WO2022135327A1 - Fibroblast activating protein inhibitor - Google Patents

Abstract

The present disclosure provides a compound of general formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein C is a chelating agent unit, AB is an albumin binding unit, and FAPI is a fibroblast-activated protein inhibitor unit. The present disclosure also provides a chelate of the compound with radionuclides, a pharmaceutical composition, and their use as fibroblast activation protein inhibitors for diagnosis and treatment of diseases. C-AB-FAPI (I)

Description

fibroblast activation protein inhibitor

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to Chinese Patent Application Serial No. 202011519141.6 filed on December 21, 2020, which is incorporated herein by reference in its entirety.

technical field

The present disclosure relates to the medical and diagnostic fields, in particular to compounds, chelates, compositions and uses thereof that inhibit fibroblasts.

Background technique

Tumor is the second largest killer that threatens people's health. A tumor can be thought of not only as a collection of malignant cells, but also as a collection of stromal cells, including vascular cells, inflammatory cells, and fibroblasts. In tumors with a fibroproliferative response, such as breast, colon, and pancreatic cancer, 90% or more of the stroma may be present in the tumor. A subset of fibroblasts called cancer-associated fibroblasts (CAFs) in the tumor stroma are involved in tumor growth, migration, and progression, and even become resistant and immunosuppressive to chemotherapy.

The tumor microenvironment (TME) plays an important role in the occurrence and development of tumors, and the TME is centered on activated fibroblasts (CAFs). Fibroblast activation protein (FAP) is a type II transmembrane serine proteolytic enzyme belonging to the dipeptidyl peptidase (DPP) family. FAP is selectively expressed on the CAFs of more than 90% of epithelial malignant tumors, but hardly expressed in normal tissues, and has special biological characteristics and gene stability. FAPs are widely expressed in the microenvironment of a variety of tumors, and thus different tumor entities, including pancreatic, breast, and lung cancers, can be targeted by targeting FAPs. Therefore, FAP can not only be used as a biological marker for early diagnosis of tumors, but also has good biological characteristics of targeted therapy, and is expected to play an important role in the clinical diagnosis and treatment of malignant tumors.

At present, the research on FAP inhibitors has not been in-depth. The first FAP activity inhibitor to enter clinical trials was Talabostat, but it showed insufficient clinical activity in various cancers, so it did not continue to develop further. Later, some researchers used 131I-labeled anti-FAP antibody ^sibrotuzumab for tumor treatment research, but there were defects such as low clearance rate and lack of clinical activity.

In the past two years, the Haberkorn, Uwe team of Heidelberg University in Germany has developed a series of quinoline-based small-molecule radiopharmaceuticals targeting FAP for diagnosis and treatment, see WO2019154886A1. The resulting inhibitor binds rapidly and almost completely to human and mouse FAP and, importantly, does not cross-react with DPP family member DPP4, thus laying the foundation for further development. By linking this FAP inhibitor (fibroblast activation protein inhibitor, FAPI) to the chelating agent DOTA, a radionuclide tracer with good pharmacokinetic properties was formed. The most interesting of the whole tracers is FAPI-04, which has a high affinity for FAP, and the tracer is rapidly cleared from the blood and cleared by the kidneys. These properties enable ^68Ga -FAPI-04 PET/CT tumor imaging with high contrast and high sensitivity. However, the rapid clearance of FAPI-04 in vivo limits its application in tumor nuclide therapy. It is therefore particularly desirable to retain its excellent targeting properties and address the short circulation time of FAP inhibitor small molecules.

SUMMARY OF THE INVENTION

One aspect of the present disclosure provides a compound of general formula (I) or a pharmaceutically acceptable salt, isomer or solvate thereof,

C-AB-FAPI (I)

Wherein C is a chelator unit; AB is an albumin binding unit; FAPI is a fibroblastin inhibitor unit.

In some embodiments, the C units in general formula (I) are selected from:

or

In some embodiments, the FAPI units in general formula (I) are selected from:

or

In some specific embodiments, the C unit in general formula (I) is

The FAPI unit is

In some embodiments, the AB unit in formula (I) comprises

group.

In some embodiments, the AB units in general formula (I) are selected from

In some specific embodiments, the compound of general formula (I) is

Or a pharmaceutically acceptable salt, isomer or solvate thereof.

Another aspect of the present disclosure provides a chelate compound comprising a compound of formula (I) above and a radionuclide.

In some embodiments, the radionuclide is selected from the group consisting of: ¹⁸ F, ⁵¹ Cr, ⁶⁷ Ga, ⁶⁸ Ga, ¹¹¹ In, ⁹⁹ mTc, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹³⁹ La, ¹⁴⁰ La, ¹⁷⁵ Yb, ¹⁵ 3Sm, ¹⁶⁶ Ho, ⁸⁶ Y, ⁸⁸ Y, ⁹⁰ Y, ¹⁴⁹ Pm, ¹⁶⁵ Dy, ¹⁶⁹ Er, ¹⁷⁷ Lu, ⁴⁷ Sc, ¹⁴² Pr, ¹⁵⁹ Gd, ²¹² Bi, ²¹³ Bi, ⁷² As, ⁷² Se, ⁹⁷ Ru, ¹⁰⁹ Pd , ¹⁰⁵ Rh, ^101m Rh, ¹¹⁹ Sb, ¹²⁸ Ba, ¹²³ I, ¹²⁴ I, ¹³¹ I, ¹⁹⁷ Hg, ²¹¹ At, ¹⁵¹ Eu, ¹⁵³ Eu, ¹⁶⁹ Eu, ²⁰¹ Tl, ²⁰³ Pb, ²¹² Pb, ⁶⁴ Cu, ⁶⁷ One or more of Cu, ¹⁸⁸ Re, ¹⁸⁶ Re, ¹⁹⁸ Au, ²²⁵ Ac, ²²⁷ Th and ¹⁹⁹ Ag.

In some embodiments, the radionuclide ^{is68Ga or86Y} .

Yet another aspect of the present disclosure provides a pharmaceutical composition comprising or consisting of: at least one compound of formula (I) above, optionally and pharmaceutically acceptable adjuvants.

Yet another aspect of the present disclosure also provides the above-mentioned chelate complex or pharmaceutical composition

Use in the manufacture of a reagent or kit for diagnosing or treating a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject.

Yet another aspect of the present disclosure also provides a method of diagnosing or treating a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject, by administering to a subject in need of treatment an effective dose of the aforementioned chelating agent compound or pharmaceutical composition.

Yet another aspect of the present disclosure also provides the aforementioned chelate or pharmaceutical composition for use in diagnosing or treating a disease characterized by overexpression of fibroblast activation protein (FAP) in a subject.

In some embodiments, the disease characterized by overexpression of fibroblast activation protein (FAP) is selected from cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling, and scarring, preferably, wherein the cancer is selected from breast Cancer, pancreatic cancer, small bowel cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular cancer, esophagus cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cell, bladder cancer, cholangiocarcinoma , clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, glioma, glioma, astrocytoma, cervical cancer, and prostate cancer one or more of.

Yet another aspect of the present disclosure also provides a kit comprising or consisting of the above-mentioned chelate complex or pharmaceutical composition, and instructions for diagnosing or treating a disease.

Description of drawings

In order to illustrate the technical solutions of the embodiments of the present disclosure more clearly, the accompanying drawings of the embodiments will be briefly introduced below. Obviously, the drawings in the following description only relate to some embodiments of the present disclosure, rather than limit the present disclosure. .

Figure 1 shows the results of in vivo half-life determination by imaging healthy mice ^using68Ga -TEFAPI-07.

Figure 2 shows the results of PET imaging using ⁸⁶ Y-TEFAPI-07 in a mouse model of pancreatic cancer PDX.

Figure 3 shows the results of the competitive inhibition experiment of TEFAPI-07 in PDX pancreatic cancer mice.

Detailed ways

In order to make the purpose, technical solutions and advantages of the embodiments of the present disclosure more clear, the technical solutions of the embodiments of the present disclosure will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present disclosure. Obviously, the described embodiments are some, but not all, embodiments of the present disclosure. Based on the described embodiments of the present disclosure, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

The present invention may be embodied in other specific forms without departing from the essential attributes of the invention. It should be understood that any and all embodiments of the present invention may be combined with technical features from any other embodiment or embodiments to obtain further embodiments, provided that there is no conflict. The present invention includes such combinations resulting in additional embodiments.

All publications and patents mentioned in this disclosure are hereby incorporated by reference into this disclosure in their entirety. To the extent that the usage or terminology used in any publications and patents incorporated by reference conflicts with the usage or terminology used in this disclosure, the usage and terminology of this disclosure controls.

Section headings used herein are for the purpose of organizing the article only and should not be construed as limiting the subject matter described.

Unless otherwise defined, all technical and scientific terms used herein have the ordinary meaning in the art to which the claimed subject matter belongs. If more than one definition exists for a term, the definitions herein prevail.

Unless otherwise indicated, when a range of any type is disclosed or claimed, it is intended that each possible value that the range could reasonably cover, including any sub-ranges subsumed therein, be separately disclosed or claimed. For example, the number of substituents from 1 to 5 indicates an integer within this range, wherein 1-5 should be understood to include 1, 2, 3, 4, 5, and sub-ranges of 1-4 and 1-3.

The specification of the present disclosure should be construed to be consistent with the laws and principles of chemical bonding. In some cases, hydrogen atoms may be removed in order to accommodate substituents at a given position.

As used in this disclosure, "comprising," "containing," or "comprising" and similar words mean that the elements appearing before the word encompass the recited elements appearing after the word and their equivalents, but do not exclude unrecited elements. The terms "containing" or "including (including)" as used herein can be open, semi-closed and closed. In other words, the term also includes "consisting essentially of," or "consisting of."

The term "pharmaceutically acceptable" as used in this application means: a compound or composition that is chemically and/or toxicologically compatible with the other ingredients that make up the formulation and/or with the human or human with which it is used to prevent or treat a disease or disorder. Mammal compatible.

The term "subject" or "patient" in this application includes humans and mammals.

In the context of this application, unless specifically stated to the contrary, the term "treatment" may also include prophylaxis.

The term "solvate" as used herein refers to a complex formed by combining a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a solvent. It will be appreciated that any solvate of a compound of formula (I) for use in the diagnosis or treatment of the diseases or conditions described herein, while likely to provide different properties (including pharmacokinetic properties), will not In this experiment, compounds of formula (I) will be obtained, such that the use of compounds of formula (I) encompasses the use of any solvates of compounds of formula (I), respectively.

The term "hydrate" refers to the case where the solvent in the above term "solvate" is water.

It is further understood that the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be isolated as a solvate, and therefore any such solvate is included within the scope of the present invention. For example, a compound of formula (I), or a pharmaceutically acceptable salt thereof, can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

The term "pharmaceutically acceptable salts" refers to relatively nontoxic addition salts of compounds of the present disclosure. See, eg, S.M. Berge et al. "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19.

Suitable pharmaceutically acceptable salts of the compounds of the present disclosure may be, for example, acid addition salts of sufficiently basic compounds of the present disclosure carrying a nitrogen atom in the chain or ring, such as acid addition salts with the following inorganic acids: For example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or nitric acid, or acid addition salts with organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, Caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentane propionic acid, 3-hydroxy- 2-Naphthoic acid, Niacin, Pamoic acid, Pectic acid, Persulfuric acid, 3-Phenylpropionic acid, Picric acid, Pivalic acid, 2-Hydroxyethanesulfonic acid, Itaconic acid, Sulfamic acid, Trifluoro Methanesulfonic acid, dodecyl sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid , lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartame amino acid, sulfosalicylic acid or thiocyanate.

Additionally, another suitable pharmaceutically acceptable salt of a compound of the present invention that is sufficiently acidic is an alkali metal salt such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt, or a Acceptable salts of cationic organic bases, such as salts with N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1 , 6-Hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropanediol, 1-amino-2,3,4-butanetriol. In addition, basic nitrogen-containing groups can be quaternized with the following reagents: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as sulfuric acid Dimethyl, diethyl, dibutyl and dipentyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides compounds such as benzyl and phenethyl bromide.

Those skilled in the art will also recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid by any of a variety of known methods. Alternatively, the alkali metal and alkaline earth metal salts of the acidic compounds of the present disclosure are prepared by reacting them with an appropriate base by various known methods.

The present invention includes all possible salts of the disclosed compounds, either as a single salt or as any mixture of said salts in any ratio.

It should be understood that the term "compound of the present disclosure" as used in this application may include: the compound represented by formula (I), its pharmaceutically acceptable salt, its solvate, and its pharmaceutically acceptable salt solvent according to the context compounds, and their mixtures.

The compounds of the present disclosure may contain one or more asymmetric centers, depending on the location and nature of the various substituents desired. Asymmetric carbon atoms can exist in the (R) or (S) configuration, giving racemic mixtures in the case of one asymmetric center, and diastereomeric mixtures in the case of multiple asymmetric centers . In some cases, asymmetry may also exist due to hindered rotation about a particular bond, such as the central bond connecting two substituted aromatic rings of a particular compound.

Preferred compounds are those that produce the more desirable biological activity. Isolated, purified or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures of the disclosed compounds are included within the scope of the present invention. Purification and isolation of such materials can be accomplished by standard techniques known in the art.

References in this disclosure to "chelator units" with respect to compounds of general formula (I) refer to molecular fragments derived from chelators. For example, a chelator unit is a molecular fragment derived from 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA), which may be through one of the carboxyl groups of DOTA amide formation

and introduced into the compound of general formula (I).

"Fibroblastin inhibitor units" referred to in this disclosure with respect to compounds of general formula (I) refer to molecular fragments derived from fibroblastin inhibitors. For example, when the inhibitor is a FAPI series compound disclosed in Table 1 and Table 3 of WO2019154886A1, the "fibroblastin inhibitor unit" is a molecular fragment obtained by removing R ⁸ in the FAPI series compound.

The "albumin-binding unit" referred to in the present disclosure for the compound of general formula (I) refers to a molecular fragment having a high affinity for albumin, and the molecular fragment has a chelator unit and a fibroblastin inhibitor unit linked the group.

The "FAPI unit and the C unit together" mentioned in the present disclosure for the compound of the general formula (I) does not mean that the FAPI unit and the C unit are directly connected in the compound of the general formula (I), but refers to a false situation, That is, the FAPI unit and the C unit in the compound of the general formula (I) are extracted and connected (the albumin-binding unit in the middle is removed).

It should be understood that singular forms (eg, "a") used in this disclosure may include plural referents unless stated otherwise.

Unless otherwise indicated, the present disclosure employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and coordination chemistry. Unless otherwise specified, the present disclosure adopts traditional methods of mass spectrometry and elemental analysis, and each step and condition may refer to the conventional operation steps and conditions in the art.

The reagents and starting materials used in the present disclosure are commercially available or can be prepared by conventional chemical synthesis methods.

The term "optional" is used herein to describe an event, meaning that the event may or may not occur. For example, the term "optionally substituted" refers to being unsubstituted or having at least one non-hydrogen substituent that does not destroy the intended properties possessed by the unsubstituted analog. For example, with respect to pharmaceutical compositions, the expression "optionally, and pharmaceutically acceptable excipients" as used herein means that pharmaceutically acceptable excipients may or may not be present in the pharmaceutical composition.

In the present disclosure, unless otherwise specified, the number of "substitutions" can be one or more; when there are more than one, it can be 2, 3 or 4. In addition, when the number of the "substitution" is plural, the "substitution" may be the same or different.

In the present disclosure, the position of "substitution" can be arbitrary unless otherwise specified.

The term "C ₁ -C ₁₀ alkyl" as used herein refers to a straight or branched alkane chain containing from 1 to 10 carbon atoms. For example, representative examples of C ₁ -C ₆ alkyl include, but are not limited to, methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), tert-butyl (C ₄ ), sec-butyl (C ₄ ), isobutyl (C ₄ ), n-pentyl (C ₅ ), 3-pentyl (C ₅ ), neopentyl (C ₅ ), 3-methyl-2-butanyl (C ₅ ), tert-amyl (C ₅ ), n-hexyl (C ₆ ) and the like. The term "lower alkyl" refers to straight or branched chain alkyl groups having 1 to 4 carbon atoms. "Substituted alkyl" refers to an alkyl group substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. The term "haloalkyl" refers to an alkyl group having one or more halogen substituents including, but not limited to, such as _-CH2Br , _-CH2I , _-CH2Cl , _-CH2F , -CHF2, and _- groups like CF ₃ .

The term "alkylene" as used herein refers to a divalent hydrocarbon group as described above for "alkyl" but having two points of attachment. For example, a methylene group is a _-CH2- group and an ethylene group is a _{-CH2 -} CH2- group.

The terms "alkoxy" and "alkylthio" as used herein refer to an alkyl group as described above attached via an oxygen bond (-O-) or sulfur bond (-S-), respectively. The terms "substituted alkoxy" and "substituted alkylthio" refer to substituted alkyl groups attached via an oxygen bond or a sulfur bond, respectively. "Lower alkoxy" is the group OR where R is lower alkyl (an alkyl group containing from 1 to 4 carbon atoms).

The term "halogen" as used herein refers to fluorine, chlorine, iodine or bromine.

The application of albumin as a drug carrier has become more and more extensive, and it is often used to improve the hemodynamic properties of drugs, thereby increasing the blood half-life. Albumin is the most abundant protein in human plasma and is responsible for various storage and transportation tasks in the body. Compared with normal tissue, tumor tissue has abundant blood vessels and larger vascular endothelial space. Albumin, as a macromolecular substance, can penetrate into tumor tissue but cannot enter normal tissue. In addition, substances with smaller molecular weight are cleared faster from tumor stroma. , and macromolecules are retained, this effect is also known as the enhanced permeability and retention effect (EPR) of macromolecules in tumor tissue. In addition, the tumor microenvironment has high expression of receptors that bind albumin, such as the gp60 receptor and SPARC134, which further retain albumin in the vicinity of the tumor. Thus, the use of albumin as a carrier for anticancer drugs not only improves the half-life of these drugs, but also improves delivery to and retention in tumors. The albumin drug loading system mainly includes chemically coupled and physically bound albumin drug loading.

In the present disclosure, the albumin binding agent is linked with the chelator unit and the FAP inhibitor unit to form a small molecule compound (TEFAPI) that can be dual-targeted with FAP and albumin, with the purpose of prolonging the blood circulation half-life of the FAPI molecule, increasing the tumor uptake.

The present disclosure provides a compound of general formula (I) or a pharmaceutically acceptable salt, isomer or solvate thereof,

C-AB-FAPI (I)

Wherein C is a chelator unit; AB is an albumin binding unit; FAPI is a fibroblastin inhibitor unit.

In one embodiment, the C unit is derived from a chelating agent selected from the group consisting of 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA), ethyl acetate Diaminetetraacetic acid (EDTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), triethylenetetramine (TETA), iminodiacetic acid, diethylene triamine-N,N,N',N',N"-pentaacetic acid (DTPA), bis-(carboxymethylimidazole)glycine or 6-hydrazinopyridine-3-carboxylic acid (HYNIC).

For example, the C unit is

It is derived from 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA), which can form an amide through one of the carboxyl groups of DOTA

and introduced into the compound of general formula (I).

For example, the C unit is

It is derived from 11,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), which can form an amide through one of the carboxyl groups of NOTA

and introduced into the compound of general formula (I).

In one embodiment, the C unit in the compound of formula (I) is selected from:

or

In one embodiment, the FAPI unit in the compound of formula (I) is selected from

or

In one embodiment, the FAPI unit and the C unit in the compound of general formula (I) satisfy the following conditions:

If the FAPI unit and the C unit are connected (remove the albumin binding unit in the middle), the new compound obtained by the connection is selected from:

In other words, in this embodiment, the compound of general formula (I) can be regarded as the compound FAPI-02, FAPI-04, FAPI-21, FAPI-34, FAPI-42, FAPI-46, FAPI-52, FAPI -69, FAPI-70, FAPI-71, FAPI-72, FAPI-73, FAPI-74 were inserted into the molecular structure of albumin-binding unit AB. Compounds FAPI-02, FAPI-04, FAPI-21, FAPI-34, FAPI-42, FAPI-46, FAPI-52, FAPI-69, FAPI-70, FAPI-71, FAPI-72, FAPI-73, FAPI -74 is disclosed in WO2019154886A1 as a FAP inhibitor.

In a preferred embodiment, the FAPI unit and the C unit in the compound of the general formula (I) satisfy the following conditions: if the FAPI unit and the C unit are connected (remove the albumin binding unit in the middle), the resulting The new compound is selected from: FAPI-04, FAPI-21 or FAPI-46. In one embodiment, the FAPI unit and the C unit in the compound of general formula (I) satisfy the following conditions: if the FAPI unit and the C unit are connected (remove the albumin binding unit in the middle), the new The compound is FAPI-04.

In one embodiment, the AB unit comprises

group.

In one embodiment, the AB units are selected from

In one embodiment, the AB unit is connected to the terminal end in the FAPI unit

An amide bond is formed to connect it to the FAPI unit, and the AB unit is connected to the C unit by forming an amide bond with the terminal carbonyl group in the C unit.

In one embodiment, the compound of general formula (I) is

Or a pharmaceutically acceptable salt, isomer or solvate thereof.

Based on the high-affinity small molecule FAP inhibitor (FAPI) designed by Jansen et al., Loktev et al. first developed the radiotracers FAPI-01 and FAPI-02, which can rapidly bind to FAP in human and murine cells and internalize . The accumulation in normal tissue is very low and clearance is rapid, so high contrast can be obtained for PET imaging. Furthermore, FAPI-02 can be rapidly cleared from the organism by renal clearance without being retained in the renal parenchyma, which is beneficial for therapeutic applications. To optimize uptake and tracer retention in tumors, a series of FAPI-02-based compounds were developed, of which PET imaging of FAPI-04 showed higher tumor uptake, longer retention time, and higher retention in normal organs There was no significant increase in activity. FAPI-04 performed PET imaging on patients with 28 different cancers in clinical trials. It was found that only the cancer site had uptake and normal tissues had almost no uptake, showing very excellent cancer targeting properties. The diagnostic reagent is now in clinical use. has been applied. Since the FAP target is still an excellent therapeutic target, for patients with advanced metastatic disease, conventional methods such as surgery, radiotherapy and chemotherapy cannot inhibit tumor development and prolong the patient's life. The use of FAP inhibitors to carry radionuclides will be a promising treatment. method. Therefore, it is expected to solve the problem of short circulation time of FAP inhibitor small molecules on the premise of retaining their excellent targeting properties.

TEFAPI-07 was introduced in the FAPI-04 structure

group. The introduction of this Evans blue structure with high affinity to albumin in the FAPI-04 structure can preserve the targeting of the drug molecule fibroblast activation protein, prolong the half-life of blood circulation, and enhance the enrichment and retention of drugs in the tumor site. Improve treatment effect. TEFAPI-07 is expected to be used as an imaging and radionuclide carrier for a variety of cancers.

The present disclosure also provides a chelate compound comprising:

A compound of general formula (I) above, or a pharmaceutically acceptable salt, isomer or solvate thereof, and

radionuclide.

In such chelates, the chelator unit chelates directly with the radionuclide (eg, ^68Ga chelates with a chelator unit derived from DOTA), or the radionuclide is introduced indirectly through chelation with other metals (eg, , Al ³⁺ is chelated with a chelator unit derived from DOTA, and the radionuclide ¹⁸ F is introduced into the chelate in the form of a counter ion).

In one embodiment, the radionuclide is selected from the group consisting of: ¹⁸ F, ⁵¹ Cr, ⁶⁷ Ga, ⁶⁸ Ga, ¹¹¹ In, ⁹⁹ mTc, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹³⁹ La, ¹⁴⁰ La, ¹⁷⁵ Yb, ¹⁵ 3Sm, ¹⁶⁶ Ho, ⁸⁶ Y, ⁸⁸ Y, ⁹⁰ Y, ¹⁴⁹ Pm, ¹⁶⁵ Dy, ¹⁶⁹ Er, ¹⁷⁷ Lu, ⁴⁷ Sc, ¹⁴² Pr, ¹⁵⁹ Gd, ²¹² Bi, ²¹³ Bi, ⁷² As, ⁷² Se, ⁹⁷ Ru, ¹⁰⁹ Pd, ¹⁰⁵ Rh, ^101m Rh, ¹¹⁹ Sb, ¹²⁸ Ba, ¹²³ I, ¹²⁴ I, ¹³¹ I, ¹⁹⁷ Hg, ²¹¹ At, ¹⁵¹ Eu, ¹⁵³ Eu, ¹⁶⁹ Eu, ²⁰¹ Tl, ²⁰³ Pb, ²¹² Pb, ⁶⁴ Cu, ⁶⁷ Cu , ¹⁸⁸ Re, ¹⁸⁶ Re, ¹⁹⁸ Au, ²²⁵ Ac, ²²⁷ Th and ¹⁹⁹ Ag. For example, the radionuclide ^{is68Ga or86Y} .

The present disclosure also provides a pharmaceutical composition comprising or consisting of:

at least one of the above-mentioned chelates,

Optionally, and pharmaceutically acceptable excipients.

In one embodiment, the pharmaceutical composition comprises or consists of at least one of the chelates described above. In another embodiment, the pharmaceutical composition comprises or consists of at least one of the above-mentioned chelates and a pharmaceutically acceptable excipient.

The compositions of the present disclosure must or may optionally also contain pharmaceutically acceptable excipients for formulating the chelate for the intended route of administration. Adjuvants include, but are not limited to, diluents, disintegrants, precipitation inhibitors, surfactants, glidants, binders, lubricants, coating materials, and the like. Excipients are generally described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Examples of excipients include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethyl cellulose, sodium carboxymethyl cellulose, crospovidone, glyceryl isostearate, glyceryl monostearate, Hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxydioctate hydroxystearate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, lactose, lactose monohydrate, magnesium stearate, mannitol , microcrystalline cellulose, etc.

Agents that can be used to formulate the composition for the intended route of administration, as appropriate, include:

acidulants (examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);

Alkalizing agents (examples include, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine);

Buffers (examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, sodium citrate anhydrous, and sodium citrate dihydrate); and the like.

WO2019154886A1 discloses that chelates or compositions comprising FAPI series compounds and radionuclides can be used to diagnose or treat diseases characterized by fibroblast activation protein overexpression in mammals or humans. In the present disclosure, by introducing an albumin-binding unit into the structure of the FAPI compound disclosed in WO2019154886A1, its excellent FAP targeting property is retained, while the circulation time of the FAP inhibitor is prolonged.

Another aspect of the present disclosure pertains to the aforementioned chelates or compositions for use in the diagnosis or treatment of diseases characterized by overexpression of fibroblast activation protein in mammals or humans. For example the disease characterized by overexpression of fibroblast activating protein (FAP) is selected from cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and scarring, preferably wherein the cancer is selected from breast cancer, pancreatic cancer , Small bowel cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular cancer, esophagus cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell kidney Carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, glioma, glioma, astrocytoma, cervical cancer, and prostate cancer.

Yet another aspect of the present disclosure relates to a kit comprising or consisting of the above-mentioned chelate complex or the above-mentioned pharmaceutical composition, and instructions for diagnosing or treating a disease. In a preferred embodiment, the disease is the above-mentioned disease characterized by overexpression of fibroblast activation protein.

Example

The starting materials for the examples are commercially available and/or can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. Those skilled in the art of organic synthesis will appropriately select reaction conditions (including solvent, reaction atmosphere, reaction temperature, duration of experiments, and work-up) in the following synthetic methods. Those skilled in the art of organic synthesis will understand that the functional groups present on various parts of the molecule should be compatible with the reagents and reactions presented.

All synthetic reagents and compounds can be purchased in China through general commercial channels, suppliers include Sinopharm Chemical Reagent Co., Ltd., San Chemical Technology (Shanghai) Co., Ltd., Jiuding Chemical (Shanghai) Technology Co., Ltd., Beijing Bailingwei Technology Co., Ltd. Company, Beijing Tongguang Fine Chemical Co., Ltd., Shanghai Bide Pharmaceutical Technology Co., Ltd., Beijing Inoke Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma Aldrich (Shanghai) Trading Co., Ltd.

1. Chemical synthesis of TEFAPI-07

The specific preparation method is as follows:

1) Preparation of TEFAPI-07-F2

TEFAPI-07_F1 (40 g, 188.42 mmol, 39.60 mL, 1 eq) was dissolved in dichloromethane (400 mL), and the solution was added dropwise to Boc ₂ O (41.12 g, 188.42 mmol, 43.29 mL, 1 eq) in dichloromethane In the solution (200 mL), the reaction was stirred at 25 °C for 12 h. After the reaction, the reaction solvent was removed using a rotary evaporator, and purified by silica gel column chromatography. The mobile phase was petroleum ether: ethyl acetate=1:1 to obtain the product TEFAPI-07_F2 (17 g, yield 23.39%) as a pale yellow solid . The resulting product was identified by mass spectrometry: m/z (ESI ⁺ ): 313.2 (M+H) ⁺ .

2) Preparation of TEFAPI-07-F3

TEFAPI-07_F2 (3.12 g, 9.99 mmol, 1 eq) was dissolved in acetonitrile (40 mL), and HCl (2 M, 14.98 mL, 3 eq) was added at 0°C. Then, the NaNO ₂ solution (2.07 g, 29.96 mmol, 3 eq, dissolved in 20 mL of water) previously placed in an ice-water bath was added dropwise to the above mixture, and the reaction was stirred for 30 min. Then the mixed solution was added dropwise to a 20 mL aqueous solution of EB_M (3.19 g, 9.35 mmol, 0.9 eq) and NaHCO ₃ (3.36 g, 39.95 mmol, 1.55 mL, 4 eq) in an ice-water bath. After the dropwise addition, the reaction was stirred at 0 °C for 2 h. The progress of the reaction was monitored using a liquid chromatography-mass spectrometer. After the reaction, the reaction solution was lyophilized and purified by preparative high performance liquid chromatography to obtain the product TEFAPI-07_F3 (6 g, yield 93.48%) as a purple solid. The product was identified by mass spectrometry: m/z (ESI ⁻ ): m/z 641.1 (MH) ⁻ .

3) Preparation of TEFAPI-07-F4

To a dichloromethane solution (1 mL) of TEFAPI-07_F3 (2.2 g, 3.42 mmol, 1 eq) was added TFA (6.78 g, 59.43 mmol, 4.40 mL, 17.36 eq), and the reaction was stirred at 25° C. for 5 h. After the reaction, the solvent was removed and lyophilized to obtain the crude product TEFAPI-07_F 4 (2.2 g, yield 97.88%), which was directly used for the next reaction. The product was identified by mass spectrometry: m/z (ESI ⁻ ): m/z 541.0 (MH) ⁻ .

4) Preparation of TEFAPI-07-F5

To a solution of TEFAPI-07_F4 (2.3g, 4.24mmol, 990.10uL, 1eq) in tetrahydrofuran (30mL) was added tetrahydropyran-2,6-dione (532.03mg, 4.66mmol, 1.1eq) and TEA (1.29g) , 12.72mmol, 1.77mL, 3eq), and the reaction was stirred at 25°C for 12h. After the reaction, the solvent was removed by a rotary evaporator, and purified by a preparative high performance liquid chromatography to obtain the product TEFAPI-07_F5 (500 mg, yield 17.96%) as a purple solid. The product was identified by mass spectrometry: m/z (ESI ⁻ ): m/z 655.1 (MH) ⁻ .

5) Preparation of TEFAPI-07-F6

HOSu (96.39 mg, 837.54 umol, 1.1 eq) and EDCI (145.96 mg, 761.40 umol, 1 eq) were added to a DMSO solution (5 mL) of TEFAPI-07_F5 (500 mg, 761.40 umol, 1 eq), and the reaction was stirred at 25° C. for 12 h. The formation of the target product was monitored by liquid chromatography-mass spectrometry, and the reaction solution was directly used for the next reaction. m/z(ESI ^- ): m/z752.0(MH) ^- .

6) Preparation of TEFAPI-07-F7

To the DMSO solution (0.5mL) of F6_A (163.38mg, 663.35umol, 1eq) was added TEFAPI-07_F6 (500mg, 663.35umol, 1eq) and DIEA (171.47mg, 1.33mmol, 231.09uL, 2eq), and stirred at 25°C The reaction was carried out for 12h. After the reaction, the solvent was removed using a rotary evaporator, and then purified by preparative high performance liquid chromatography to obtain the product TEFAPI-07_F7 (200 mg, yield 34.07%) as a dark purple solid. The product was identified by mass spectrometry: m/z (ESI ⁻ ): m/z 883.3 (MH) ⁻ .

7) Preparation of TEFAPI-07_8

To TEFAPI_C8 (100mg, 113.00umol, 1eq) in DMF solution (1mL) was added TEFAPI-007_F7 (67.86mg, 113.00umol, 1eq, TFA), HBTU (53.57mg, 141.25umol, 1.25eq), HOBt (19.85mg, 146.90umol, 1.3eq) and DIEA (73.02mg, 564.99umol, 98.41uL, 5eq), and the reaction was stirred at 25oC for 12h. After the reaction, a rotary evaporator was used to remove the solvent, and a preparative liquid chromatograph was used for purification. The preparative column was Phenomenex Gemini-NX C18 75*30mm*3um, and the mobile phase conditions were [water(0.1%TFA)-ACN]; B %: 15%-45%, 10min, the product TEFAPI-07_8 (30mg, yield 19.62%) was obtained as a purple solid. The product was identified by mass spectrometry: m/z (ESI+): m/z 1354.3 (M+H)+.

8) Preparation of TEFAPI-007_9

To the acetonitrile solution (1 mL) of TEFAPI-07_8 (30 mg, 22.17 umol, 1 eq) was added TFA (308.00 mg, 2.70 mmol, 0.2 mL, 121.87 eq), and the reaction was stirred at 25 oC for 2 h. After the reaction, the solvent was removed using a rotary evaporator to obtain a crude product TEFAPI-07_9 (30 mg, yield 98.98%), which was directly used for the next reaction.

9) Preparation of TEFAPI-007_10

To TEFAPI-07_9 (15mg, 10.97umol, 1eq, TFA) in DMSO solution (1mL) was added FAPI_D2 (8.82mg, 13.16umol, 1.2eq) and DIEA (7.09mg, 54.85umol, 9.55uL, 5eq) at 25oC The reaction was stirred for 12h. After the reaction was completed, the solvent was removed using a rotary evaporator. The above operation was repeated three times, and the obtained samples were combined and purified using a preparative high performance liquid chromatograph. The preparative column was Phenomenex Gemini-NX 150*30mm*5um, and the mobile phase conditions were [0.1M TEAB-ACN]; B%: 10% -75%, 10min, the product TEFAPI-07_10 (20mg, yield 75.82%) was obtained as a purple solid. The product was identified by mass spectrometry: m/z (ESI+): m/z 1847.0 (M+MeCN)+.

10) Preparation of TEFAPI-07

To a dichloromethane solution (3 mL) of TEFAPI-07_10 (20 mg, 11.06 umol, 1 eq) was added TFA (18.48 g, 162.07 mmol, 12.00 mL, 14651.92 eq), and the reaction was stirred at 25° C. for 8 h. After the reaction, a rotary evaporator was used to remove the solvent, and a preparative high performance liquid chromatography was used for purification. The preparative column was Phenomenex Gemini-NX 150*30mm*5um, and the mobile phase conditions were [0.1M TEAB-ACN]; B%: 10% -35%, 20 min), the final product TEFAPI-07 (7.62 mg, 41.38% yield) was obtained as a purple solid. The product was identified by nuclear magnetic resonance spectroscopy. ¹ H NMR (400MHz, DMSO-d ₆ )δ=1.18-1.30(m,3H), 1.33-1.42(m,2H), 1.44-1.58(m,2H), 1.74-2.13(m,11H), 2.17 -2.25(m,3H),2.28(s,3H),2.31-2.40(m,5H),2.57-2.72(m,6H),2.89(br s,22H),4.05-4.40(m,7H), 4.60-4.76(m,1H),5.11-5.22(m,1H),6.99(br d,J=9.63Hz,1H),7.42-7.60(m,5H),7.64(br s,2H),7.88( br d,J=8.38Hz,2H),7.93-8.07(m,2H),8.28-8.41(m,1H),8.57-8.71(m,1H),8.80(br d,J=4.13Hz,1H) , 9.15-9.31 (m, 1H), 9.31-9.47 (m, 1H), 15.84-16.05 (m, 1H).

2. Determination of blood circulation half-life of ^68Ga -TEFAPI-07

1) Preparation of ^68Ga -TEFAPI-07

Take 82ug of the precursor (50nmol, freeze-dried in a 1.5mL centrifuge tube), add the ^68GaCl3 solution (1mL, 0.6M HCl solution ₎ obtained by washing into the precursor, use NaOH solution (100uL, 3M) and acetic acid The pH was adjusted to 4.5 with sodium solution (130uL, 3M), and the reaction was carried out at 90°C for 10min. After the reaction, the reaction solution was diluted into 3 mL of physiological saline, purified using an activated C18 cartridge, and then continued to be rinsed with 5 mL of physiological saline to remove free ⁶⁸ Ga ³⁺ ions. The labeled product ^68Ga -TEFAPI-07 was obtained by rinsing with 80% ethanol solution. The labeled product was diluted into physiological saline and passed through a 0.22um sterile filter for use.

2) Determination of blood circulation half-life of ^68Ga -TEFAPI-07

The ^68Ga -TEFAPI-07 was injected into normal NOD/SCID mice using a retention needle in the tail vein, and the dynamic PET data was collected immediately, continuously monitored for 1h, and then static data were obtained at 2h, 3h, 4h, 5h, and 6h after the injection Collection (15min). After reconstruction of the collected data, quantitative analysis of the signal of the probe uptake in the heart region was carried out to obtain the blood circulation half-life of ^68Ga -TEFAPI-07. The results are shown in Figure 1.

As shown in Figure ₁ , after the probe was labeled with ⁶⁸ Ga, normal mice were used for PET imaging, and the imaging results were quantitatively analyzed. _1/2 (Mean) is 512.4 min.

3. ⁸⁶ Y-TEFAPI-07PET imaging

1) Preparation of ⁸⁶ Y-TEFAPI-07

Take 82ug _of the precursor (50nmol, lyophilized in a 1.5mL centrifuge tube), add the prepared ^86YCl3 solution (0.5mL, 0.1M HCl solution) to the precursor, and use NaOAc solution (50uL, 3M) to adjust the pH Adjusted to 4.5, and reacted at 90 °C for 10 min. After the reaction, the reaction solution was diluted into 3 mL of physiological saline, purified using an activated C18 cartridge, and then continuously rinsed with 5 mL of physiological saline to remove free ⁸⁶ Y ³⁺ ions. The labeled product ⁸⁶ Y-TEFAPI-07 was obtained by rinsing with 80% ethanol solution. The labeled product was diluted into physiological saline and passed through a 0.22um sterile filter for use.

2) ⁸⁶ Y-TEFAPI-07PET imaging

Tail vein injection of ⁸⁶ Y-TEFAPI-07 into pancreatic cancer PDX model mice (NOD/SCID) was performed at 1h, 2h, 4h, 8h, 12h, 18h, 24h, 36h, 48h, 60h, 72h after injection. Data acquisition (15min) and reconstruction. The imaging results are shown in Figure 2.

As shown in Fig. 2, after the drug was labeled with radionuclide ⁸⁶ Y, PET imaging was performed using a pancreatic cancer PDX model. The imaging results showed that the blood circulation half-life of the drug in the body was effectively prolonged, and the signal in the blood pool could still be clearly observed after 24 hours. And the drug has high enrichment and long-term retention in the tumor site, while the uptake of normal organs is low.

4. Inhibition experiment

1) Preparation of ^68Ga -FAPI-04

Take 50ug of the precursor (lyophilized in a 1.5mL centrifuge tube), add the ^68GaCl3 solution (1mL, 0.6M HCl solution ₎ obtained by washing into the precursor, use NaOH solution (100uL, 3M) and NaOAc solution ( 130uL, 3M) to adjust the pH to 4.5 and react at 90°C for 10min. After the reaction, the reaction solution was diluted into 3 mL of physiological saline, purified using an activated C18 cartridge, and then continued to be rinsed with 5 mL of physiological saline to remove free ⁶⁸ Ga ³⁺ ions. The labeled product ^68Ga -FAPI-04 was obtained by rinsing with 80% ethanol solution. The labeled product was diluted into physiological saline and passed through a 0.22um sterile filter.

2) ⁶⁸ Ga-FAPI-04PET imaging

Tail vein injection of ⁶⁸ Ga-FAPI-04 into pancreatic cancer PDX model mice (NOD/SCID), static data acquisition (15 min) and reconstruction were performed 15 min after injection. The tumor of this model mouse was screened and determined to be FAP-positive by ^68Ga -FAPI-04 imaging.

3) Inhibition experiment of TEFAPI-07

Using the above-mentioned pancreatic cancer PDX model mice screened by ⁶⁸ Ga-FAPI-04 imaging, each was injected with TEFAPI-07 (400ug) dissolved in normal saline through the tail vein, 12h and 24h after the injection of TEFAPI-07, respectively. The ^68Ga -FAPI-04 imaging was performed again and compared with the 68Ga-FAPI-04 imaging results when ^TEFAPI -07 was not injected. The acquired data was reconstructed, and the uptake probe signal was quantitatively analyzed at the tumor site. The results are shown in Figure 3.

As shown in Figure 3, the imaging results showed that the mice could successfully occupy the FAP target after injection of TEFAPI-07, and when the 68Ga-FAPI-04 PET imaging was performed again, the uptake of ^68Ga - ^FAPI -04 in the tumor site significantly reduced. The above experiments verified that TEFAPI-07 has excellent FAP targeting.

The above descriptions are only exemplary embodiments of the present invention, and are not intended to limit the protection scope of the present invention, which is determined by the appended claims.

Claims (14)

1. A compound of general formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof,

   C-AB-FAPI (I)

   wherein C is a chelating agent unit;

   AB is the albumin binding unit;

   FAPI is a fibroblastin inhibitor unit.
2. The compound of claim 1, wherein the C unit is selected from the group consisting of:

   

   

   or

   
3. The compound of claim 1 or 2, wherein the FAPI unit is selected from the group consisting of:

   

   

   or

   
4. The compound of claim 3, wherein:

   Unit C is

   

   The FAPI unit is

   
5. A compound according to any preceding claim, wherein the AB unit comprises

   

   group; preferably, the AB unit is selected from

   
6. A compound according to any one of the preceding claims, wherein the AB unit passes through the terminal in the FAPI unit

   

   An amide bond is formed to connect it to the FAPI unit, and the AB unit is connected to the C unit by forming an amide bond with the terminal carbonyl group in the C unit.
7. The compound of claim 1, which is

   

   Or a pharmaceutically acceptable salt, isomer or solvate thereof.
8. A chelate comprising a compound of any one of claims 1-7 and a radionuclide.
9. The chelate of claim 8, wherein the radionuclide is selected from the group consisting of: ¹⁸ F, ⁵¹ Cr, ⁶⁷ Ga, ⁶⁸ Ga, ¹¹¹ In, ⁹⁹ mTc, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹³⁹ La, ¹⁴⁰ La, ¹⁷⁵ Yb, ¹⁵ 3Sm, ¹⁶⁶ Ho, ⁸⁶ Y, ⁸⁸ Y, ⁹⁰ Y, ¹⁴⁹ Pm, ¹⁶⁵ Dy, ¹⁶⁹ Er, ¹⁷⁷ Lu, ⁴⁷ Sc, ¹⁴² Pr, ¹⁵⁹ Gd, ²¹² Bi, ²¹³ Bi, ⁷² As, ⁷² Se , ⁹⁷ Ru, ¹⁰⁹ Pd, ¹⁰⁵ Rh, ^101m Rh, ¹¹⁹ Sb, ¹²⁸ Ba, ¹²³ I, ¹²⁴ I, ¹³¹ I, ¹⁹⁷ Hg, ²¹¹ At, ¹⁵¹ Eu, ¹⁵³ Eu, ¹⁶⁹ Eu, ²⁰¹ Tl, ²⁰³ Pb, ²¹² One or more of Pb, ⁶⁴ Cu, ⁶⁷ Cu, ¹⁸⁸ Re, ¹⁸⁶ Re, ¹⁹⁸ Au, ²²⁵ Ac, ²²⁷ Th and ¹⁹⁹ Ag.
10. The chelate of claim 9, wherein the radionuclide ^{is68Ga or86Y} .
11. A pharmaceutical composition comprising or consisting of:

    at least one chelate compound according to any one of claims 8-10,

    Optionally, and pharmaceutically acceptable excipients.
12. The chelate of any one of claims 8-10 or the pharmaceutical composition of claim 11 in preparation for diagnosis or treatment of overexpression of fibroblast-activated protein (FAP) in a subject Use of a reagent or kit for a characterized disease.
13. Use according to claim 12, wherein the disease characterized by overexpression of fibroblast activation protein (FAP) is selected from cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling and scarring, preferably, Wherein the cancer is selected from breast cancer, pancreatic cancer, small bowel cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer Carcinoma, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, carcinomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, glioma, glioma, astrocytoma, subcutaneous One or more of cervical cancer and prostate cancer.
14. A kit comprising or consisting of a chelate according to any one of claims 8-10 or a pharmaceutical composition according to claim 11, and instructions for diagnosing or treating a disease.

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