Low-pH insertion type compound targeting FAP as well as preparation method and application of low-pH insertion type compound

Abstract

The invention relates to a low-pH insertion type compound for targeting FAP as well as a preparation method and application of the low-pH insertion type compound. The existing FAP targeting probe has the problems of low tumor uptake and short residence time. The invention provides a low-pH insertion type compound targeting FAP, which is formed by connecting an FAP targeting group, a low-pH insertion group and a bifunctional chelating agent, and provides a low-pH insertion type radiolabeled complex targeting FAP, which is used for preparing a human or animal tumor radiodiagnosis probe or treatment probe. The FAP targeting probe with a brand new structure is designed by adopting a mode of combining the FAP targeting small molecules with the low-pH insertion peptide, the uptake and retention of the FAP targeting small molecules in tumors are improved by utilizing the anchoring characteristic of the low-pH insertion peptide in cell membranes, the problems of low tumor uptake and short retention time in the prior art are effectively solved, and the FAP targeting probe has a good application prospect. The compound has appropriate physicochemical and radiology properties and ideal biological characteristics, and is beneficial to clinical application.

Description

Technical Field

[0001] The present invention relates to the technical field of clinical nuclear medicine, and particularly relates to a low pH insertable compound targeting FAP, a preparation method thereof, and an application thereof. Background Art

[0002] Diagnostic imaging and treatment targeting the stroma in the tumor microenvironment have become a research hotspot. Cancer-associated fibroblasts (CAFs) are the main components of the tumor stroma in epithelial cell carcinomas, especially accounting for 90% of the total tumor volume in desmoplastic cancers such as pancreatic cancer. Molecular markers on their surfaces include fibroblast activation protein (FAP), α-smooth muscle actin (α-SMA), and vimentin, etc. α-SMA and vimentin are expressed in quiescent fibroblasts, pericytes, and vascular smooth muscle cells, while FAP is specifically overexpressed only in CAFs. At the same time, the expression level of FAP in healthy adult tissues is very low or not expressed. Therefore, FAP has become one of the most promising targets for integrated diagnosis and treatment.

[0003] However, at present, there is great room for optimization of FAP-targeted probes. Existing FAP-targeted probes generally have problems such as low tumor uptake and short retention time. Therefore, it is necessary to design new FAP-targeted probes to overcome existing defects. Summary of the Invention

[0004] The purpose of the present invention is to provide a low pH insertable compound targeting FAP, a preparation method thereof, and an application thereof, so as to at least solve the problems of low tumor uptake and short retention time existing in existing FAP-targeted probes.

[0005] In order to achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0006] There is provided a low pH insertable compound targeting FAP, and the low pH insertable compound targeting FAP is composed of an FAP targeting group, a low pH insertion group, and a bifunctional chelator connected.

[0007] Further, the structure of the low pH insertable compound targeting FAP is:

[0008]

[0009] Wherein:

[0010] R1 is the FAP targeting group FAPI, and its structure is:

[0011]

[0012] R2 is the low pH insertion group Var3, and its structure is:

[0013]

[0014] R3 is a bifunctional chelating agent, which is DO3A, DO3A-NCS or DOTA-NCS, and its structure is:

[0015]

[0016] On the other hand, a method for preparing a low-pH insertable compound targeting FAP as described above is provided, and the method includes:

[0017]

[0018] On the other hand, a low-pH insertable radiolabeled complex targeting FAP is provided, and the low-pH insertable radiolabeled complex targeting FAP is obtained by radiolabeling the low-pH insertable compound targeting FAP as described above.

[0019] Furthermore, the radionuclide is selected from 68 Ga, 161 Tb, 177 Lu.

[0020] Furthermore, the structure of the low-pH insertable radiolabeled complex targeting FAP is:

[0021]

[0022] Wherein:

[0023] R3' is a radionuclide 68 A Ga-labeled bifunctional chelating agent, which is 68 Ga-DO3A, 68 Ga-DO3A-NCS or 68 Ga-DOTA-NCS, and the structure is:

[0024]

[0025] Alternatively, the structure of the low-pH insertable radiolabeled complex targeting FAP is:

[0026]

[0027] Wherein:

[0028] R3' is a radionuclide 161 A Tb-labeled bifunctional chelating agent, which is 161 Tb-DO3A, 161 Tb-DO3A-NCS or 161 Tb-DOTA-NCS, and the structure is:

[0029]

[0030] Alternatively, the structure of the low-pH insertable radiolabeled complex targeting FAP is:

[0031]

[0032] Wherein:

[0033] R3’ is a radionuclide 177 a Lu-labeled bifunctional chelating agent, being 177 Lu-DO3A, 177 Lu-DO3A-NCS or 177 Lu-DOTA-NCS, and the structure is:

[0034]

[0035] On the other hand, provided is the use of the low-pH insertable radiolabeled complex targeting FAP as described above in the preparation of a radioactive diagnostic probe or a therapeutic probe for tumors in humans or animals.

[0036] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0037] The present invention provides a low-pH insertable compound targeting FAP, its preparation method and use, which consists of an FAP targeting group, a low-pH insertable group and a bifunctional chelating agent. The radiolabeled complex based on this low-pH insertable compound can be used as a radioactive diagnostic probe for tumor diagnosis or as a radioactive therapeutic probe for tumor treatment, having suitable physicochemical and radiological properties and relatively ideal biological characteristics. Experiments prove that it significantly improves the uptake and retention of FAP-targeted small molecules in tumors, effectively overcomes the problems of low tumor uptake and short retention time existing in the prior art, can be used for tumor radioactive diagnosis or treatment, and is beneficial to clinical application. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for use in the description of the embodiments or the prior art. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0039] Figure 1 It is the HPLC identification result of the chemical purity of the FAP-targeted low-pH insertable compound prepared in Example 1.

[0040] Figure 2MS identification results of the chemical purity of the FAP-targeted low-pH insertable compound prepared in Example 1.

[0041] Figure 3 Prepared for Example 2 68 Ga and 177 Radiochemical purity identification results of the FAP-targeted low-pH insertable radiolabeled complex labeled with Lu.

[0042] Figure 4 Prepared for Example 2 68 Ga(A) and 177 In vitro stability HPLC identification results of the FAP-targeted low-pH insertable radiolabeled complex labeled with Lu(B). In vitro stability HPLC identification results.

[0043] Figure 5 Prepared for Example 2 68 Micro-PET imaging results of Ga-DO3A-FAPI-Var3 in tumor-bearing mice with U87MG cells.

[0044] Figure 6 Prepared for Example 2 68 In vivo distribution results of Ga-DO3A-FAPI-Var3 in tumor-bearing mice with U87MG cells 4 hours after injection.

[0045] Figure 7 Prepared for Example 2 68 Tumor / tissue uptake ratio of Ga-DO3A-FAPI-Var3 in tumor-bearing mice with U87MG cells 4 hours after injection.

[0046] Figure 8 Prepared for Example 2 177 In vivo distribution results of Lu-DO3A-FAPI-Var3 in tumor-bearing mice with U87MG cells 24 hours after injection. Detailed implementation manners

[0047] To facilitate the understanding of the present invention, the present invention will be described more comprehensively below with reference to the relevant drawings. Preferred embodiments of the present invention are shown in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, these embodiments are provided to make the disclosure of the present invention more thorough and comprehensive.

[0048] In the description of the present invention, it should be understood that all the technologies and scientific terms used have the same meanings as those commonly understood by those of ordinary skill in the technical field to which the present invention pertains. In case of any contradiction, the definitions in this specification shall prevail. Unless otherwise specified, the technical means used in the embodiments are conventional means well-known to those skilled in the art, the reagents used in the embodiments are commercially available products, and the devices used in the embodiments are existing devices. The limitation of the means, reagents, or devices shall not be construed as a limitation to the present invention, and the means, reagents, or devices of the same type for solving the same technical problems are within the protection scope of the present invention.

[0049] In the description of the present invention, it should be understood that when an amount, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper preferred values and lower preferred values, this should be understood as specifically disclosing all the ranges formed by any pairing of any range upper limit or preferred value with any range lower limit or preferred value, regardless of whether the range is disclosed individually. When a numerical range is described in this specification, unless otherwise stated, this range is intended to include its end values and all integers and fractions within the range.

[0050] In the description of the present invention, it should be understood that when multiple steps are involved in the process of describing a method, it should not be construed as a limitation on the order of the method steps. The technical solutions obtained only by changing the order of the steps when solving the same technical problem are also within the protection scope of the present invention.

[0051] Positron Emission Computed Tomography (PET) is a clinical examination imaging technology in the field of nuclear medicine. During the examination process, markers are involved. After being injected into the human body, by observing the accumulation of this substance during metabolism, it can reflect the situation of life metabolic activities, thereby achieving the purpose of diagnosis.

[0052] Due to the high metabolism of tumor cells, they often produce large amounts of lactic acid through glycolysis, which makes the pH of the tumor microenvironment lower than that of normal tissues and more acidic. A pH-low insertion peptide (pHLIP) is a polypeptide composed of two flanking regions and a central insertion region. Under acidic conditions, pHLIP undergoes a conformational transition, inserting its C-terminus into the cell membrane phospholipid bilayer and stably anchoring it in the cell. The accumulation of pHLIP in tumor tissue is closely related to pH, with lower pH values leading to greater accumulation. pHLIP not only effectively accumulates in low-pH tissues but also binds to cells, resulting in stable retention in low-pH tumor tissues. Its non-toxic and non-immunogenic properties further facilitate clinical translation. Within the pHLIP family, pHLIP (Var3) exhibits superior tumor affinity, making it a promising tumor-targeting vector. Using pHLIP as a carrier can mediate the aggregation of FAPI in tumor tissues, effectively enhancing the efficacy of positron-ionized diagnostics or radionuclide therapy for tumors.

[0053] The conjugation design method can greatly preserve the biological activity of small molecule probes on target receptors. Introducing low-pH insertion groups into small molecule probes can significantly enhance tumor uptake and retention. Based on this, the present invention constructs a probe structure with high affinity and selectivity for FAP. Further structural modification is performed through the conjugation design method to prepare a low-pH insertion-type radioactive complex targeting FAP with clinical application potential, providing an alternative solution for non-invasive and precise tumor diagnosis and treatment.

[0054] Specifically, the present invention provides a low-pH insertion compound targeting FAP, which is composed of a FAP targeting group, a low-pH insertion group, and a bifunctional chelating agent, and has the structure:

[0055]

[0056] in:

[0057] R1 is the FAP targeting group FAPI, and its structure is:

[0058]

[0059] R2 is a low pH insertion group Var3, whose structure is:

[0060]

[0061] R3 is a bifunctional chelating agent, which is DO3A, DO3A-NCS or DOTA-NCS, and its structure is:

[0062]

[0063] The present invention uses Wang resin as a carrier and prepares the above-mentioned low-pH insertable compound targeting FAP through solid-phase synthesis method using a peptide synthesizer, and finally purifies it by preparative HPLC (high-performance liquid chromatograph). The specific synthesis route is as follows:

[0064]

[0065] The specific preparation process includes the following steps:

[0066] Step 1: Prepare the low-pH insertion group compd 1.

[0067] Using Wang resin as a carrier, in a peptide synthesizer, under the conditions of DIC, DMAP, and DCM, it reacts cyclically with amino acids such as Fmoc-Ala-OH in sequence and uses 20% Pip / DMF for deprotection. After the cyclic reaction ends, it is deprotected under the conditions of acetic anhydride, DIEA, DMF, and TFA to obtain the target product Ac-Ala-Lys-Asp-Asp-Gln-Asn-Pro-Trp-Arg-Ala-Tyr-Leu-Asp-Leu-Leu-Phe-Pro-Thr-Asp-Thr-Leu-Leu-Leu-Asp-Leu-Leu-Trp-Ala-OH.

[0068] Step 2: Prepare the low-pH insertable compound FAPI-Var3 targeting FAP.

[0069] Compd 2 first reacts with Compd 3 under the conditions of EDCH, HOBt, NMM, and DMF and is deprotected in TFA; then the product reacts with tert-butyl-protected DO3A-tBu, DO3A-NCS-tBu, or DOTA-NCS-tBu under the conditions of HATU, DIEA, and DMF and uses 20% Pip / DMF for deprotection; the product further reacts with adipic anhydride under the conditions of DIEA and DMF; finally, the product reacts with Compd 1 obtained in Step 1 under the conditions of DCC, HOSu, DIPEA, and DMF and is deprotected in TFA to obtain the target product FAPI-Var3. The final product is purified by preparative HPLC (high-performance liquid chromatograph) and identified by mass spectrometry.

[0070] On the other hand, based on the above-mentioned low-pH insertable compound targeting FAP, the present invention also provides a radiolabeled complex, that is, a low-pH insertable radiolabeled complex targeting FAP, which is obtained by radiolabeling the above-mentioned low-pH insertable compound targeting FAP. The radionuclide is selected from 68 Ga, 161 Tb, 177One of Lu. The above-mentioned low-pH insertable radiolabeled complex targeting FAP can be used to prepare a radioactive diagnostic probe or a therapeutic probe for human or animal tumors, and can be specifically prepared into an injection solution containing the above-mentioned low-pH insertable radioactive probe targeting FAP, and can be obtained by 68 The wet labeling method of Ga, and the specific preparation process is as follows:

[0071] Step 1: Dissolve the low-pH insertable compound targeting FAP in a small amount of dimethyl sulfoxide, then add an appropriate amount of sodium acetate solution or other buffer solution, and add the freshly eluted 68 GaCl3 hydrochloric acid solution, seal and react at 100 °C for 10 min. Dilute the reaction solution with water for injection and separate and purify it through a C18 reverse-phase solid-phase extraction column, and rinse the extraction column with buffer solution or water for injection;

[0072] Step 2: Then elute the adsorbate on the C18 reverse-phase solid-phase extraction column with ethanol and water for injection in sequence, and filter through a sterilizing filter to obtain an injection solution containing the 68 Ga-labeled complex.

[0073] Of course, when other radionuclides are selected, the method of the above preparation process can also be adopted.

[0074] In the above wet labeling method, the buffer solution is a substance that stabilizes the pH of the reaction solution, and can be any one or a mixture of two or more of acetate, lactate, tartrate, malate, maleate, succinate, ascorbate, carbonate or phosphate.

[0075] Example 1: Preparation of the low-pH insertable compound DO3A-FAPI-Var3 targeting FAP

[0076] The synthetic route is as follows:

[0077]

[0078] Specifically: Using Wang resin as a carrier, through solid-phase synthesis, use a peptide synthesizer to prepare a low-pH insertable compound targeting FAP, and purify it by preparative HPLC.

[0079] Identified by high performance liquid chromatography ( Figure 1 ), the chemical purity of DO3A-FAPI-Var3 is 96.10%, and the conditions are: binary gradient elution, the initial concentration of phase B is 42%, and it is 62% at 20 minutes. Mobile phase A is water (containing 0.1% TFA), and B is acetonitrile (containing 0.1% TFA). Identified by mass spectrometry ( Figure 2 ), the [M + 3H] of the compound DO3A-FAPI-Var3 + / 3 is 1491.35, and the calculated value (m / z) is 4471.05.

[0080] Example 2: 68 Ga and 177 Preparation of FAP-targeted low pH insertable radiolabeled complexes labeled with Lu

[0081] 68 The wet labeling method of Ga-DO3A-FAP-Var3 is as follows:

[0082] Dissolve 20 micrograms of the compound DO3A-FAPI-Var3 prepared in Example 1 in 40 microliters of dimethyl sulfoxide, add about 18.5 - 1850 megabecquerels (MBq) 68 GaCl3 hydrochloric acid solution (eluted from a germanium-gallium generator), then add 0.25 mol / L sodium acetate solution to adjust the pH to 3.0 - 4.0, and react at 100 °C for 10 min. Take a C18 reversed-phase solid-phase extraction column and slowly wash it successively with 5 mL of absolute ethanol and 10 mL of injection water. After the reaction, cool to room temperature, dilute the reaction solution with 5 mL of injection water, load it onto the C18 reversed-phase solid-phase extraction column, wash the purification column with 5 mL of injection water, and then elute the adsorbed substances on the C18 reversed-phase solid-phase extraction column successively with 1.0 mL of 60% ethanol and 6.0 mL of injection water, and filter through a sterilizing filter to obtain the injection solution containing the 68 Ga-DO3A-FAPI-Var3. The uncorrected labeling rates are respectively: 65.3 ± 4.6% (n = 5).

[0083] 177 The wet labeling method of Lu-DO3A-FAP-Var3 is as follows:

[0084] Dissolve the compound DO3A-FAPI-Var3 prepared in Example 1 in 40 microliters of dimethyl sulfoxide, and add 177 LuCl3 hydrochloric acid solution, and the ratio of precursor to radioactivity is: 3.7 - 5.0 megabecquerels / microgram. Then add 0.25 mol / L sodium acetate solution to adjust the pH to 4.0 - 5.0, and react at 100 °C for 20 min. Take a C18 reversed-phase solid-phase extraction column and slowly wash it successively with 5 mL of absolute ethanol and 10 mL of injection water. After the reaction, cool to room temperature, load it onto the C18 reversed-phase solid-phase extraction column, wash the purification column with 5 mL of injection water, and then elute the adsorbed substances on the C18 reversed-phase solid-phase extraction column successively with 1.0 mL of 60% ethanol and 6.0 mL of injection water, and filter through a sterilizing filter to obtain the injection solution containing the 177 Lu-DO3A-FAPI-Var3. The uncorrected labeling rate is 92.3 ± 3.3% (n = 5).

[0085] Example 3: Analysis and Application Effect:

[0086] Taking the radioactive 68 Ga and 177 Lu-labeled probe prepared in Example 2 as an example, its performance determination is described as follows:

[0087] 1. Radio-HPLC Radiochemical Purity Identification

[0088] Identification conditions: Binary gradient elution, initial B-phase concentration 5%, increasing from 5 minutes to 95% at 12 minutes and continuing to 20 minutes. Mobile phase A is water (containing 0.1% TFA), and B is acetonitrile (containing 0.1% TFA).

[0089] After identification, 68 Ga and 177 the radiochemical purities of the Lu-labeled probes are both greater than 98%, higher than the specified standard in the pharmacopoeia that the radiochemical purity of 18 F-deoxyglucose is greater than 90% (Chinese Pharmacopoeia 2020 Edition, Part II). The results are shown in Figure 3 .

[0090] 2. Inspection

[0091] The pH value is 4.0 - 7.0 (Chinese Pharmacopoeia 2020 Edition, Part II, Appendix VI H). Bacterial endotoxin test: Take an appropriate amount of this product (that is, the 68 Ga and 177 Lu-labeled probe solution obtained after filtration through a sterilizing filter), dilute it 60 times with water for bacterial endotoxin test, and then detect it according to the standard method (Chinese Pharmacopoeia 2020 Edition, Part II, Appendix XI E). The endotoxin content of each 1 mL of this product is less than 15 EU. Sterility test: Take an appropriate amount of this product and detect it according to the standard method (Chinese Pharmacopoeia 2020 Edition, Part II, Appendix XI H). This product meets the requirements.

[0092] 3. Radioactive Concentration: Accurately measure a certain volume of this product, place it in an activity meter to measure the activity, and calculate the radioactive concentration based on the sample volume and its activity. The radioactive concentration of this product is 1.50 - 150 MBq / mL.

[0093] 4. Shelf Life: Calculated from the calibration time for 3 h. After in vitro stability experiments, the results show that 68 the radiochemical purity of Ga-DO3A-FAPI-Var3 is still higher than 98% after incubation in physiological saline and mouse serum for 3 h, 177 the radiochemical purity of Lu-DO3A-FAPI-Var3 is still higher than 98% after incubation in physiological saline and mouse serum for 24 h, indicating that the probes all have high in vitro stability. ( Figure 4 )

[0094] 5. Lipophilicity: Measured by the shake-flask method 68 Ga-DO3A-FAPI-Var3 and 177 The lipophilicity logD of Lu-DO3A-FAPI-Var3 was -2.21 ± 0.20 and -2.03 ± 0.17, respectively.

[0095] 6. 68 Micro-PET imaging and biodistribution of Ga-FAPI-Var3 in U87MG cell xenograft mice

[0096] U87MG cells express FAP. A U87MG cell xenograft mouse model was constructed. Through the tail vein injection 68 Normal saline (containing 7% ethanol) of Ga-DO3A-FAPI-Var3 (0.1 mL, about 10 MBq). After injection, dynamic imaging was performed using micro-PET. Figure 5 The results showed that 68 Ga-DO3A-FAPI-Var3 could image tumors. Compared with existing FAP-targeted probes, 68 The tumor uptake of Ga-FAP-Var3 gradually increased over time, reached the highest at 180 min after injection, and the retention time was significantly prolonged. The uptake in normal organs gradually decreased over time.

[0097] In U87MG cell xenograft mice 68 After 4 hours of micro-PET imaging of Ga-DO3A-FAPI-Var3 injection in U87MG cell xenograft mice, the mice were anesthetized and sacrificed. Blood, whole brain, heart, liver, spleen, lung, kidney, small intestine, stomach, muscle, and bone and other organs, as well as tumors, were taken, weighed, and their radioactivity counts (CPM) were measured using a γ-counter. The percentage of radioactivity in each organ was expressed as the percentage of radioactivity per gram of organ (%ID / g), and the tail count was measured for data correction. The results are as Figure 6 and Figure 7 shown 68 Ga-DO3A-FAPI-Var3 was mainly metabolized by the kidneys in mice, had high uptake in tumors, and low uptake in normal organs. Therefore, 68 Ga-DO3A-FAPI-Var3 had a high tumor / normal organ uptake ratio, such as the tumor / muscle uptake ratio of about 8, which showed low background uptake and was beneficial for tumor diagnosis.

[0098] 7. 177 Biodistribution of Lu-DO3A-FAPI-Var3 in U87MG cell xenograft mice

[0099] In the tail vein injection of U87MG cell xenograft mice 177After injecting Lu-DO3A-FAPI-Var3, the mice were sacrificed by anesthesia 24 hours later. Organs such as blood, whole brain, heart, liver, spleen, lung, kidney, muscle and bone, as well as tumors were collected, weighed and their radioactivity counts (CPM) were measured using a γ-counter. The percentage dose of radioactivity in each organ was expressed as the percentage dose of radioactivity per gram of organ (%ID / g), and the tail count was measured for data correction. The results are as Figure 8 shown, 177 The distribution of Lu-DO3A-FAPI-Var3 in mice is similar to that of 68 Ga-DO3A-FAPI-Var3. It is mainly metabolized through the kidneys in mice, has a high uptake in tumors, and a low uptake in normal organs. Therefore, 68 Ga-DO3A-FAPI-Var3 has a high tumor / normal organ uptake ratio, which is beneficial to radionuclide therapy for tumors.

[0100] The above performance determination proves that the novel FAP-targeted probe designed by the present invention adopts the method of combining FAP-targeted small molecules with low-pH insertion peptides. By utilizing the anchoring property of low-pH insertion peptides on the cell membrane, the uptake and retention of FAP-targeted small molecules in tumors are enhanced, effectively overcoming the problems of low tumor uptake and short retention time existing in the prior art. It has suitable physical, chemical and radiological properties, as well as relatively ideal biological characteristics, and can be used for tumor radioactive diagnosis or treatment, which is beneficial to clinical application.

[0101] The above uses specific examples to elaborate on the present invention, which is only used to help understand the present invention and is not intended to limit the present invention. For those skilled in the technical field to which the present invention pertains, based on the idea of the present invention, several simple deductions, deformations or substitutions can also be made.

Claims

1. A low pH insertable compound targeting FAP, characterized in that: The low pH insertable compound targeting FAP is composed of an FAP targeting group, a low pH insertable group and a bifunctional chelator linker.

2. The low pH insertable compound targeting FAP according to claim 1, characterized in that: The structure of the low pH insertable compound targeting FAP is: Wherein: R1 is the FAP targeting group FAPI, and its structure is: R2 is the low pH insertable group Var3, and its structure is: R3 is a bifunctional chelating agent, which is DO3A, DO3A-NCS or DOTA-NCS, and its structure is:

3. The preparation method of the low pH insertable compound targeting FAP according to claim 2, characterized in that: The method includes:

4. A low pH insertable radiolabeled complex targeting FAP, characterized in that: The low pH insertable radiolabeled complex targeting FAP is obtained by radiolabeling the low pH insertable compound targeting FAP according to claim 2 with a radionuclide.

5. The low pH insertable radiolabeled complex targeting FAP according to claim 4, characterized in that: The radionuclide is selected from 68 Ga, 161 Tb, 177 Lu.

6. The low pH insertable radiolabeled complex targeting FAP according to claim 4, characterized in that: The structure of the low pH insertable radiolabeled complex targeting FAP is: Wherein: R3’ is a radionuclide 68 a Ga-labeled bifunctional chelating agent, being 68 Ga-DO3A, 68 Ga-DO3A-NCS or 68 Ga-DOTA-NCS, with the structure:

7. The low pH insertable radiolabeled complex targeting FAP according to claim 4, characterized in that: The structure of the low pH insertable radiolabeled complex targeting FAP is: Wherein: R3’ is a radionuclide 161 a terbium-labeled bifunctional chelating agent, being 161 Tb-DO3A, 161 Tb-DO3A-NCS or 161 Tb-DOTA-NCS, with the structure:

8. The low pH insertable radiolabeled complex targeting FAP according to claim 4, characterized in that: The structure of the low pH insertable radiolabeled complex targeting FAP is: Wherein: R3’ is a radionuclide 177 a bifunctional chelating agent labeled with 177 Lu-DO3A, 177 Lu-DO3A-NCS or 177 Lu-DOTA-NCS, and the structure is:

9. The application of the low pH insertable radiolabeled complex targeting FAP according to claim 4 in the preparation of a radioactive diagnostic probe or a therapeutic probe for human or animal tumors.

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