Compounds targeting fibroblast activating proteins and uses thereof

Abstract

The invention discloses a compound targeting fibroblast activating protein and application of the compound. The compound is a compound as shown in a formula I or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound as shown in the formula I. The compound has high affinity with the fibroblast activating protein, can target the fibroblast activating protein, gathers at a tumor part, and can visualize the tumor through an imaging technology. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, in particular to a compound targeting fibroblast activation protein and a use thereof. Background Art

[0002] Fibroblast activation protein (FAP) is highly overexpressed in cancer-associated fibroblasts (CAFs) of solid tumors, but is usually not expressed in normal tissues and benign tumors. CAFs can promote the growth and invasion of tumor cells, and therefore become an important target for tumor intervention. Overexpression of FAP is a significant feature of CAFs, making it a potential target for tumor diagnosis and treatment. FAP is a type II transmembrane serine protease that exists on the cell surface in the form of a homodimer and belongs to the proline oligopeptidase family. Its enzymatic activity plays a key role in tumor growth and tissue remodeling. CAF surface-specific FAPα enhances the ability of tumor cells to invade along the fibers by promoting matrix reconstruction and participating in signal transduction pathways such as VEGF / AKT / ERK, and participates in tumor angiogenesis, thereby forming a tumor biological barrier, inhibiting the function of effector T cells, and promoting tumor progression.

[0003] The combination of fluorescence and radiopharmaceuticals offers significant potential benefits in tumor treatment and surgery. This integrated approach combines the high resolution of fluorescence imaging with the deep detection capabilities of radiopharmaceuticals, which can significantly improve the accuracy, effectiveness and safety of treatment. Among them, fluorescence navigation technology provides real-time high-definition visualization images to help doctors clearly mark tumor tissue and important structures during surgery, especially in small or difficult-to-reach tumors. This technology enables doctors to observe the tumor boundaries in real time, thereby ensuring that the tumor is removed as completely as possible. At the same time, radiopharmaceuticals (such as molecular probes labeled with radioisotopes) can penetrate deep into the body and use radioactive imaging technologies such as PET (positron emission tomography) or SPECT (single photon emission computed tomography) to accurately locate the distribution and boundaries of the tumor, which is particularly suitable for the detection of deep tumors. By combining these two technologies, the efficiency and safety of tumor treatment can be significantly improved.

[0004] Therefore, there is an urgent need to develop a drug that has better targeting, avoids uptake by normal tissues, and can be used for integrated radioactivity and fluorescence. Summary of the invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art to a certain extent. To this end, the present invention provides a compound that has a high affinity with fibroblast activation protein, can target fibroblast activation protein, and accumulate at the tumor site, and can visualize the tumor through imaging technology, helping doctors to accurately identify tumor tissue during surgery, thereby achieving precise resection.

[0006] Therefore, in the first aspect of the present invention, the present invention provides a compound, which is a compound of formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula I:

[0007]

[0008] Wherein, L is selected from -NH-C 1～6 Alkylene-; X is selected from a fluorescent group; Y is selected from a chelating agent; and n is selected from any integer between 1-6.

[0009] In the present invention, the definitions of certain substituents in the compound as shown in Formula I can be as described below, and the definitions of substituents not mentioned are as described in any of the above schemes.

[0010] According to an embodiment of the present invention, L has the following structure:

[0011]

[0012] According to an embodiment of the present invention, the L is selected from -NH-C 2～6 Alkylene-.

[0013] According to an embodiment of the present invention, the L is selected from -NH-C 2～5 Alkylene-.

[0014] According to an embodiment of the present invention, n is any integer selected from 1, 2, 3, 4, 5, and 6.

[0015] According to an embodiment of the present invention, the compound is a compound represented by Formula II or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by Formula II:

[0016]

[0017] Wherein, X is selected from a fluorescent group; and Y is selected from a chelating agent.

[0018] According to an embodiment of the present invention, the fluorescent group is selected from anthocyanin fluorescent groups.

[0019] According to an embodiment of the present invention, the fluorescent group is derived from Cy3, Cy3.5, Cy5, Cy5.5, Cy7, Cy7.5, sulfonated-Cy3, sulfonated-Cy5, sulfonated-Cy7 or ICG.

[0020] According to an embodiment of the present invention, the fluorescent group has the following structure:

[0021]

[0022] According to an embodiment of the present invention, the chelating agent is derived from 1,4,7,10-tetraazacyclododecane-N,N',N",N",tetraacetic acid, N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid, 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)pentanedioic acid, 2 -(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid, 1,4,7-triazacyclononanephosphinic acid, 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid], 3,6,9,15-tetraazabicyclo[9.3.1.]pentadeca-1(15),11,13 -triene-3,6,9-triacetic acid, N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide, diethylenetriaminepentaacetic acid, trans-cyclohexyl-diethylenetriaminepentaacetic acid, 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid, para-isothiocyanate At least one of 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA, 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA, 1-(2)-methyl-4-isothiocyanatobenzyl-DTPA, [R]-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid, and 6-hydrazinopyridine-3-carboxylic acid.

[0023] According to an embodiment of the present invention, the chelating agent has the following structure:

[0024]

[0025] In the second aspect of the present invention, the present invention provides a compound. According to an embodiment of the present invention, the compound has the following structure:

[0026]

[0027] According to an embodiment of the present invention, the compound has the following structure:

[0028]

[0029] In the third aspect of the present invention, the present invention provides a complex. According to an embodiment of the present invention, the complex is formed by the compound described in the first aspect or the second aspect and M, wherein M is at least one of a radioactive nuclide or a non-radioactive element.

[0030] According to an embodiment of the present invention, the radioactive nuclide includes at least one of a diagnostic nuclide or a therapeutic nuclide.

[0031] According to an embodiment of the present invention, the diagnostic nuclide comprises 68 Ga, 18 F. 99m Tc, 89 Zr, 124 I. 76 Br, 43 Sc, 111 In, 45 Ti, 52 Mn, 59 Fe, 64 Cu, 94m Tc, 67 Ga, 71 / 72 / 74 As, 82m Rb, 86 At least one of Y.

[0032] According to an embodiment of the present invention, the therapeutic nuclide comprises 177 Lu, 90 Y. 131 I. 153 Sm, 67 Cu, 89 Sr. 166 Ho, 177 Yb, 47 Sc, 186 / 188 Re, 212 / 213 Bi, 149 Pm, 212 Pb, 211 At 223 Ra, 225 Ac, 227 At least one of Th.

[0033] According to an embodiment of the present invention, the radionuclide is selected from 68 Ga, 18 F. 89 Zr, 99m Tc, 177 At least one of Lu.

[0034] According to an embodiment of the present invention, the M is selected from 68 Ga, 177 Lu, 18 At least one of F.

[0035] According to an embodiment of the present invention, the diagnostic nuclide 18 F is obtained by 18 F]AlF is complexed with the compound.

[0036] According to an embodiment of the present invention, the complex has the following structure:

[0037]

[0038] According to an embodiment of the present invention, the complex has the following structure:

[0039]

[0040] In a fourth aspect of the present invention, the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises: the compound described in the first aspect or the second aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the complex described in the third aspect.

[0041] According to an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

[0042] In the fifth aspect of the present invention, the present invention proposes the use of the compound described in the first aspect or the second aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the complex described in the third aspect, or the pharmaceutical composition described in the fourth aspect in the preparation of reagents and / or drugs, wherein the reagents and / or drugs have at least one of the following functions: used for diagnosing and / or treating tumors, cancers or cells characterized by expressing fibroblast activation protein; used for inhibiting the expression of fibroblast activation protein.

[0043] According to an embodiment of the present invention, the diagnostic method is selected from optical imaging and / or nuclear imaging.

[0044] According to an embodiment of the present invention, the diagnostic method is selected from fluorescence imaging, PET imaging and / or SPECT imaging.

[0045] According to an embodiment of the present invention, the treatment is selected from radiation therapy.

[0046] According to an embodiment of the present invention, the tumor or cancer includes at least one of melanoma, esophageal cancer, breast cancer, bile duct cancer, lung cancer, liver cancer, colorectal cancer, head and neck cancer, gastric cancer, follicular dendritic cell sarcoma (FDCS), fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, cervical cancer, bladder cancer, brain cancer, and neuroendocrine tumors.

[0047] According to an embodiment of the present invention, the tumor or cancer includes at least one of follicular dendritic cell sarcoma, gastric cancer, fibrosarcoma, osteosarcoma, pancreatic cancer, and ovarian cancer.

[0048] In the sixth aspect of the present invention, the present invention proposes the use of the compound described in the first aspect or the second aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the complex described in the third aspect, or the pharmaceutical composition described in the fourth aspect in the preparation of a molecular imaging agent, wherein the molecular imaging includes imaging of various cells, tissues or other living organisms, and the imaging agent is used to image tumors and cancers characterized by expressing fibroblast activation protein.

[0049] According to an embodiment of the present invention, the imaging method is selected from fluorescence imaging, PET imaging and / or SPECT imaging.

[0050] According to an embodiment of the present invention, the tumor or cancer includes at least one of melanoma, esophageal cancer, breast cancer, bile duct cancer, lung cancer, liver cancer, colorectal cancer, head and neck cancer, gastric cancer, follicular dendritic cell sarcoma (FDCS), fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, cervical cancer, bladder cancer, brain cancer, and neuroendocrine tumors.

[0051] According to an embodiment of the present invention, the tumor or cancer includes at least one of follicular dendritic cell sarcoma, gastric cancer, fibrosarcoma, osteosarcoma, pancreatic cancer, and ovarian cancer.

[0052] In the seventh aspect of the present invention, the present invention provides a method for diagnosing and / or treating a tumor, cancer or cell characterized by expressing fibroblast activation protein. According to an embodiment of the present invention, the method comprises administering to a patient a pharmaceutically acceptable dose of the compound of the first aspect or the second aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the complex of the third aspect, or the pharmaceutical composition of the fourth aspect.

[0053] In the eighth aspect of the present invention, the present invention proposes the use of the compound described in the first aspect or the second aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the complex described in the third aspect, or the pharmaceutical composition described in the fourth aspect for diagnosing and / or treating tumors, cancers or cells characterized by expressing fibroblast activation protein.

[0054] According to an embodiment of the present invention, the diagnostic method is selected from optical imaging and / or nuclear imaging.

[0055] According to an embodiment of the present invention, the diagnostic method is selected from fluorescence imaging, PET imaging and / or SPECT imaging.

[0056] According to an embodiment of the present invention, the treatment is selected from radiation therapy.

[0057] According to an embodiment of the present invention, the tumor or cancer includes at least one of melanoma, esophageal cancer, breast cancer, bile duct cancer, lung cancer, liver cancer, colorectal cancer, head and neck cancer, gastric cancer, follicular dendritic cell sarcoma (FDCS), fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, cervical cancer, bladder cancer, brain cancer, and neuroendocrine tumors.

[0058] According to an embodiment of the present invention, the tumor or cancer includes at least one of follicular dendritic cell sarcoma, gastric cancer, fibrosarcoma, osteosarcoma, pancreatic cancer, and ovarian cancer.

[0059] In the ninth aspect of the present invention, the present invention provides a method for imaging a tissue expressing fibroblast activation protein. According to an embodiment of the present invention, the method comprises administering the compound of the first aspect or the second aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the complex of the third aspect, or the pharmaceutical composition of the fourth aspect to the tissue, and imaging the tissue after administration.

[0060] According to an embodiment of the present invention, the imaging is performed by emission computed tomography or fluorescence imaging.

[0061] According to an embodiment of the present invention, the emission computed tomography is performed by positron emission tomography (PET imaging) or single photon emission computed tomography (SPECT imaging).

[0062] Beneficial effects:

[0063] 1) The compounds, complexes and pharmaceutical compositions of the present invention have high affinity with fibroblast activation protein (FAP), can target tumors characterized by overexpression of fibroblast activation protein, and have good specific targeting binding;

[0064] 2) The compounds, complexes and pharmaceutical compositions of the present invention can achieve fluorescence imaging, PET imaging and / or SPECT imaging, thereby effectively visualizing the targeted tumor. In animal models, these compounds, complexes and pharmaceutical compositions can specifically bind to tumors for a long time, which is helpful for the application of clinical fluorescence imaging surgical navigation.

[0065] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] The above and / or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:

[0067] Figure 1 is the LCMS spectrum of target compound 8 according to an embodiment of the present invention;

[0068] Figure 2 is the HPLC spectrum of target compound 8 according to an embodiment of the present invention;

[0069] Figure 3 According to an embodiment of the present invention 68 Radioactive thin layer chromatography scanning result of Ga-target compound 8;

[0070] Figure 4 According to an embodiment of the present invention 68 PET / CT SUV mean values ​​of tumor and normal organs of Ga-target compound 8 at different times in B-hFAP MC38 tumor-bearing mouse model;

[0071] Figure 5 According to an embodiment of the present invention 68 PET / CT SUV mean values ​​of tumor and normal organs of Ga-target compound 8 at different times in NCI-N87 tumor-bearing mouse model;

[0072] Figure 6 is a real-time fluorescence image of the NCI-N87 model at 1 hour and 4 hours after injection of target compound 8 according to an embodiment of the present invention;

[0073] Figure 7 is an in vitro fluorescent image of the tumor and main organs of the NCI-N87 model 4 hours after injection of the target compound 8 according to an embodiment of the present invention;

[0074] Figure 8It is a real-time fluorescence image of the B-hFAP MC38 model at 1h, 2h, 3h, and 4h after injection of the target compound 8 according to an embodiment of the present invention;

[0075] Fig. 9 4 hours after injection of target compound 8 according to an embodiment of the present invention, the in vitro fluorescence image of the tumor and main organs of the B-hFAP MC38 model. DETAILED DESCRIPTION

[0076] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0077] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0078] As used herein, the terms "optionally", "optional" or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0079] Definitions and general terms

[0080] It should be noted that, for the structural formula and chemical formula description in the embodiments or embodiments of the present invention, the present invention is intended to cover all substitutions, modifications and equivalent technical solutions, which are all within the scope of the present invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described in the present invention can be used to practice the present invention. The present invention is by no means limited to the methods and materials described in the present invention. In the event that one or more of the combined documents, patents and similar materials are different from or contradictory to the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present invention shall prevail.

[0081] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments or implementations, may also be provided in combination in a single embodiment or implementation. Conversely, various features of the invention, which for brevity are described in a single embodiment or implementation, may also be provided separately or in any suitable sub-combination.

[0082] Unless otherwise noted, technical and scientific terms used in the present invention have the same meanings as commonly understood by those skilled in the art to which the present invention belongs. Unless otherwise noted, all patent publications cited in the entire disclosure of the present invention are incorporated herein by reference in their entirety.

[0083] Unless otherwise indicated, the following definitions apply to the present invention. For the purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS version and Handbook of Chemicals, 75, th Ed, 1994. In addition, general principles of organic chemistry are found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, and all of the contents of the present invention are incorporated by reference.

[0084] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention but not excluding other contents.

[0085] As used herein, the compounds of the present invention also include isotopically labeled compounds of the present invention, which are identical to those described herein except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that may also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 14 C. 15 N. 16 O. 17 O. 31 P. 32 P. 36 S. 18 F and 37 Cl.

[0086] Compounds of the invention containing the aforementioned isotopes and / or other isotopes of other atoms and pharmaceutically acceptable salts of the compounds are included within the scope of the invention. Isotopically labeled compounds of the invention, for example radioactive isotopes, such as 3 H and 14 C incorporation into the compounds of the present invention can be used for drug and / or substrate tissue distribution analysis. 3H), and carbon-14 (i.e. 14 C), isotopes are particularly preferred. In addition, heavy isotopes, such as deuterium (i.e. 2 H substitution), may offer some therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Therefore, it may be preferred in some circumstances.

[0087] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, CH2O is equivalent to OCH2. As used herein, Indicates the attachment site of a group.

[0088] The stereochemical definitions and conventions used herein are generally in accordance with SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and mixtures thereof such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes d and l or (+) and (-) are the signs used to designate the rotation of plane polarized light caused by a compound, where (-) or l indicates that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. With respect to a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0089] Depending on the choice of starting materials and processes, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, for example as pure optical isomers, or as isomer mixtures, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral agents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis- or trans- configuration.

[0090] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0091] Unless otherwise indicated, structures depicted herein are also meant to include all isomers (e.g., enantiomers, diastereomeric atropisomers, and geometric (or conformational) forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.

[0092] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the invention may exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R, S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of (R)- or (S)-configuration. Substituents on atoms with unsaturated double bonds may exist in cis-(Z)- or trans-(E)-forms, if possible.

[0093] Therefore, as described herein, the compounds of the present invention may exist in the form of one or a mixture of possible isomers, rotamers, atropisomers, tautomers, for example, in the form of substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0094] Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the components into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0095] Any racemate of the final product or intermediate obtained can be separated into optical antipodes by known methods by methods familiar to those skilled in the art, such as by separation of the salts of the diastereoisomers obtained. The racemic product can also be separated by chiral chromatography, such as high pressure liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis (e.g., Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0096] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions performed by the reorganization of some bonding electrons. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0097] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0098] As used herein, the term "solvate" refers to an association formed by one or more solvent molecules and the compounds of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association formed by a solvent molecule that is water.

[0099] As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0100] As used herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.

[0101] The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. The prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.

[0102] In this article, the term “C 1～6 "Alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as C 1～5 Alkyl, C 1～4 Alkyl, C 1～3 Alkyl, C 2～5 Alkyl, C 2～4 Alkyl, C 2～3Alkyl. These include, but are not limited to, methyl, ethyl, n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2C H2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl ( -CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), wherein the alkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0103] In this context, the term "alkylene" refers to a group formed by removing a hydrogen atom from an "alkyl" group, wherein "C 1～6 "Alkylene" includes methylene, ethylene, propylene, isopropylene (such as ), butylene (such as ), pentylene (such as ), hexamethylene (such as )wait.

[0104] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key Indicates the relative configuration of a stereocenter.

[0105] In the chemical structure of the ligand or compound disclosed in the present invention, the bond Indicates that the configuration is not specified. If chiral isomerism exists in the chemical structure, the bond Can be or include both Although all of the above structural formulae are drawn in certain isomeric forms for simplicity, the present disclosure may include all isomers, for example, tautomers, rotational isomers, geometric isomers, diastereomers, racemates, and enantiomers.

[0106] The group description of the present invention It is used to describe the position of group substitution.

[0107] In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0108] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0109] In this article, the term "pharmaceutically acceptable excipients" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, coloring agent, or a combination thereof, which are all known to those skilled in the art (such as Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except for the case where any conventional carrier is incompatible with the active ingredient, its use in treatment or pharmaceutical composition is covered.

[0110] In this article, the term "administration" refers to the introduction of a predetermined amount of material into a patient by a suitable method. The compound or pharmaceutical composition of the present invention can be administered by any common route as long as it can reach the desired tissue. Various modes of administration are expected, including peritoneal, intravenous, intramuscular, subcutaneous injection, etc., but the present invention is not limited to these exemplified modes of administration. Preferably, the composition of the present invention is administered by intravenous or subcutaneous injection.

[0111] As used herein, the term "treatment" refers to the use of drugs to obtain the desired pharmacological and / or physiological effects. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, and / or may be therapeutic in terms of partially or completely curing a disease and / or the adverse effects caused by the disease. "Treatment" as used herein covers diseases in mammals, particularly humans, and includes: (a) preventing the occurrence of a disease or condition in an individual who is susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting the disease, such as blocking the progression of the disease; or (c) alleviating the disease, such as alleviating symptoms associated with the disease. "Treatment" as used herein covers any medication that administers a drug or compound to an individual to treat, cure, alleviate, improve, reduce or inhibit an individual's disease, including but not limited to administering a drug containing a compound described herein to an individual in need.

[0112] The term "patient" refers to any animal, preferably a mammal, that is about to or has been administered the compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., preferably humans.

[0113] The term "therapeutically effective amount" refers to an amount of a compound that is effective in treating a disease or condition described herein when administered to a patient."Therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and can be adjusted as needed by those skilled in the art.

[0114] The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used are not indicated by the manufacturer and are all conventional products that can be obtained commercially.

[0115] Chemical Abbreviation

[0116] DMF: N,N-dimethylformamide

[0117] MeI: methyl iodide

[0118] DIEA: N,N-diisopropylethylamine

[0119] HATU: peptide condensation reagent, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl) urea hexafluorophosphate

[0120] THF: Tetrahydrofuran

[0121] HOBt: 1-Hydroxybenzotriazole

[0122] EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;

[0123] DCM: dichloromethane

[0124] TFA: trifluoroacetic acid

[0125] CY7-NHS: CY7-N-hydroxysuccinimide

[0126] Example 1: Preparation of target compound

[0127]

[0128] Step 1:

[0129]

[0130] At 20°C, NaHCO3 (5.52 g, 5.00 eq) and MeI (9.33 g, 5.00 eq) were added to DMF (50.0 mL) containing compound 1 (5.00 g, 1.00 eq), and the mixture was stirred at 20°C for 12 h. The reaction solution was diluted with H2O (200 mL), extracted with ethyl acetate, and the organic phases were combined, washed with saturated saline solution, dried over anhydrous sodium sulfate, and then spin-dried to obtain a crude product. The crude product was separated and purified by column chromatography to obtain compound 2 (5.00 g).

[0131] Step 2:

[0132]

[0133] Compound 2 (2.00 g, 1.00 eq) was dissolved in MeOH (40.0 mL), Pd / C (320 mg, purity 10.0%) was added, and the reaction was stirred at 20°C and H2 (15.0 psi) for 1 h. After filtration, the filtrate was concentrated under reduced pressure to obtain compound 3 (1.10 g).

[0134] Step 3:

[0135]

[0136] Compound 3 (129 mg, 1.50 eq) was dissolved in DMF (2.00 mL), and DIEA (171 mg, 4.00 eq), HATU (189 mg, 4.00 eq), and compound 3a (138 mg, 1.00 eq) were added in sequence. The reaction was stirred at 20°C for 12 h. The reaction solution was directly prepared by reverse phase (10 mM ammonium bicarbonate) to obtain compound 4 (200 mg).

[0137] Step 4:

[0138]

[0139] At 0°C, LiOH (19.1 mg, 1.50 eq) dissolved in H2O (2.00 mL) was added to compound 4 (200 mg, 1.00 eq) in THF (3.00 mL), and the mixture was stirred at 20°C for 12 h. The reaction solution was directly prepared by reverse phase (10 mM ammonium bicarbonate) to obtain compound 5 (50.0 mg).

[0140] Step 5:

[0141]

[0142] Compound 5 (129 mg, 1.50 eq) was dissolved in DMF (0.50 mL), and HOBt (13.3 mg, 1.50 eq), EDCI (18.9 mg, 1.50 eq), DIEA (51.1 mg, 6.00 eq), and compound 5a (62.0 mg, 1.40 eq) were added in sequence. The reaction was stirred at 20°C for 12 h. The reaction solution was directly prepared by reverse phase (0.075% TFA conditions) to obtain compound 6 (50.0 mg).

[0143] Step 6:

[0144]

[0145] Compound 6 (40.0 mg, 1.00 eq) was dissolved in DCM (1.00 mL) and TFA (6.00 mL) was added. The reaction was stirred at 20°C for 12 h. The reaction solution was concentrated under reduced pressure to obtain unpurified compound 7, which was directly used in the next step.

[0146] Step 7:

[0147]

[0148] Compound 7 (40.0 mg) was dissolved in DMF (1.00 mL), and DIEA (50.3 mg, 10.0 eq) and CY7-NHS (27.3 mg, 0.90 eq) were added in sequence. The reaction was stirred at 20°C for 2 h. The reaction solution was directly prepared by reverse phase (0.075% TFA) to obtain the target compound 8 (13.0 mg, purity: 97.9%).

[0149] LCMS cal.:1576.7,MS observed:[M / 2+H] + =789.8 (e.g. Figure 1 (shown)

[0150] HPLC: Purity: 97.9% (as Figure 2 (shown)

[0151] Example 2: Method for labeling compounds with radioactive elements

[0152] Add 1 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to the vial, then add 60 μL of the aqueous solution of target compound 8 prepared in Example 1 (containing 60 μg of target compound 8), mix thoroughly, and add 1 mL 68 The reaction solution was reacted at 25°C for 15 min, and then the reaction was terminated. After separation and purification, samples were taken for testing.

[0153] The radiochemical purity of the product was determined by Radio-iTLC method. 68 The radioactive thin layer chromatography scanning results of Ga-target compound 8 are as follows Figure 3 As shown, the results showed that the radiochemical purity was >90%.

[0154] Example 3: Affinity (SPR) test of target compounds

[0155] The affinity of the test compound (target compound 8 prepared in Example 1) to FAP was determined using the Biacore 8K protein interaction system. FAP protein (purchased from ACROBiosystems Inc) was coupled to the surface of the CM5 chip. Five different concentrations of the test compound were configured for affinity determination, with the highest concentration of the test compound being 70 nM and the dilution ratio being 2. The sample was injected and the affinity of the test sample to FAP was measured. The affinity of the test sample to FAP is represented by the equilibrium dissociation constant KD (Kd / Ka) value, where Kd is the dissociation constant and Ka is the binding constant. The smaller the KD value, the higher the affinity of the test sample to the protein.

[0156] The test results are as follows: The equilibrium dissociation constant KD value of the target compound 8 binding to FAP is (4.25±0.17)E-10M, which shows that the target compound 8 has a strong affinity with the FAP protein.

[0157] Example 4: Animal Experiment

[0158] Experimental equipment:

[0159] PET / CT: SNPC-303 SuperNova, purchased from Pingsheng Medical Technology (Kunshan) Co., Ltd.

[0160] IVIS Spectrum Small Animal Intravital Imaging System.

[0161] Experimental Animals:

[0162] The B-hFAP MC38 model is provided by Biocytogen Jiangsu Gene Biotechnology Co., Ltd. It is a transgenic model constructed from MC38 mouse colon cancer cells. Human FAP is highly expressed on the surface of B-hFAP MC38 cells. It is a subcutaneous heterotopic transplant tumor model established based on C57BL / 6 mice.

[0163] The NCI-N87 model is provided by Shanghai Runnuo Biotechnology Co., Ltd. It is an NCI-N87 tumor xenograft mouse model, which is a mouse model constructed from human gastric cancer cells.

[0164] 4.1 68 Tissue distribution and targeting experiment of Ga-target compound 8 in PET / CT scanning of tumor model mice

[0165] Three B-hFAP MC38 models and three NCI-N87 models were randomly selected and each was given the above 68 The Ga-target compound 8 drug was about 80 μCi, and the animals were placed in the MicroPET / CT imaging cabin. The B-hFAPMC38 model group underwent dynamic 30 minutes, static 1 hour, 2 hours, and 3 hours MicroPET / CT scanning after administration; the NCI-N87 model group underwent dynamic 30 minutes, static 1 hour, and 2 hours MicroPET / CT scanning after administration; the scanned images were obtained and analyzed using PMOD software.

[0166] Scanning images of the B-hFAP MC38 model group are shown in Figure 4 The average radioactive uptake values ​​of each tissue are shown in Table 1. 68 Ga-target compound 8 had a high uptake in the tumor site of the B-hFAP MC38 model, and the uptake increased with time, with a high uptake still at 4 h.

[0167] Table 1: 68 Radioactive uptake values ​​of Ga-target compound 8 in different tissues at different times in B-hFAPMC38 tumor-bearing mouse model

[0168]

[0169] Scanning images of the NCI-N87 model group are shown in Figure 5 The average radioactive uptake values ​​of each tissue are shown in Table 2. 68 Ga-target compound 8 had high uptake at the tumor site of the NCI-N87 model, and the uptake increased with time, with a high uptake still at 2 h.

[0170] Table 2: 68 Radioactive uptake values ​​of Ga-target compound 8 in different tissues at different times in the NCI-N87 tumor-bearing mouse model

[0171]

[0172]

[0173] 4.2 Fluorescence imaging experiment

[0174] 1. Three NCI-N87 models were randomly selected and injected with the target compound 8 via the coccygeal vein. Fluorescence images were obtained using the IVIS system 1h and 4h after injection. The tumors, pancreas, lungs, kidneys, liver, heart, spleen, gastrointestinal tract (duodenum), and colorectum were removed for fluorescence imaging after 4 hours of administration.

[0175] The experimental results are as follows Figure 6 and Figure 7 As shown, it is an imaging image of an NCI-N87 model. The results show that the target compound 8 has a high uptake in the tumor site 4 hours after injection, and it can also be seen from the resected organs that the target compound 8 has high fluorescence in the tumor.

[0176] 2. Three B-hFAP MC38 models were randomly selected and injected with the target compound 8 via the coccygeal vein. Fluorescence images were obtained using the IVIS system 1h, 2h, 3h, and 4h after injection. The animals were dissected 4 hours after administration and the tumors, pancreas, lungs, kidneys, liver, heart, spleen, gastrointestinal tract (duodenum), and colorectum were removed for fluorescence imaging.

[0177] The experimental results are as follows Figure 8 and Fig. 9 As shown, it is an imaging image of a B-hFAP MC38 model, and the results show that the target compound 8 can accumulate in the tumor site, and as time goes by, the uptake increases, the fluorescence increases, and it still has extremely high uptake at 4 hours. In addition, it can also be seen from the resected organs that the target compound 8 still has high fluorescence in the tumor 4 hours after injection.

[0178] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0179] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A compound, which is a compound of formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula I: in, L is selected from -NH-C 1～6 Alkylene-; X is selected from a fluorescent group; Y is selected from chelating agents; n is selected from any integer between 1 and 6.

2. The compound according to claim 1, characterized in that The L has the following structure:

3. The compound according to claim 2, characterized in that It is a compound represented by formula II or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula II:

4. The compound according to any one of claims 1 to 3, characterized in that The fluorescent group is selected from anthocyanin fluorescent groups; Optionally, the fluorescent group is derived from Cy3, Cy3.5, Cy5, Cy5.5, Cy7, Cy7.5, sulfonated-Cy3, sulfonated-Cy5, sulfonated-Cy7 or ICG; Optionally, the fluorescent group has the following structure: Optionally, the chelating agent is derived from 1,4,7,10-tetraazacyclododecane-N,N',N",N",tetraacetic acid, N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid, 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)pentanedioic acid, 2-(4,7 ,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid, 1,4,7-triazacyclononanephosphinic acid, 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid], 3,6,9,15-tetraazabicyclo[9.3.1.]pentadeca-1(15),11,13-triene -3,6,9-triacetic acid, N'-{5-[acetyl (hydroxy) amino] pentyl}-N-[5-({4-[(5-aminopentyl) (hydroxy) amino] -4-oxobutyryl} amino) pentyl] -N-hydroxysuccinamide, diethylenetriamine pentaacetic acid, trans-cyclohexyl-diethylenetriamine pentaacetic acid, 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid, p-isothiocyanatobenzyl at least one of: 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA, 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA, 1-(2)-methyl-4-isothiocyanatobenzyl-DTPA, [R]-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid, and 6-hydrazinopyridine-3-carboxylic acid; Optionally, the chelating agent has the following structure:

5. A compound, characterized in that It has the following structure:

6. The compound according to claim 5, characterized in that It has the following structure:

7. A complex, characterized in that It is formed by complexing the compound according to any one of claims 1 to 6 with M, wherein M is at least one of a radioactive nuclide or a non-radioactive element; Optionally, the radionuclide comprises at least one of a diagnostic nuclide or a therapeutic nuclide; Optionally, the diagnostic nuclide comprises 68 Ga, 18 F. 99m Tc, 89 Zr, 124 I. 76 Br, 43 Sc, 111 In, 45 Ti, 52 Mn, 59 Fe, 64 Cu, 94m Tc, 67 Ga, 71 / 72 / 74 As, 82m Rb, 86 At least one of Y; Optionally, the therapeutic nuclide comprises 177 Lu, 90 Y. 131 I. 153 Sm, 67 Cu, 89 Sr. 166 Ho, 177 Yb, 47 Sc, 186 / 188 Re, 212 / 213 Bi, 149 Pm, 212 Pb, 211 At 223 Ra, 225 Ac, 227 At least one of Th; Optionally, the radionuclide comprises 68 Ga, 18 F. 89 Zr, 99m Tc, 177 At least one of Lu; Optionally, the M comprises 68 Ga, 177 Lu, 18 F, wherein the 18 F through [ 18 F]AlF is complexed with the compound.

8. The complex according to claim 7, characterized in that It has the following structure:

9. A pharmaceutical composition, characterized in that include: The compound according to any one of claims 1 to 6, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the complex according to any one of claims 7 to 8; Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

10. Use of the compound according to any one of claims 1 to 6, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the complex according to any one of claims 7 to 8, or the pharmaceutical composition according to claim 9 in the preparation of an agent and / or a drug, wherein the agent and / or drug has at least one of the following effects: For use in diagnosing tumors, cancers or cells characterized by expression of fibroblast activation protein; Used to inhibit the expression of fibroblast activation protein.

11. The use according to claim 10, characterized in that The diagnostic method is selected from optical imaging and / or nuclear imaging; Optionally, the method of diagnosis is selected from fluorescence imaging, PET imaging and / or SPECT imaging.

12. The use according to claim 11, characterized in that The tumor or cancer includes at least one of melanoma, esophageal cancer, breast cancer, bile duct cancer, lung cancer, liver cancer, colorectal cancer, head and neck cancer, gastric cancer, follicular dendritic cell sarcoma, fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, cervical cancer, bladder cancer, brain cancer, and neuroendocrine tumors; Preferably, the tumor or cancer includes at least one of follicular dendritic cell sarcoma, gastric cancer, fibrosarcoma, osteosarcoma, pancreatic cancer, and ovarian cancer.

13. Use of the compound according to any one of claims 1 to 6, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the complex according to any one of claims 7 to 8, or the pharmaceutical composition according to claim 9 in the preparation of a molecular imaging developer, wherein the molecular imaging includes imaging in various cells, tissues or other living organisms, and the developer is used to image tumors and cancers characterized by expressing fibroblast activation protein.

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