and -C(S)-NH-(CH2)4-NH-. In one embodiment, (Y2)n2 The structure is selected from covalent bond, C(O)-C 1-10 Alkylene-C(O), -NH-(C2H4-O) d -C 1-10 Alkylene-C(O)-, NH-C 1-10 Alkylene-C(O), -NH-C 1-10 Alkylene-C(O)-NH-C 1-10 Alkylene- and -NH-C 1-10 Alkylene-NH-C(S)-. In one embodiment, (Y2) n2 The structure is selected from the group consisting of a covalent bond, C(O)-(CH2)3-C(O), -NH-(C2H4-O)5-CH2-C(O), NH-(CH2)5-C(O), -NH-CH2-C(O)-NH-(CH2)2- and -NH-(CH2)4-NH-C(S)-. In one embodiment, (Y1) n1 The structure is C(O)-C 1-10 Alkylene-(O-C2H4) d -NH, (Y2) n2 The structure is -NH-(C2H4-O) d -C 1-10 Alkylene-C(O). In one embodiment, (Y1) n1 The structure is C(O)-C 1-10 Alkylene-NH, (Y2) n2 The structure is C(O)-C 1-10 Alkylene-C(O). In one embodiment, (Y1) n1 The structure is -C(S)-NH-C 1-10 Alkylene-NH-, (Y2) n2 The structure is -NH-C 1-10 Alkylene-NH-C(S)-. In one embodiment, (Y1) n1 The structure is C(O)-C 1-10 Alkylene-C(O),(Y2) n2 The structure is NH-C 1-10 Alkylene-C(O). In one embodiment, (Y1) n1 The structure is -C 1-10 Alkylene-NH-C(O)-C 1-10 Alkylene-NH-, (Y2) n2 The structure is -NH-C 1-10 Alkylene-C(O)-NH-C 1-10 Alkylene-.

[0169] In one embodiment, Z is selected from C 1-10Haloalkyl, -N(C 1-10 Haloalkyl, -N(C 1-10 Haloalkyl, -N(C 1-10 Haloalkyl, -N(C 1-6 Haloalkyl, -N(C 1-6 Haloalkyl, -N(C 1-10 Haloalkyl, -N(C 1-10 Haloalkyl, -N(C 1-10 Haloalkyl, -N(C 1-10 Haloalkyl, -N(C 1-6 Haloalkyl, -N(C 1-6 Haloalkyl, -N(C 1-10 Haloalkyl, -N(C 1-10 Haloalkyl, -N(C 1-10 Haloalkyl, -N(C 1-10 Haloalkyl, -N(C 1-10 Haloalkyl, -N(C 1-6 Haloalkyl, -N(C 1-6 Haloalkyl, -N(C 1-10 Haloalkyl, -N(C 1-6 Haloalkyl, -N(C 1-10 Haloalkyl, -N(C 1-6 Haloalkyl, -N(C XZ Haloalkyl, -N(C k Haloalkyl, -N(C k Haloalkyl, -N(C k Haloalkyl, -N(C k Haloalkyl, -N(C k Haloalkyl, -N(C Haloalkyl, -N(C

[0170] In an embodiment, L is selected from metal chelators, wherein the metal chelator contains a ligand moiety L0capable of coordinating to a metal, and optionally further contains a conjugation handle moiety Lkconnecting L0to the rest of the molecule. When Lkis present, L can be represented as L0-Lk. When Lkis not present, L can be represented as L0. In an embodiment, L0is selected from ligands containing 2 to 15 (e.g., 2 to 8, 4 to 8, or 6 to 8) coordinating atoms selected from N and O. In an embodiment, the coordinating atoms in L are selected from N and O. In an embodiment, L0is selected from DOTA, NOTA, DOTAGA, NETA, HBED-CC, TETA, and CB-TE2A, in particular DOTA. In an embodiment, the conjugation handle moiety Lkis 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 alkylene-C(O). In an embodiment, the conjugation handle moiety Lkis selected from C(O)(CH2) g and (CH2) g C(O), g is an integer selected from 0 to 10. In an embodiment, Lkis C(O)(CH2)2. In an embodiment, g is an integer selected from 1 to 5, in particular 2.

[0171] In an embodiment, L coordinates to M through one or more coordination bonds. In an embodiment, L coordinates to M through at least 2 (e.g., 2 to 15, in particular 4, 6, or 8) coordination bonds. In an embodiment, L coordinates to M through 6 coordination bonds.

[0172] In an embodiment, L is selected from DOTA, NOTA, DOTAGA, NETA, HBED-CC, TETA, or CB-TE2A. In a particular embodiment, L is selected from DOTA and DOTAGA. In a particular embodiment, L is

[0173] In one embodiment, R1and R2are each independently selected from H and halogen, in particular halogen. In one embodiment, R1and R2are F. In one embodiment, R1and R2are H.

[0174] In one embodiment, X1and X2are NH or O; R1and R2are F or H.

[0175] In one embodiment, each of A1and A2is selected from an amino acid; each of Y1and Y2is a covalent bond.

[0176] In one embodiment, X1and X2are NH, R1, R2are each F; A1is C(O)(CH2) i NH, A2is C(O)(CH2) i NH or NH(CH2) i C(O), i is a natural number selected from 1 to 6, m1and m2are each independently an integer selected from 1 to 5; Y1is C(O), n1is an integer selected from 1 to 3; Y2is C(O)(CH2) j or (CH2) j C(O), j is a natural number selected from 1 to 6, n2is an integer selected from 1 to 3.

[0177] In one embodiment, i is a natural number selected from 1 to 3, m1and m2are each independently an integer selected from 1 to 3; j is a natural number selected from 1 to 3, n1is an integer selected from 1 to 3, n2is an integer selected from 1 to 3.

[0178] In one embodiment, formula (I) has the structure of formula (I-1) as follows:

[0179] wherein X1, X2, A1, A2, Y1, Y2, Z, L, R1, R2, m1, m2, n1and n2are as defined in formula (I).

[0180] In one embodiment, formula (I) has the structure of formula (I-i), (I-ii), (I-iii) or (I-iv) as follows:

[0181] wherein X1, X2, A1, A2, Y1, Y2, Z, L, R1, R2, m1, m2, n1and n2are as defined in formula (I).

[0182] In one embodiment, formula (I) has the structure of formula (I-i-1), (I-ii-1), (I-iii-1) or (I-iv-1) as follows:

[0183] wherein X1, X2, A1, A2, Y1, Y2, Z, L, R1, R2, m1, m2, n1 and n2 are as defined in formula (I).

[0184] In one embodiment, the present application provides a compound selected from:

[0185] In one embodiment, the compound of formula (I) of the present application is not

[0186] a metal complex of formula (II)

[0187] The present application also discloses a metal complex of the compound of formula (I) having the structure as shown in formula (II):

[0188] wherein M is a metal;

[0189] X1, X2, A1, A2, Y1, Y2, Z, L, R1, R2, m1, m2, n1 and n2 are as defined in formula (I).

[0190] In one embodiment, the compound of formula (II) is a metal complex of a FAP binding agent.

[0191] In one embodiment, M is a radioisotope metal.

[0192] In one embodiment, M is any one of Ga, Lu, Y, Ac, Bi, Re.

[0193] In a preferred embodiment, M is any one of Ga-68, Lu-177, Y-90, Ac-225, Bi-213 and Re-188.

[0194] In a particular embodiment, M is Ga-68 or Lu-177.

[0195] In one embodiment, M is any one of Lu, Y, Ac, Bi, Re.

[0196] In a preferred embodiment, M is any one of Lu-177, Y-90, Ac-225, Bi-213 and Re-188.

[0197] In a particular embodiment, M is Lu-177.

[0198] In an embodiment, In the structure denotes complexation by one or more coordination bonds. In an embodiment, In the structure denotes complexation by at least 2 (e.g. 2 to 15) coordination bonds. In the structure may also be used, again denoting complexation by one or more coordination bonds.

[0199] In an embodiment, the structure complexed to M is a compound of formula (I) as described hereinabove.

[0200] In a particular embodiment, L is selected from DOTA and DOTAGA, and M is Lu-177; preferably, L is complexed to M by 6 coordination bonds.

[0201] In an embodiment, The structure is selected from

[0202] In an embodiment, The structure is selected from

[0203] In an embodiment, formula (II) has the structure of formula (II-1) as follows:

[0204] wherein X1, X2, A1, A2, Y1, Y2, Z, L, R1, R2, m1, m2, n1 and n2 are as defined in formula (II).

[0205] In an embodiment, the present application provides a metal complex of a compound selected from:

[0206] In an embodiment, the present application provides a metal complex of a compound selected from:

[0207] In an embodiment, the compound of formula (I) of the present application is not

[0208] ​​In one embodiment, the FAP binding agent of the present application can also be represented by formula (I'):

[0209] wherein,

[0210] X is NH, NR, O or S, wherein R is C 1-6 alkyl;

[0211] 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;

[0212] Y1and Y2are 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;

[0213] 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 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;

[0214] L is a metal chelator;

[0215] R1, R2are each independently selected from H, halogen or C 1-6 alkyl;

[0216] m is an integer selected from 0 to 10;

[0217] n1is an integer selected from 0 to 10;

[0218] n2is an integer selected from 0 to 10.

[0219] Further, in formula (I'), X is NH, R1, R2are 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; Y1is C(O), n1is an integer selected from 1 to 3; Y2is C(O)(CH2)j j is a natural number selected from 1 to 6, and n2 is an integer selected from 1 to 3.

[0220] Further, in the 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, n1 is an integer selected from 1 to 3, and n2 is an integer selected from 1 to 3.

[0221] Further, in the formula (I’), L is selected from DOTA, NOTA, DOTAGA, NETA, HEBD-CC, TETA or CB-TE2A.

[0222] In one embodiment, the metal complex of the FAP binding agent of the present application can also be represented by formula (II’):

[0223] In the formula (II’), M is a metal;

[0224] X is NH, NR, O or S, wherein R is C 1-6 alkyl;

[0225] 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;

[0226] Y1and Y2are 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;

[0227] 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 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;

[0228] L is a metal chelator;

[0229] R1, R2are each independently selected from H, halogen or C1-6 alkyl;

[0230] m is an integer selected from 0 to 10;

[0231] n1 is an integer selected from 0 to 10;

[0232] n2 is an integer selected from 0 to 10.

[0233] In one embodiment, the FAP-binding agent of the invention can also be represented by formula (I"):

[0234] In formula (I"):

[0235] X is NH, NR, O or S, wherein R is C 1-6 alkyl;

[0236] 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;

[0237] 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;

[0238] L is a metal chelating agent;

[0239] R1 and R2 are each independently selected from H, halogen or C 1-6 alkyl;

[0240] m is an integer selected from 0 to 10;

[0241] n is an integer selected from 0 to 10.

[0242] 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.

[0243] Further, 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, n is an integer selected from 1 to 3.

[0244] Further, in formula (I”), L is selected from DOTA, NOTA, HEBD-CC, TETA or CB-TE2A.

[0245] In an embodiment, the metal complex of the FAP binding agent of the present application can also be represented by formula (II”):

[0246] In formula (II”), M is a metal;

[0247] X is NH, NR, O or S, wherein R is C 1-6 alkyl;

[0248] 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;

[0249] 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;

[0250] L is a metal chelator;

[0251] R1, R2are each independently selected from H, halogen or C 1-6 alkyl;

[0252] m is an integer selected from 0 to 10;

[0253] n is an integer selected from 0 to 10.

[0254] In an embodiment, in formula (II’) or formula (II”), M is a radioisotope metal.

[0255] Further, M is any one of Lu, Y, Ac, Bi, Re.

[0256] Further, M is any one of Lu-177, Y-90, Ac-225, Bi-213 and Re-188.

[0257] The present application also discloses the use of the FAP binding agent as described above or the metal complex of the FAP binding agent as described above for the preparation of a targeted radiotherapeutic nuclear pharmaceutical, contacting a cell or tissue with a compound as shown in Formula (II') or Formula (II"), detecting the compound within the cell or tissue and treating the compound within the cell or tissue.

[0258] Further, the therapeutic monitoring is by single photon emission computed tomography (SPECT).

[0259] Further, the cell or tissue is in vivo or in vitro.

[0260] Further, the use is for the preparation of a therapeutic agent for cancer, tumor or neoplasm;

[0261] Further, the cancer includes any one or several of ocular 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, throat cancer, skin 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 lymphoid cancer.

[0262] Pharmaceutical composition and pharmaceutical preparation

[0263] Another object of the present application is to provide a pharmaceutical composition comprising the FAP binding agent of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically- substituted compound, metabolite or prodrug thereof, or a metal complex of the FAP binding agent of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically- substituted compound, metabolite or prodrug thereof, and at least one pharmaceutically acceptable carrier.

[0264] The pharmaceutical composition of the present application can be administered in any manner that achieves the desired prophylactic, palliative, prophylactic or therapeutic effect on the symptoms of a human or animal. For example, various suitable dosage forms can be prepared according to the route of administration. For example, it can be administered to a patient in the form of a conventional preparation. The conventional preparation is, for example, a capsule, a microcapsule, a suppository, an injection and a patch.

[0265] The dose of the compound administered to the subject can be adjusted to a considerable extent. The dose can vary depending on the specific route of administration and the needs of the subject, and can be judged by a healthcare professional.

[0266] Imaging and diagnostic or therapeutic methods and uses

[0267] According to certain embodiments of the application, the FAP binding agent of the application or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically enriched compound, metabolite or prodrug thereof, or a metal complex of the FAP binding agent of the application or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically enriched compound, metabolite or prodrug thereof, or a pharmaceutical composition of the application can be used for detection or imaging, or for the prevention or treatment of a disease in which FAP is overexpressed.

[0268] The application also discloses the use of a metal complex of the FAP binding agent of the application for the preparation of a radiopharmaceutical for targeted radiotherapy, contacting a cell or tissue with a compound as shown in formula (II), detecting the compound within the cell or tissue and treating the compound within the cell or tissue.

[0269] Thus, in one aspect, the application provides the use of a metal complex of the FAP binding agent of the application for the preparation of an imaging agent.

[0270] In one embodiment, the method of imaging is by contacting a cell or tissue with a metal complex of the FAP binding agent of the application, imaging by detecting the compound within the cell or tissue and treating the compound within the cell or tissue. In one embodiment, the cell or tissue is in vivo or in vitro.

[0271] In one embodiment, the imaging is by positron emission tomography (PET).

[0272] In one embodiment, the imaging is by single photon emission tomography (SPECT).

[0273] In one embodiment, the imaging agent is an imaging agent for cancer, a tumor or a neoplasm.

[0274] The application also discloses the use of a metal complex of the FAP binding agent of the application for the preparation of a theranostic probe, contacting a cell or tissue with a compound as shown in formula (II), detecting the compound within the cell or tissue and treating the compound within the cell or tissue. In one embodiment, the use is for the preparation of a theranostic probe for cancer, a tumor or a neoplasm.

[0275] Thus, in yet another aspect, the application provides the use of a metal complex of the FAP binding agent of the application for the preparation of a theranostic probe.

[0276] In one embodiment, the method of diagnosis and therapy integration is contacting a cell or tissue with a metal complex of a FAP binding agent of the application, detecting the compound within the cell or tissue and treating the compound within the cell or tissue.

[0277] In one embodiment, the detecting is by single photon emission tomography (SPECT).

[0278] In one embodiment, the therapy monitoring is by single photon emission tomography (SPECT). In one embodiment, the diagnosis and therapy integration is by single photon emission tomography (SPECT).

[0279] In one embodiment, the diagnosis and therapy integration probe is a diagnosis and therapy integration probe for a cancer, tumor or neoplasm.

[0280] In a further aspect, the application also provides the use of a metal complex of a FAP binding agent of the application or a pharmaceutical composition of the application for the manufacture of a medicament for the treatment of a disease, disorder or condition selected from a FAP overexpressing disease, optionally in combination with a second therapeutic agent.

[0281] In another aspect, the application provides a metal complex of a FAP binding agent of the application or a pharmaceutical composition of the application, optionally in combination with a second therapeutic agent, for use in the treatment of a FAP overexpressing disease.

[0282] In a further aspect, the application provides a method of treating a FAP overexpressing disease, the method comprising administering to an individual in need thereof an effective amount of a metal complex of a FAP binding agent of the application or a pharmaceutical composition of the application, optionally in combination with a second therapeutic agent.

[0283] In one embodiment, the FAP overexpressing disease is a cancer, tumor or neoplasm.

[0284] In a particular embodiment, the cancer is fibrosarcoma.

[0285] In a preferred embodiment, the cancer includes any one or several of ocular 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, throat cancer, skin melanoma, acute lymphocytic 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, nephroblastoma, neuroblastoma, esophageal cancer, laryngeal cancer, lymphoma, neurofibroma, tuberous sclerosis, angioma or lymphatic cancer. Advantages and effects

[0286] Advantages and effects of the present application:

[0287] (1) By modifying the structure of the FAP inhibitor, a compound with higher affinity for FAP is obtained.

[0288] (2) By modifying the structure of the FAP inhibitor, a compound with longer retention time in the tumor is obtained.

[0289] The FAP binding agent of the present application and the metal complex of the FAP binding agent of the present application have excellent stability. The tumor imaging effect of the metal complex of the FAP binding agent of the present application is long in vivo retention time, and in a FAP-positive tumor model, it can significantly inhibit the growth of tumors and has good safety. The FAP binding agent of the present application and the metal complex of the FAP binding agent of the present application have the following advantages and effects. 177 The Lu complex achieves far superior 177 The tumor imaging performance and therapeutic effect of the Lu-labeled monomer.

[0290] Examples

[0291] The present application is further specifically described below by way of examples, but these examples do not limit the present application in any way.

[0292] In the following examples, the specific experimental methods not mentioned are carried out according to conventional experimental methods.

[0293] Abbreviations

[0294] DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

[0295] NOTA: 1,4,7-triazacyclononane-1,4,7-triacetic acid

[0296] DOTAGA: 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid

[0297] DOTAGA-tetra(t-Bu ester): 5-(tert-butoxy)-5-oxo-4-{4,7,10-tris[2-(tert-butoxy)-2-oxoethyl]-1,4,7,10-tetraazacyclododecan-1-yl}pentanoic acid

[0298] NETA: {4-[2-(bis-carboxy-methylamino)-5-(4-nitrophenyl)pentyl]-7-carboxymethyl-triazanonan-1-yl}acetic acid

[0299] HBED-CC: N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid

[0300] TETA: 1,4,8,11-Tetraazacyclotetradecane-1,4,8,11-tetraacetic acid

[0301] CB-TE2A: 2-[4-(Carboxymethyl)-1,4,8,11-tetrazabicyclo[6.6.2]hexadecan-11-yl]acetic acid

[0302] HOSu: N-hydroxysuccinimide

[0303] HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0304] DIEA, DIPEA: N,N-diisopropylethylamine

[0305] EDC-HCl, EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0306] NMM: N-methylmorpholine

[0307] HBSS: Hanks' Balanced Salt Solution

[0308] Pip / DMF: piperidine / DMF

[0309] Instruments, materials and reagents

[0310] HT1080 cells: from Cell Bank of Chinese Academy of Sciences (Shanghai, China)

[0311] LCMS: Agilent 6100

[0312] HPLC: Agilent 1260

[0313] Reversed-phase preparative liquid chromatography: Column: Agilent 300SB C-18 5 μm 4.6 x 250 mm; mobile phase: 0-20 min, 18% ACN-38% ACN.

[0314] Radio-HPLC: Lablogic Dual Scan-Ram

[0315] Radio-TLC: Lablogic Dual Scan-Ram

[0316] PET: SIEMENS Micro PET / CT

[0317] SPECT: Mediso Nano

[0318] Intermediate compound A3

[0319] Compound A1 (188 mg) was dissolved in 4 mL DMF, then HATU (570 mg) and DIPEA (387 mg) were added, stirred at room temperature for 5 min, then compound A2 (229 mg) was added, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by LC-MS, and the solvent was removed by rotary evaporation. Compound A3 (145 mg, Yield: 45%) was obtained by purification by reversed-phase preparative liquid chromatography. The relevant spectrum is shown in Figure 1.

[0320] Intermediate compound A5

[0321] Compound A4 (188 mg) was dissolved in 4 mL DMF, then HATU (570 mg) and DIPEA (387 mg) were added, stirred at room temperature for 5 min, then compound A2 (229 mg) was added, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by LC-MS, and the reaction was complete. The reaction was spin-dried, and compound A5 (127.4 mg, Yield: 39.4%) was obtained by reverse phase preparative liquid chromatography purification. The relevant spectrum is shown in Figure 2.

[0322] Intermediate compound A7

[0323] Compound A1 (188 mg) was dissolved in 4 mL DMF, then HATU (570 mg) and DIPEA (387 mg) were added, stirred at room temperature for 5 min, then compound A6 (283.5 mg) was added, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by LC-MS, and the reaction was complete. The reaction was spin-dried, and compound A7 (150.8 mg, Yield: 42%) was obtained by reverse phase preparative liquid chromatography purification.

[0324] Example 1 Preparation of compound FAPI-FUSCC-02-DIMER label precursor

[0325] Scheme 1 FAPI-FUSCC-02-DIMER synthesis schematic diagram

[0326] 1) Synthesis of compound 1

[0327] In a 50 mL round-bottom flask, 1.75 g of Boc-Glycine, 4.56 g of HATU and 1.55 g of DIPEA were sequentially dissolved in 7 mL of anhydrous DMF. After the reaction system was stirred at room temperature for 0.5 h, compound (S)-4,4-difluoropyrrolidine-2-carbonitrile hydrochloride (1.68 g) dissolved in 3 mL of anhydrous DMF was added to the solution. The reaction system was stirred at room temperature overnight. After the reaction process was monitored by TLC, saturated NaHCO3 solution (2 x 30 mL) was added to the reaction system to wash, then EA (3 x 50 mL) was added to extract. The organic phase was combined. The organic phase was sequentially 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.

[0328] 2) Synthesis of compound 2

[0329] In a 50 mL eggplant-shaped flask, add 2.89 g of compound 1 and dissolve it in 10 mL of 4.0 M hydrogen chloride in dioxane. Stir the reaction system at room temperature for 3 h. Monitor the reaction progress by TLC. After completion, concentrate the reaction system under reduced pressure. Wash with diethyl ether. Vacuum filter to remove the remaining hydrochloric acid to obtain the final product, compound 2.

[0330] 3) Synthesis of Compound 3

[0331] In a 50 mL eggplant-shaped flask, 1.89 g of compound 2, 4.56 g of HATU, and 1.55 g of DIPEA were dissolved in 7 mL of anhydrous DMF. After stirring the reaction system at room temperature for 0.5 h, 8-aminoquinoline-4-carboxylic acid (i.e., intermediate compound A1, 1.88 g) 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 (i.e., intermediate compound A3) as a solid powder.

[0332] 4) Synthesis of Compound 4

[0333] In a 50 mL eggplant-shaped flask, 2.89 g of compound Boc-GLY-GLY-GLY-OH, 4.56 g of HATU, and 1.55 g of DIPEA were dissolved in 7 mL of anhydrous DMF. After the reaction system was stirred at room temperature for 0.5 h, compound 3 (3.6 g) 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.

[0334] 5) Synthesis of Compound 5

[0335] In a 50 mL eggplant-shaped flask, add 0.63 g of compound 4 and dissolve it in 10 mL of 4.0 M hydrogen chloride in dioxane. Stir the reaction system at room temperature for 3 h. Monitor the reaction progress by TLC. After completion, concentrate the reaction system under reduced pressure. Wash with diethyl ether. Vacuum filtration to remove the remaining hydrochloric acid yields the final product, compound 5.

[0336] 6) Synthesis of Compound 6

[0337] In a 50 mL vial, compound 0.12 g BOC-Glu-OH, 0.456 g HATU and 0.155 g DIPEA were sequentially dissolved in 7 mL anhydrous DMF. After the reaction system was stirred at room temperature for 0.5 h, compound 5 (0.52 g) dissolved in 3 mL 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 x 30 mL) was added to the reaction system to wash, and then EA (3 x 50 mL) was added to extract. The organic phases were combined. The organic phase was sequentially dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain product 6 as a solid powder.

[0338] 7) Synthesis of compound 7

[0339] In a 50 mL vial, 0.12 g compound 6 was dissolved in 10 mL 6.0 M hydrochloric acid solution. 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. Ethyl ether was added to wash. The remaining hydrochloric acid was removed by vacuum filtration to obtain the final product compound 7.

[0340] 8) Synthesis of compound 8

[0341] In a 50 mL vial, compound 0.7 g DOTAGA-tetra(t-Bu ester), 0.456 g HATU and 0.155 g DIPEA were sequentially dissolved in 7 mL anhydrous DMF. After the reaction system was stirred at room temperature for 0.5 h, compound 7 (0.1 g) dissolved in 3 mL 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 x 30 mL) was added to the reaction system to wash, and then EA (3 x 50 mL) was added to extract. The organic phases were combined. The organic phase was sequentially dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain product 8 as a solid powder.

[0342] 9) Synthesis of compound 9

[0343] In a 50 mL vial, 0.09 g compound 8 was dissolved in 10 mL 6.0 M hydrochloric acid solution. 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. Ethyl ether was added to wash. The remaining hydrochloric acid was removed by vacuum filtration to obtain the final product compound 9, i.e., FAPI binding agent FAPI-FUSCC-02-DIMER.

[0344] Compound 9 was confirmed by HPLC and LC-MS for structure. The relevant spectra are shown in FIG. 3 and FIG. 4.

[0345] Example 2 Compound 177 Preparation of Lu-FAPI-FUSCC-02-DIMER

[0346] The FAPI-FUSCC-02-DIMER labeled precursor prepared in Example 1 was dissolved in sterile water for injection to prepare a precursor solution with a concentration of 1 μg / μL. 177 LuCl3 solution. 4 μL precursor solution, 10 μL 0.5M sodium acetate solution, 10 μL 0.05M hydrochloric acid, 10 μL water for injection, 10 μL 177 Add LuCl3 solution to the precursor reagent bottle. Heat the solution in the precursor reagent bottle to 90℃ and react for 20 minutes to obtain the final product. 177 Lu-FAPI-FUSCC-02-DIMER. Its radiochemical purity was determined by Radio-TLC and Radio-HPLC. The relevant analysis spectra are shown in Figures 5, 6, and 7. The specific reaction route is as follows:

[0347] 177 Schematic diagram of the synthesis of Lu-FAPI-FUSCC-02-DIMER

[0348] Example 3 177 In vitro stability study of Lu-FAPI-FUSCC-02-DIMER

[0349] Take a certain amount 177 Lu-FAPI-FUSCC-02-DIMER was added to normal saline, and its radiochemical purity was measured at different time points to test its stability. The results are shown in Figure 8. Day 7 177 The radiochemical purity of Lu-FAPI-FUSCC-02-DIMER was still greater than 98%, and it maintained good stability.

[0350] Example 4 Preparation of compound FAPI-FX-01

[0351] Synthesis route of FAPI-FX-01:

[0352] 1) Synthesis of compound 4-2

[0353] Compound 4-1 (118 mg) was dissolved in 10 mL DMF. HATU (171 mg) and DIEA (116 mg) were added, and finally compound A7 (107 mg) was added. The reaction was allowed to proceed at room temperature for 2 hours. LC-MS was used to monitor the completion of the reaction. The solvent was removed. 10 mL TFA was added and the reaction was allowed to proceed for 5 minutes. 100 mL ether was added. A large amount of solid precipitated. The solid was centrifuged, dried, and purified by reverse phase preparative liquid chromatography to obtain compound 4-2 (85.8 mg, yield: 45%). The relevant spectra are shown in Figure 9.

[0354] 2) Synthesis of compound 4-3

[0355] Boc-Glu-OH (13.3 mg) was dissolved in 3 mL DMF. HOBt (19 mg) and EDCI (26 mg) were added at 0 °C. The reaction was allowed to proceed at 0 °C for 10 minutes. Compound 4-2 (85.8 mg) and N-methylmorpholine (NMM, 41 mg) were added. The reaction was allowed to proceed at room temperature for 2 hours. LC-MS was used to monitor the completion of the reaction. The solvent was removed. 10 mL TFA was added and the reaction was allowed to proceed for 5 minutes. 100 mL ether was added. A large amount of solid precipitated. The solid was centrifuged, dried, and purified by reverse phase preparative liquid chromatography to obtain compound 4-3 (20 mg, Yield: 26%). The relevant spectra are shown in Figure 10.

[0356] 3) Synthesis of FAPI-FX-01

[0357] Compound 4-3 (20 mg) was dissolved in 5 mL DMF, DIEA (7.5 mg) and compound 4-4 (14.5 mg) were added, and the reaction was allowed to proceed at room temperature overnight. LC-MS was used to monitor the completion of the reaction. The solvent was removed. FAPI-FX-01 (12.8 mg, Yield: 50%) was obtained by reverse phase preparative liquid chromatography. The relevant spectra are shown in Figures 11 and 12.

[0358] Example 5 Preparation of compound FAPI-FX-02

[0359] 5.1 Synthesis of compound 5-3

[0360] 1) Synthesis of compound 5-2

[0361] Boc-L-alanine (compound 5-1, 416 mg) was dissolved in 20 mL DMF. HATU (1140 mg), DIEA (774 mg) were added, and finally compound A7 (720 mg) was added. The reaction was carried out at room temperature for 2 hours. LC-MS was used to monitor the reaction completion. The solvent was removed, and 20 ml TFA was added for 5 minutes. 200 mL ether was added. A large amount of solid precipitated. Centrifugation, dry, and purified by reverse phase preparative liquid chromatography to obtain compound 5-2 (500 mg, yield: 58%). The relevant spectra are shown in Figure 13.

[0362] 2) Synthesis of compound 5-3

[0363] Compound 5-2 (250 mg) was dissolved in 10 mL DMF. Glutaric anhydride (100 mg), DIEA (225 mg) were added. The reaction was carried out at room temperature for 2 hours. LC-MS was used to monitor the reaction completion. The solvent was removed. Purified by reverse phase preparative liquid chromatography to obtain compound 5-3 (190 mg, yield: 60%). The relevant spectra are shown in Figure 14.

[0364] 5.2 Synthesis of compound 5-6

[0365] Compound 5-5 (from Nanchang Zhenbi Biological Technology Co., Ltd.) (655 mg) was dissolved in 10 mL DMF. HOBt (68 mg), EDCI (96 mg) were added at 0 °C. The reaction was carried out at 0 °C for 10 minutes. Compound 5-2 (215 mg), NMM (152 mg) were added. The reaction was carried out at room temperature for 2 hours. LC-MS was used to monitor the reaction completion. The solvent was removed. 10 mL 4% hydrazine hydrate / DMF solution was added and the reaction was carried out at room temperature for 10 minutes. The solvent was removed. Purified by reverse phase preparative liquid chromatography to obtain compound 5-6 (218 mg, Yield: 28%). The relevant spectra are shown in Figure 15.

[0366] 5.3 Synthesis of FAPI-FX-02

[0367] Compound 5-3 (76 mg) was dissolved in 5 mL DMF. HATU (80 mg), DIEA (54 mg) were added, and finally compound 5-6 (218 mg) was added. The reaction was carried out at room temperature for 2 hours. LC-MS was used to monitor the reaction completion. The solvent was removed. 10 ml TFA was added for 5 minutes. 100 mL ether was added. A large amount of solid precipitated. Centrifugation, dry, and purified by reverse phase preparative liquid chromatography to obtain FAPI-FX-02 (93 mg, yield: 36%). The relevant spectra are shown in Figures 16 and 17.

[0368] Example 6 Preparation of compound FAPI-FX-03

[0369] Synthesis route of FAPI-FX-03:

[0370] 1) Synthesis of compound 6-1

[0371] Boc-Gly-Gly-Gly-OH (289 mg) was dissolved in 10 mL DMF. HATU (570 mg), DIEA (387 mg) were added, and finally compound A3 (323 mg) was added. The reaction was stirred at room temperature for 2 hours. LC-MS was used to monitor the reaction completion. The solvent was removed. 10 mL TFA was added and reacted for 5 minutes. 100 mL ether was added. A large amount of solid precipitated. Centrifugation, dry, and purified by reverse phase preparative liquid chromatography to obtain compound 6-1 (198 mg, yield: 40%). The relevant spectra are shown in Figure 18.

[0372] 2) Synthesis of compound 6-2

[0373] Boc-Glu-OH (45 mg) was dissolved in 10 mL DMF. HATU (205 mg), DIEA (139 mg) were added, and finally compound 6-1 (198 mg) was added. The reaction was stirred at room temperature for 2 hours. LC-MS was used to monitor the reaction completion. The solvent was removed. 10 mL TFA was added and reacted for 5 minutes. 100 mL ether was added. A large amount of solid precipitated. Centrifugation, dry, and purified by reverse phase preparative liquid chromatography to obtain compound 6-2 (84 mg, yield: 42%). The relevant spectra are shown in Figure 19.

[0374] 3) Synthesis of FAPI-FX-03

[0375] DOTAGA-(COOt-Bu)4 (50 mg) was dissolved in 10 mL DMF. HATU (41 mg), DIEA (28 mg) were added, and finally compound 6-2 (80 mg) was added. The reaction was stirred at room temperature for 2 hours. LC-MS was used to monitor the reaction completion. The solvent was removed. 10 mL TFA was added and reacted for 5 minutes. 100 mL ether was added. A large amount of solid precipitated. Centrifugation, dry, and purified by reverse phase preparative liquid chromatography to obtain FAPI-FX-03 (42 mg, yield: 38%). The relevant spectra are shown in Figures 20 and 21.

[0376] Example 7 Preparation of compound FAPI-FX-04

[0377] 7.1 Synthesis of compound 7-1

[0378] Boc-Gly-Gly-Gly-OH (289 mg) was dissolved in 10 mL DMF. HATU (570 mg), DIEA (387 mg) were added, and finally compound A5 (323 mg) was added. The reaction was allowed to proceed at room temperature for 2 hours. LC-MS was used to monitor the completion of the reaction. The solvent was evaporated, and 10 mL TFA was added for 5 minutes. 100 mL ether was added. A large amount of solid precipitated. Centrifugation, dry, and purified by reverse phase preparative liquid chromatography to obtain compound 7-1 (222 mg, yield: 45%). See Figure 22 for related spectra.

[0379] 7.2 Synthesis of FAPI-FX-04

[0380] 1) Synthesis of compound 7-2

[0381] Fmoc-Glu(OtBu)-OH (106 mg) was dissolved in 10 mL DMF. HOBt (51 mg) and EDC.HCl (72 mg) were added. The reaction was allowed to proceed at 0 °C for 10 minutes. Then compound 6-1 (123 mg) and NMM (76 mg) were added. The reaction was allowed to proceed at room temperature for 3 hours. LC-MS was used to monitor the completion of the reaction. The DMF was evaporated, and 10 mL TFA was added. The reaction was allowed to proceed at room temperature for 5 minutes. 100 mL ether was added. A large amount of solid precipitated. Centrifugation, dry, and purified by reverse phase preparative to obtain compound 7-2 (103 mg, Yield: 49%). See Figure 23 for related spectra.

[0382] 2) Synthesis of compound 7-3

[0383] Compound 7-2 (103 mg) was dissolved in 10 mL DMF. HOBt (25 mg) and EDC.HCl (35 mg) were added. The reaction was allowed to proceed at 0 °C for 10 minutes. Then compound 7-1 (60 mg) and NMM (40 mg) were added. The reaction was allowed to proceed at room temperature for 3 hours. LC-MS was used to monitor the completion of the reaction. The DMF was evaporated, and 10 mL 20% Pip / DMF was added. The reaction was allowed to proceed at room temperature for 2 hours. 100 mL ether was added. A large amount of solid precipitated. Centrifugation, dry, and purified by reverse phase preparative to obtain compound 7-3 (50 mg, Yield: 38%). See Figure 24 for related spectra.

[0384] 3) Synthesis of FAPI-FX-04

[0385] DOTAGA-(COOt-Bu)4(32 mg) was dissolved in 10 mL DMF. HATU (26 mg), DIEA (18 mg) were added, and finally compound 7-3 (50 mg) was added. The reaction was stirred at room temperature for 2 hours. LC-MS was used to monitor the reaction completion. The solvent was evaporated. 10 mL TFA was added and the reaction was stirred for 5 minutes. 100 mL ether was added. A large amount of solid was precipitated. The solid was centrifuged, dried and purified by preparative reverse phase liquid chromatography to give FAPI-FX-04 (37 mg, yield: 52%). The relevant spectra are shown in Figures 25 and 26.

[0386] Example 8 Preparation of compound FAPI-FX-05

[0387] Synthetic route of FAPI-FX-05:

[0388] 1) Synthesis of compound 8-1

[0389] Boc-Gly-OH (35 mg) was dissolved in 10 mL DMF. HATU (76 mg) and DIPEA (26 mg) were added. The reaction was stirred at room temperature for 5 minutes. Compound A7 (72 mg) was added. The reaction was stirred for 2 hours. LC-MS was used to monitor the reaction completion. The solvent was evaporated. 10 mL TFA was added and the reaction was stirred for 5 minutes. 100 mL ether was added. A large amount of solid was precipitated. The solid was centrifuged, dried and purified by preparative reverse phase liquid chromatography to give compound 8-1 (48 mg, Yield: 57.4%). The relevant spectra are shown in Figure 27.

[0390] 2) Synthesis of compound 8-2

[0391] Boc-Gly-Gly-Gly-Gly-OH (40 mg) was dissolved in 4 mL DMF. HATU (66 mg) and DIPEA (45 mg) were added. The reaction was stirred at room temperature for 5 minutes. Compound 8-1 (48 mg) was added. The reaction was stirred at room temperature for 2 hours. LC-MS was used to monitor the reaction completion. The solvent was evaporated. 5 mL TFA was added and the reaction was stirred for 5 minutes. 50 mL ether was added. A large amount of solid was precipitated. The solid was centrifuged, dried and purified by preparative reverse phase liquid chromatography to give compound 8-2 (31 mg, Yield: 41.3%). The relevant spectra are shown in Figure 28.

[0392] 3) Synthesis of compound 8-3

[0393] Boc-Glu-OH (5 mg) was dissolved in 3 mL DMF. HOBt (6.5 mg) and EDC.HC1 (9 mg) were added. The reaction was stirred at 0 °C for 10 min. Then compound 8-2 (31 mg) and NMM (12 mg) were added. The reaction was stirred at room temperature for 3 h. LC-MS was used to monitor the reaction. The DMF was evaporated, and 5 mL TFA was added. The reaction was stirred at room temperature for 5 min. 50 mL ether was added. A large amount of solid was precipitated. The solid was centrifuged, dried, and purified by reverse phase preparative HPLC to give compound 8-3 (11 mg, Yield: 40%). See Figures 29 for related spectra.

[0394] 4) Synthesis of FAPI-FX-05

[0395] DOTAGA-(COOt-Bu)4 (6 mg) was dissolved in 3 mL DMF. HATU (4.5 mg) and DIPEA (3 mg) were added. The reaction was stirred at room temperature for 5 min. Compound 8-3 (11 mg) was added. The reaction was stirred at room temperature for 2 h. LC-MS was used to monitor the reaction. The solvent was evaporated. 5 mL TFA was added. The reaction was stirred at room temperature for 2 h. 50 mL ether was added. A large amount of solid was precipitated. The solid was centrifuged, dried, and purified by reverse phase preparative HPLC to give FAPI-FX-05 (2.5 mg, Yield: 17%). See Figures 30 and 31 for related spectra.

[0396] Example 9 Preparation of compound FAPI-FX-06

[0397] Synthetic route of FAPI-FX-06:

[0398] 1) Synthesis of compound 9-1

[0399] Boc-Gln(Trt)-Asp(OtBu)-OH (198 mg) was dissolved in 10 mL DMF. HATU (114 mg) and DIPEA (116 mg) were added. The reaction was stirred at room temperature for 5 min. Compound 8-1 (79 mg) was added. The reaction was stirred for 2 h. LC-MS was used to monitor the reaction. The solvent was evaporated. 10 mL TFA was added. The reaction was stirred at room temperature for 2 h. 100 mL ether was added. A large amount of solid was precipitated. The solid was centrifuged, dried, and purified by reverse phase preparative HPLC to give compound 9-1 (56 mg, Yield: 42.3%). See Figure 32 for related spectra.

[0400] 2) Synthesis of compound 9-2

[0401] Compound 9-1 (8.4 mg) was dissolved in 10 mL DMF. DCC (8.4 mg) and HOSu (4.7 mg) were added. The reaction was carried out at room temperature for 6 hours. Compound 9-1 (56 mg) and DIPEA (13 mg) were added. The reaction was carried out at room temperature for 1 hour. The reaction was monitored by LC-MS. DMF was evaporated, and 10 mL TFA was added. The reaction was carried out at room temperature for 5 minutes. 100 mL ether was added. A large amount of solid was precipitated. Compound 9-2 (21 mg, Yield: 43.7%) was obtained after reversed-phase preparative liquid chromatography purification. The relevant spectra are shown in Figure 33.

[0402] 3) Synthesis of FAPI-FX-06

[0403] DOTAGA-(COOt-Bu)4 (10 mg) was dissolved in 10 mL DMF. HOBt (2.5 mg) and EDC.HCl (3.4 mg) were added. The reaction was carried out at 0 °C for 10 minutes. Then compound 9-2 (21 mg) and NMM (4.5 mg) were added. The reaction was carried out at room temperature for 3 hours. The reaction was monitored by LC-MS. DMF was evaporated, and 10 mL 95% TFA was added. The reaction was carried out at room temperature for 2 hours. 100 mL ether was added. A large amount of solid was precipitated. After centrifugation, drying, and reversed-phase preparative purification, FAPI-FX-06 (3.4 mg, Yield: 12%) was obtained. The relevant spectra are shown in Figures 34 and 35.

[0404] Example 10 Preparation of compound FAPI-FX-07

[0405] Synthetic route of FAPI-FX-07:

[0406] 1) Synthesis of compound 10-1

[0407] Compound 8-1 (125 mg) and N-BOC-4-isothiocyanatobutylamine (69 mg) were dissolved in 10 mL DMF. Triethylamine (91 mg) was added. The reaction was carried out at room temperature for 3 hours. The reaction was monitored by LC-MS. After evaporation and concentration under reduced pressure, compound 10-1 (55 mg, Yield: 33.7%) was obtained after reversed-phase preparative liquid chromatography purification. The relevant spectra are shown in Figure 36.

[0408] 2) Synthesis of compound 10-2

[0409] Boc-Asp-OH (10 mg) was dissolved in 10 mL DMF. HOBt (12.5 mg) and EDC.HCl (17.5 mg) were added. The reaction was stirred at 0 °C for 10 min. Then compound 10-1 (55 mg) and NMM (14 mg) were added. The reaction was stirred at room temperature for 3 h. LC-MS was used to monitor the reaction. The DMF was evaporated, and 10 mL TFA was added. The reaction was stirred at room temperature for 5 min. 100 mL ether was added. A large amount of solid was precipitated. After centrifugation and drying, compound 10-2 (21 mg, Yield: 39.1%) was obtained by preparative reverse phase purification. The relevant spectra are shown in Figure 37.

[0410] 3) Synthesis of FAPI-FX-07

[0411] Compound 10-2 (21 mg) was dissolved in 40 mL DMF. DOTAGA-Anhydride (24 mg) and DIPEA (7 mg) were added. The reaction was stirred for 2 h. LC-MS was used to monitor the reaction. The DMF was evaporated. FAPI-FX-07 (11.5 mg, Yield: 39.2%) was obtained by preparative reverse phase purification. The relevant spectra are shown in Figures 38 and 39.

[0412] Example 11 Preparation of compound FAPI-FX-08

[0413] 11.1 Synthesis of compound 11-1

[0414] 1) Synthesis of compound 11-1

[0415] Compound 8-1 (208 mg) was dissolved in 10 mL DMF. Glutaric anhydride (114 mg) and DIPEA (194 mg) were added. The reaction was stirred for 2 h. LC-MS was used to monitor the reaction. The DMF was evaporated. Compound 11-1 (162 mg, Yield: 61%) was obtained by preparative reverse phase purification. The relevant spectra are shown in Figure 40.

[0416] 2) Synthesis of compound 11-2

[0417] Boc-amino hexanoic acid (231 mg) was dissolved in 10 mL DMF. HATU (570 mg) and DIPEA (387 mg) were added. The reaction was stirred at room temperature for 5 min. Compound 8-1 (208 mg) was added. The reaction was stirred for 2 h. LC-MS was used to monitor the reaction. The DMF was evaporated. 5 mL TFA was added. The reaction was stirred at room temperature for 5 min. 50 mL ether was added. A large amount of solid was precipitated. After centrifugation and drying, the crude product was obtained. Compound 11-2 (154 mg, Yield: 58%) was obtained by preparative reverse phase purification. The relevant spectra are shown in Figure 41.

[0418] 3) Synthesis of compound 11-3

[0419] Boc-Lys(Fmoc)-OH (136 mg) was dissolved in 10 mL DMF. HATU (111 mg) and DIPEA (113 mg) were added. Stirring at room temperature for 5 min. Compound 11-2 (154 mg) was added. Reaction at room temperature for 2 h. LC-MS monitoring reaction complete. Spin dry. 5 mL TFA was added, reaction at room temperature for 5 min. 50 mL ether was added. A large amount of solid precipitated. After centrifugal suction dry, the crude product was obtained. Compound 11-3 (119 mg, Yield: 46.5%) was obtained by reverse phase preparative liquid chromatography. The relevant spectra are shown in Figure 42.

[0420] 4) Synthesis of compound 11-4

[0421] Compound 11-1 (72 mg) was dissolved in 10 mL DMF. HATU (52 mg) and DIPEA (52 mg) were added. Stirring at room temperature for 5 min. Compound 11-3 (119 mg) was added. Stirring for 2 h. LC-MS monitoring reaction complete. Spin dry. PIPERIDINE / DMF was added. Reaction at room temperature for 2 h. 100 mL ether was added. A large amount of solid precipitated. After centrifugal suction dry, the crude product was obtained. Compound 11-4 (63 mg, Yield: 40.1%) was obtained by reverse phase preparative liquid chromatography. The relevant spectra are shown in Figure 43.

[0422] 5) Synthesis of FAPI-FX-08

[0423] DOTAGA-(COOt-Bu)4 (56 mg) was dissolved in 10 mL DMF. HATU (31 mg) and DIPEA (21 mg) were added. Stirring at room temperature for 5 min. Compound 11-4 (63 mg) was added. Stirring for 2 h. LC-MS monitoring reaction complete. Spin dry. 10 mL TFA was added, reaction at room temperature for 2 h. 100 mL ether was added. A large amount of solid precipitated. After centrifugal suction dry, the crude product was obtained. FAPI-FX-08 (33.5 mg, Yield: 38.4%) was obtained by reverse phase preparative liquid chromatography. The relevant spectra are shown in Figures 44 and 45.

[0424] Example 12 Preparation of compound FAPI-FX-09

[0425] Synthesis route of FAPI-FX-09:

[0426] 1) Synthesis of compound 12-2

[0427] Compound 12-1 (180 mg) and N-Boc-3aminopropyl bromide (149 mg) were dissolved in DMF. K2CO3(207 mg) and KI (42 mg) were added and reacted at 60 °C for 1 hour. The reaction was monitored by LC-MS. The solvent was evaporated. 5 mL of TFA was added. The reaction was carried out at room temperature for 5 minutes. 50 mL of ether was added. A large amount of solid was precipitated. After reversed phase preparative liquid chromatography, compound 12-2 (98.6 mg, Yield: 47.3%) was obtained. The relevant spectra are shown in Figure 46.

[0428] 2) Synthesis of compound 12-3

[0429] Boc-Gly-OH (62 mg) was dissolved in 4 mL of DMF. HATU (135 mg) and DIPEA (92 mg) were added. It was stirred at room temperature for 5 min. Compound 12-2 (98 mg) was added. It was stirred for 2 hours. The reaction was monitored by LC-MS. The solvent was evaporated. 5 mL of TFA was added. The reaction was carried out at room temperature for 5 minutes. 50 mL of ether was added. A large amount of solid was precipitated. After centrifugation and drying, the crude product was obtained. After reversed phase preparative liquid chromatography, compound 12-3 (48 mg, Yield: 43%) was obtained. The relevant spectra are shown in Figure 47.

[0430] 3) Synthesis of compound 12-4

[0431] Boc-Glu-OH (10 mg) was dissolved in 10 mL of DMF. HOBt (14 mg) and EDC.HC1 (20 mg) were added. The reaction was carried out at 0 °C for 10 min. Then compound 12-3 (48 mg) and NMM (25 mg) were added. The reaction was carried out at room temperature for 3 hours. The reaction was monitored by LC-MS. The DMF was evaporated, and 5 mL of TFA was added. The reaction was carried out at room temperature for 5 minutes. 50 mL of ether was added. A large amount of solid was precipitated. After centrifugation and drying, compound 12-4 (14 mg, Yield: 33%) was obtained by reversed phase preparative purification. The relevant spectra are shown in Figure 48.

[0432] 4) Synthesis of FAPI-FX-09

[0433] Compound 12-4 (14 mg) was dissolved in 2 mL of DMF. DOTA-NHS (30 mg) and DIPEA (7 mg) were added. The reaction was carried out for 2 hours. The reaction was monitored by LC-MS. The DMF was evaporated. After reversed phase preparative liquid chromatography, FAPI-FX-09 (10.5 mg, Yield: 54.5%) was obtained. The relevant spectra are shown in Figures 49 and 50.

[0434] Example 13 FAPI-FX series compound 68 Preparation of Ga complex

[0435] The labelling precursor was dissolved in sterile water for injection to make a solution of the precursor (FAPI-FX series compounds) at a concentration of 1 μg / μL. The labelling precursor solution was added to the precursor vial. The reaction system was heated to the temperature as shown in Table 1 and allowed to react for 10 min before cooling to room temperature. 68 Ge- 68 Ga generator eluate 68 GaCl3solution. The precursor solution, 1.5 M sodium acetate solution and 4 mL of 68 GaCl3solution were added to the precursor vial, respectively. The solution in the precursor vial was heated to the temperature as shown in Table 1 and allowed to react for 10 min before cooling to room temperature.

[0436] Table 1 Labelling conditions

[0437] Purification: 15 mL of sterile water was added to the labelling system, and then purified by a C18 column (SEP-PAK), the product was adsorbed to the column, and then the product was eluted with 70% ethanol to obtain the final product.

[0438] Test: The radiochemical purity of the product was determined by radio thin layer chromatography (Radio-TLC, developing agent: ammonium acetate / methanol solution, volume ratio 1:1). The relevant analysis spectrum is shown in Figures 51 to 59. The labelling rate is shown in Table 2.

[0439] Table 2 Labelling rate of FAPI-FX series compounds 68 Ga complex

[0440] Example 14 Preparation of FAPI-FX series compounds 177 Lu complex

[0441] The labelling precursor was dissolved in sterile water for injection to make a solution of the precursor (FAPI-FX series compounds) at a concentration of 1 μg / μL (FAPI-FX). The precursor solution, 20 μL of 0.5 M sodium acetate solution, 20 μL of 0.05 M hydrochloric acid solution, 10 μL of sterile water for injection, 1 μL 177 LuCl3(2 mCi) solution were added to the precursor vial, respectively. The reaction system was heated to 90°C and allowed to react for 20 min, and then cooled to room temperature.

[0442] Purification: 15 mL of sterile water was added to the labelling system, and then purified by a C18 column (SEP-PAK), the product was adsorbed to the column, and then the product was eluted with 70% ethanol to obtain the final product.

[0443] Test: The radiochemical purity of the product was determined by radio-thin layer chromatography (Radio-TLC, developing agent: ammonium acetate / methanol solution, volume ratio 1:1). The relevant analysis spectrum is shown in Figures 60 to 63. The labeling rate is shown in Table 3.

[0444] Table 3 FAPI-FX series compounds 177 Labeling rate of Lu complex

[0445] Test Example 1 FAPI-FX series compounds 68 Experiment of Ga complex

[0446] 1.1 Log D 7.4 Method for determination:

[0447] (1) Take 5 1.5 mL EP tubes, and add 500 μL of n-octanol and 500 μL of PBS to each tube, respectively;

[0448] (2) Take FAPI-FX series compounds 68 Ga complex ( 68 Ga-FAPI-FX-01, 68 Ga-FAPI-FX-02, 68 Ga-FAPI-FX-03, 68 Ga-FAPI-FX-04, 68 Ga-FAPI-FX-05, 68 Ga-FAPI-FX-06, 68 Ga-FAPI-FX-07, 68 Ga-FAPI-FX-08 or 68 Ga-FAPI-FX-09) 74 kBq into the above 5 EP tubes, seal and mix, and stand at room temperature for 5 min;

[0449] (3) Centrifuge the above EP tubes for 10 min (15000 r / min), and stand at room temperature until the liquid is layered;

[0450] (4) Take 200 μL of liquid from the upper and lower layers of each EP tube to 10 γ counting tubes with a pipette, and measure the radioactivity count of each tube with a γ counter;

[0451] (5) Calculate the average value with the formula Log D 7.4 = Log(CPM 正辛醇 / CPM PBS );

[0452] (6) The data were analyzed by GraphPad Prism 9.0.

[0453] 1.2 Method for determining Log P:

[0454] (1) Take 5 1.5 mL EP tubes, and add 500 μL of n-octanol and 500 μL of ultrapure water to each tube, respectively;

[0455] (2) Take the marker FAPI-FX series compounds Ga complex (Ga-FAPI-FX-01, Ga-FAPI-FX-02, Ga-FAPI-FX-03, Ga-FAPI-FX-04, Ga-FAPI-FX-05, Ga-FAPI-FX-06, Ga-FAPI-FX-07, Ga-FAPI-FX-08 or Ga-FAPI-FX-09) and add them to the above 5 EP tubes, seal and mix, and stand at room temperature for 5 min; 68 68 68 68 68 68 68 68 68 68 正辛醇 超纯水

[0456] (3) Centrifuge the above EP tubes for 10 min (15000 r / min), and stand at room temperature until the liquid is layered;

[0457] (4) Take 100 μL of liquid from the upper and lower layers of each EP tube into 10 γ counting tubes with a pipette, and measure the radioactivity count of each tube with a γ counter;

[0458] (5) Calculate the average value with the formula Log P = Log(CPM 正辛醇 / CPM 超纯水 );

[0459] (6) The data are analyzed by GraphPad Prism 9.0.

[0460] 1.3 Experimental results:

[0461] The results shown in FIGS. 64 to 72 and Table 4 show that the metal complexes of the FAPI-FX series compounds have good hydrophilicity.

[0462] Table 4 Lipid-water partition coefficient of Ga complex of FAPI-FX series compounds (n = 5). 68

[0463] Test Example 2 Lipid-water partition coefficient of Ga complex of FAPI-FX series compounds 68 177 ​​​​​​​​​​Uptake of Lu complexes in HT-1080-FAP cells

[0464] 2.1 Experimental methods:

[0465] (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.

[0466] (2) Radioactive probe incubation: Aspirate the supernatant and add the freshly prepared FAPI-FX series compound 68 Ga complexes ( 68 Ga-FAPI-FX-01, 68 Ga-FAPI-FX-02, 68 Ga-FAPI-FX-03, 68 Ga-FAPI-FX-04, 68 Ga-FAPI-FX-05, 68 Ga-FAPI-FX-06, 68 Ga-FAPI-FX-07, 68 Ga-FAPI-FX-08 or 68 Ga-FAPI-FX-09) or 177 Lu complexes ( 177 Lu-FAPI-FAPI-FX-02, 177 Lu-FAPI-FAPI-FX-06, 177 Lu-FAPI-FAPI-FX-07 and 177 Lu-FAPI-FAPI-FX-08) at a concentration of 2 μCi / mL in DMEM was added to each well at 500 μL / well, and the cell culture plate was placed in a hot chamber incubator for incubation; the blocking group should be incubated with an excess of DOTA-FAPI-04 (CAS: 2374782-02-0, purchased from Shanghai Jiabiao Biotechnology Co., Ltd.) (5 μg per well) half an hour in advance, and then the radioactive medium was added together with the targeting group;

[0467] (3) Radioactivity measurement: Collect the supernatant from the wells at the corresponding time points into γ-counting tubes, wash them three times with pre-cooled PBS, and label them; lyse the cells with 1 M NaOH and collect them into corresponding γ-counting tubes, and measure the radioactivity counts in each tube using a γ-counter;

[0468] (4) Attenuation correction: The radioactivity is attenuated and the percentage of the radioactivity taken up by cells to the total radioactivity is calculated;

[0469] (5) Data processing: analysis and drawing were performed by GraphPad Prism 9.0.

[0470] 2.2 Experimental results:

[0471] Experimental results of FAPI-FX series compounds 68 Experimental results of Ga complexes are shown in FIGS. 73-81 and Table 5. The cell uptake analysis of FAPI-FX series compounds 177 Experimental results of Lu complexes are shown in FIGS. 82-85 and Table 6. The metal complexes of FAPI-FX series compounds all have significant uptake in HT-1080-FAP cells. The radioactivity uptake is roughly slow increase with time extension. The cell blocking experiment shows that the cell uptake of the metal complexes of FAPI-FX series compounds can be blocked by excess DOTA-FAPI-04. The above results show that the uptake of the metal complexes of FAPI-FX series compounds by HT-1080-FAP cells is mediated by FAP.

[0472] Table 5 Cell uptake analysis of FAPI-FX series compounds 68 Ga complexes (n = 5)

[0473] Table 6 Cell uptake analysis of FAPI-FX series compounds 177 Lu complexes (n = 5)

[0474] Test Example 3 68 PET imaging study of Ga-FAPI-FX-01, 68 Ga-FAPI-FX-07

[0475] SPF level Balb / c nude mice, female, 6 weeks old, provided by Shanghai Regen Biotechnology Co., Ltd. After adapting for two days in the animal house, FAP transfected HT1080 human fibrosarcoma cells were injected subcutaneously into the right axillary of the nude mice, with an injection amount of 0.1 mL (5 x 10 6 cells / mL dispersed in HBSS). After injection, the mice were further fed for 2-4 weeks until the solid tumor mass grew to 500-600 mm 3 When the solid tumor mass grew to 500-600 mm 68 Ga-FAPI-FX-01 or 68 Ga-FAPI-FX-07, 100-150 μCi / 0.2 mL was injected via the tail vein, and 1 h, 2 h, and 4 h after injection, imaging experiments were performed using a small animal PET. The imaging images are shown in FIGS. 86 and 87, and the semi-quantitative analysis is shown in Table 7. The results show that, 68 Ga-FAPI-FX-01 and 68Ga-FAPI-FX-07 all have good binding with FAP protein, and the tumor tissue uptake is significantly higher than that of normal tissue. The tumor uptake still maintains at a high level at 4h, which can be used as a diagnostic probe for targeting FAP.

[0476] Table 7 radioactive probes 68 Ga-FAPI-FX-01, 68 Micro-PET / CT image of Ga-FAPI-FX-07 in tumor region of interest semi-quantitative analysis (n = 3)

[0477] Test Example 4 177 SPECT imaging study of Lu-FAPI-FUSCC-02-DIMER

[0478] 4.1 Experimental method:

[0479] (1) Virus transduction: HT1080 cells were seeded in each well of a 6-well plate at a density of 5 x 10 4 cells / mL) into the cells the next day. The culture medium was replaced in the following two days. Then the positive cells were screened out with 2 mg / mL puromycin.

[0480] (2) HT1080-FAP cells stably expressing human FAP were obtained by using lentivirus infection and then screening with 2 mg / mL puromycin for two days.

[0481] (3) SPF level Balb / c nude mice, female, 6 weeks old, provided by Hangzhou Ziyuan Biotechnology Co., Ltd. After being fed in the animal room for two days, the FAP transfected HT1080 human fibrosarcoma cells were injected subcutaneously into the right axillary of the nude mice, and the injection amount was 0.1 mL (5 x 10 6 cells / mL dispersed in HBSS). After injection, continue to feed for 2-4 weeks, and when the solid tumor mass grows to 500-600 mm 3 for treatment imaging experiment: 400-500 μCi / 0.2 mL of Lu-FAPI-FUSCC-02-DIMER was injected through the tail vein, and after injection, treatment imaging experiment was performed with small animal SPECT at 1h, 4h, 24h, 48h, 72h, 96h, 120h. 177

[0482] 4.2 Experimental results:

[0483] The imaging diagram is shown in Figure 88. The SPECT / CT imaging of the FAP positive tumor model can find that 177 ​Lu-FAPI-FUSCC-02-DIMER demonstrated high radioactive uptake, with significant contrast in non-target organs. The tumor imaging effect persisted in vivo for a long time and exhibited excellent stability. Tumor uptake was maintained after 120 hours, demonstrating its suitability as a FAP-targeted therapeutic probe for tumor radioactive SPECT imaging and subsequent treatment.

[0484] Test Example 5 177 Study on SPECT Imaging of Lu-FAPI-FX-07

[0485] According to the method similar to that of Experimental Example 4, 400-500 μCi / 0.2 mL of 177 After Lu-FAPI-FX-07, small animal SPECT imaging experiments were performed at 1 hour, 4 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, and 120 hours. The imaging images are shown in Figure 89. 177 Lu-FAPI-FX-07 demonstrated high radioactive uptake, with significant contrast in non-target organs. The tumor imaging effect persisted in vivo for a long time and exhibited excellent stability. Tumor uptake was maintained after 120 hours. This demonstrates its suitability as a FAP-targeted therapeutic probe for tumor radioactive SPECT imaging and subsequent treatment.

[0486] Test Example 6 177 Study on the therapeutic efficacy of Lu-FAPI-FUSCC-02-DIMER

[0487] SPF grade Balb / c nude mice, female, 6 weeks old, were provided by Hangzhou Ziyuan 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 feed for 2-4 weeks after injection until the solid tumor mass grows to 100mm 3 For treatment experiments: the blank control group was not treated; the secondary administration group was injected with 200 μCi / 0.2 mL of 177 On the seventh day after Lu-FAPI-FUSCC-02-DIMER, 200 μCi / 0.2 mL was administered again; the high-dose group was injected with 400 μCi / 0.2 mL of Lu-FAPI-FUSCC-02-DIMER via the tail vein. 177 Lu-FAPI-FUSCC-02-DIMER; Tumor volume and body weight of mice were measured every other day after injection. Curve fitting was performed using Graphpad Prism 9.0. The results are shown in Figures 90 and 91. The treatment data for the FAP-positive tumor model showed that 177The tumor treatment effect of Lu-FAPI-FUSCC-02-DIMER significantly inhibited the growth of tumors compared with the blank control group, and there was no significant difference in body weight between each group, which proved that 177 Lu-FAPI-FUSCC-02-DIMER can be used for tumor radiotherapy.

[0488] To investigate the advantages of the dimer compared with the monomer, the present application also compared and studied the treatment effect of the 177Lu labeled monomer.

[0489] Comparative Example 1 Compound 177 Preparation of Lu-FAPI-FUSCC-02

[0490] The FAPI-FUSCC-02 precursor was dissolved in sterile injection water to prepare a precursor solution with a concentration of 1 μg / μL. A solution with a concentration of 0.04 M HCl was used 177 LuCl3solution. 4 μL of the precursor solution, 10 μL of a 0.5 M sodium acetate solution, 10 μL of a 0.05 M hydrochloric acid, 10 μL of injection water, and 10 μL of 177 LuCl3solution were added to the precursor reagent bottle, respectively. After heating the solution in the precursor reagent bottle to 90°C for 20 min, the final product 177 Lu-FAPI-FUSCC-02 was obtained. Its radiochemical purity was determined by Radio-HPLC. The relevant analysis spectrum is shown in Figure 92. The specific reaction route is as follows:

[0491] Comparative Example 2 SPECT Imaging Study

[0492] SPF level Balb / c nude mice, female, 6 weeks old, were provided by Hangzhou Ziyuan Biotechnology Co., Ltd. After being fed in the animal room for two days, FAP transfected HT1080 human fibrosarcoma cells were injected subcutaneously into the right axillary of the nude mice, and the injection amount was 0.1 mL (5×10 6 cells / mL dispersed in HBSS). After injection, they were continued to be fed for 2-4 weeks until the solid tumor mass grew to 500-600 mm 3 When used for imaging experiments: 400-500 μCi / 0.2 mL of 177 Lu-FAPI-FUSCC-02 was injected through the tail vein, and after injection, small animal SPECT was used for treatment imaging experiments at 1 h, 4 h, 24 h, 48 h, 72 h, 96 h, 120 h. The imaging diagram is shown in Figure 93. It can be found that 177 Lu-FAPI-FUSCC-02 has a certain uptake at the tumor site, but its tumor radioactive concentration is much lower than 177Lu-FAPI-FUSCC-02-DIMER, at the same time 177 The imaging results of Lu-FAPI-FUSCC-02 showed that it has a physiological distribution in organs such as the gastrointestinal tract, which may lead to non-target toxicity problems in future therapeutic applications.

[0493] Comparative Example 3: Study on therapeutic efficacy

[0494] SPF grade Balb / c nude mice, female, 6 weeks old, were provided by Hangzhou Ziyuan 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 feed for 2-4 weeks after injection until the solid tumor mass grows to 100mm 3 The blank control group was not treated; the treatment group was injected with 500 μCi / 0.2 mL of 177 Lu-FAPI02; Tumor volume and body weight of mice were measured every other day after injection. Curve fitting was performed using Graphpad Prism 9.0. The results are shown in Figures 94 and 95. The treatment data for the FAP-positive tumor model showed that 177 Compared with the blank control group, the tumor survival of the Lu-FAPI-FUSCC-02 treatment group was inhibited to a certain extent, but the inhibitory effect was far lower than 177 Lu-FAPI-FUSCC-02-DIMER.

[0495] Combining the SPECT / CT imaging and treatment experimental results of Experimental Examples 3 to 5 and Comparative Examples 2 to 3, it can be preliminarily explained that 177 Lu-FAPI-FUSCC-02-DIMER has a far better therapeutic effect on tumors than 177 Lu-FAPI-FUSCC-02.

[0496] 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 agent or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically- substituted compound, metabolite, or prodrug thereof; wherein, characterized in that The FAP binding agent has a structure as shown in Formula (I): L is a metal chelator; X1and X2are each independently selected from NH, NR, O or S, wherein R is C 1-6 alkyl; each A1and A2is 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 with at least one substituent independently selected from R XA ; each Y1and Y2is 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 with at least one substituent independently selected from R XY ; Z is selected from C 1-10 Haloalkyl, N, C(O)-C 1-10 Haloalkyl-NH, NH-C 1-10 Haloalkyl-C(O), -C(O)-C 1-10 Haloalkyl-N(C 1-6 alkyl)-, -N(C 1-6 alkyl)-C 1-10 Haloalkyl-C(O)-, C(O)-C 1-10 Haloalkyl-NHC(O), C(O)NH-C 1-10 Haloalkyl-C(O), -C(O)-C 1-10 Haloalkyl-N(C 1-6 alkyl)C(O)-, -C(O)N(C 1-6 alkyl)-C 1- 10 Haloalkyl-C(O)-, C(O)-C 1-10 Haloalkyl-NHC(S), C(S)NH-C 1-10 Haloalkyl-C(O), -C(O)-C 1-10 Haloalkyl-N(C 1-6 alkyl)C(S)-, -C(S)N(C 1-6 alkyl)-C 1-10 Haloalkyl-C(O)-, C(O)-C 1-10 Haloalkyl, C 1-10 Haloalkyl-C(O), NH-C 1-10 Haloalkyl-NH, -NH-C 1-10 Haloalkyl-N(C 1-6 alkyl)-, -N(C 1-6 alkyl)-C 1-10 Haloalkyl-NH-, -N(C 1-6 alkyl)-C 1-10 Haloalkyl-N(C 1-6 alkyl)-, amino acids and amino acid sequences, wherein each alkyl and haloalkyl is unsubstituted or substituted with at least one substituent independently selected from R XZ ; m1 is an integer selected from 0 to 10; R1, R2are each independently selected from H, halogen or C 1-6 alkyl; 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; 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. X1 and X2 are NH or O.

2. The FAP binder or pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically enriched compound, metabolite, or prodrug thereof of claim 1, characterized in that 3. The FAP binding agent of any one of claims 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically- substituted compound, metabolite, or prodrug thereof, characterized in that each A1 and A2 is independently selected from the group consisting of a covalent bond and an amino acid; preferably, each amino acid in A1 and A2 is independently selected from the group consisting of glycine, aspartic acid, glutamine, alanine, valine, and phenylglycine.

4. The FAP binding agent of any one of claims 1-3, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically- substituted compound, metabolite, or prodrug thereof, characterized in that In particular, h is 1, 3, or 5. (A1) m1 structure and (A2) m2 structure is independently selected from the group consisting of a covalent bond, (Gly) h , Ala, Gly-Asp-Gln, Gln-Asp-Gly, Ala-Phg-Val, and Val-Phg-Ala, wherein h is an integer selected from 1 to 10; 5. The FAP binding agent of any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically- substituted compound, metabolite, or prodrug thereof, characterized in that 6. The FAP binding agent of any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically- substituted compound, metabolite, or prodrug thereof, characterized in that each Y1and Y2is independently selected from a covalent bond, C 1-10 alkylene, C(O), C(S), NH, (C2H4-O) d , (O-C2H4) d , C(O)-C 1-10 alkylene-NH, NH-C 1-10 alkylene-C(O), C(O)-C 1-10 alkylene and C 1-10 alkylene-C(O).

7. The FAP binding agent of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically- substituted compound, metabolite, or prodrug thereof, characterized in that (Y1) n1 Structure and (Y2) n2 Structure is each independently selected from a covalent bond, C(O)-C 1-10 alkylene-NH, -C 1-10 alkylene-NH-C(O)-C 1-10 alkylene-NH-, -NH-C 1-10 alkylene-C(O)-NH-C 1-10 alkylene-, NH-C 1-10 alkylene-C(O), -NH-C 1-10 alkylene-C(O)-NH-C 1-10 alkylene-, 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, NH-C 1-10 alkylene-(C2H4-O) d -C 1-10 alkylene-C(O), -C 1-10 alkylene-NH-, -NH-C 1-10 alkylene-, -C(S)-NH-C 1-10 alkylene-NH- and -NH-C 1-10 alkylene-NH-C(S)-. Z is an amino acid; Preferably, Z is selected from the group consisting of glutamic acid, aspartic acid, lysine, and serine; In particular, Z is selected from the group consisting of glutamic acid, aspartic acid, and lysine.

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

9. The FAP binding agent of any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically- substituted compound, metabolite, or prodrug thereof, characterized in that 10. The FAP binding agent of any one of claims 1-9, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically- substituted compound, metabolite, or prodrug thereof, characterized in that L is R1 and R2 are each independently selected from the group consisting of H and halogen; Preferably, R1 and R2 are H or F. ​ 11. The FAP binding agent of any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopically enriched compound, metabolite, or prodrug thereof, selected from 12. A metal complex of the FAP binding agent or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopologue, metabolite or prodrug thereof of claim 1, characterized in that The metal complex has a structure as 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 of claim 12, characterized in that M is a radioisotope metal; Preferably, M is any one of Ga, Lu, Y, Ac, Bi, Re; More preferably, M is any one of Ga-68, Lu-177, Y-90, Ac-225, Bi-213 and Re-188; In particular, M is Ga-68 or Lu-177.

14. The metal complex of claim 12 or 13, having the structure:

15. A pharmaceutical composition comprising the FAP binding agent of any one of claims 1-11 or the metal complex of any one of claims 12-14, and at least one pharmaceutically acceptable carrier.

16. Use of the FAP binding agent of any one of claims 1-11 or the metal complex of any one of claims 12-14 for the manufacture of an imaging agent or theranostic probe.

17. Use according to claim 16, characterized in that, The method of achieving said imaging is contacting a cell or tissue with the metal complex of any one of claims 12-14 and imaging by detecting and imaging the compound within the cell or tissue; the method of achieving said theranostic is contacting a cell or tissue with the metal complex of any one of claims 12-14 and detecting and treating the compound within the cell or tissue.

18. Use according to claim 16 or 17, characterized in that, The imaging agent or theranostic probe is for cancer, tumor or neoplasm.

19. The use for the preparation of the point-of-care probe according to any one of claims 16-18, characterized in that, M in the metal complex is any one of Lu, Y, Ac, Bi, Re; Preferably, M is any one of Lu-177, Y-90, Ac-225, Bi-213 and Re-188; In particular, M is Lu-177.

20. Use according to any one of claims 16 to 19, characterized in that, The imaging is by positron emission tomography (PET).

21. Use according to any one of claims 16 to 19, characterized in that, The imaging or theranostic is by single photon emission tomography (SPECT).

22. Use of the FAP binding agent of any one of claims 1-11 or the metal complex of any one of claims 12-14 or the pharmaceutical composition of claim 15 for the manufacture of a medicament for the treatment of a disease, disorder, or condition; wherein, The disease, disorder or condition is selected from a FAP overexpressing disease, the FAP binding agent or metal complex or pharmaceutical composition being optionally used in combination with a second therapeutic agent.

23. Use according to claim 22, characterized in that, The FAP overexpressing disease is cancer, tumor or neoplasm.

24. Use according to claim 23, characterized in that, The cancer includes any one or several of ocular 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, throat cancer, skin melanoma, acute lymphocytic 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, nephroblastoma, neuroblastoma, esophageal cancer, laryngeal cancer, lymphoma, neurofibroma, tuberous sclerosis, hemangioma, or lymphatic cancer. The cancer includes any one or several of ocular 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, throat cancer, skin melanoma, acute lymphocytic 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, nephroblastoma, neuroblastoma, esophageal cancer, laryngeal cancer, lymphoma, neurofibroma, tuberous sclerosis, hemangioma, or lymphatic cancer.

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