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

Abstract

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

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 PSMA, a preparation method thereof, and an application thereof. Background Art

[0002] Prostate Specific Membrane Antigen (PSMA) is highly expressed in prostate cancer (PCa), especially significantly increased in high-grade well-differentiated tumors, androgen deprivation, hormone tolerance, and metastatic diseases. In addition, PSMA is highly expressed in various malignant tumors such as glioblastoma and liver cancer.

[0003] The use of positron emission tomography (PET) probes or radionuclide therapy probes targeting PSMA for imaging and treating prostate cancer has received extensive attention and shown great potential for improving the management of prostate cancer patients. For example, 68 Ga-PSMA-11 has high sensitivity (74%) and specificity (96%) for early prostate cancer, and is superior to MRI, CT, and other conventional imaging in the diagnosis of lymph node metastasis; 177 Lu-PSMA-617 has good therapeutic effects on prostate cancer and is a hot spot in clinical research. However, existing PSMA-targeted probes still have low tumor uptake, and due to their small molecular weight, they are easily cleared, resulting in a short tumor retention time, which affects the radionuclide therapy effect.

[0004] Therefore, it is necessary to design new PSMA-targeted probes to overcome the above defects. Summary of the Invention

[0005] The purpose of the present invention is to provide a low pH insertable compound targeting PSMA, a preparation method thereof, and an application thereof, so as to solve the problems of low tumor uptake and short retention time existing in existing PSMA-targeted probes.

[0006] In order to achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0007] Provide a low pH insertable compound targeting PSMA, which is composed of a PSMA targeting group, a low pH insertion group, and a bifunctional chelating agent connected.

[0008] Further, the structure of the low pH insertable compound targeting PSMA is:

[0009]

[0010] Wherein:

[0011] R1 is a PSMA targeting group, and its structure is:

[0012]

[0013] R2 is a low pH insertion group Var3, and its structure is:

[0014]

[0015] R3 is a bifunctional chelator, which is DO3A, DO3A-NCS or DOTA-NCS, and its structure is:

[0016]

[0017] On the other hand, a method for preparing a low pH insertion type compound targeting PSMA as described above is provided, and the method includes:

[0018]

[0019] On the other hand, a low pH insertion type radiolabeled complex targeting PSMA is provided, and the low pH insertion type radiolabeled complex targeting PSMA is obtained by radiolabeling the low pH insertion type compound targeting PSMA.

[0020] Furthermore, the radionuclide is selected from 68 Ga, 161 Tb, 177 Lu.

[0021] Furthermore, the structure of the low pH insertion type radiolabeled complex targeting PSMA is:

[0022]

[0023] Wherein:

[0024] R3' is a radionuclide 68 Ga-labeled bifunctional chelator, which is 68 Ga-DO3A, 68 Ga-DO3A-NCS or 68 Ga-DOTA-NCS, and the structure is:

[0025]

[0026] Or, the structure of the low pH insertion type radiolabeled complex targeting PSMA is:

[0027]

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

[0029]

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

[0031]

[0032] R3’ is a radionuclide 177 Lu-labeled bifunctional chelating agent, which is 177 Lu-DO3A, 177 Lu-DO3A-NCS or 177 Lu-DOTA-NCS, and its structure is:

[0033]

[0034] On the other hand, there is provided the use of the low-pH insertable radiolabeled complex targeting PSMA as described above in the preparation of a radioactive diagnostic probe or a therapeutic probe for human or animal tumors.

[0035] On the other hand, there is provided the use of the low-pH insertable radiolabeled complex targeting PSMA as described above in the preparation of a radioactive diagnostic probe or a therapeutic probe for human or animal prostate cancer.

[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 PSMA, its preparation method and application. The low-pH insertable compound targeting PSMA is labeled with a radionuclide through a bifunctional chelating agent to construct a PET molecular imaging probe for use as a tumor positron tracer; or a radionuclide therapeutic probe for use in tumor radionuclide therapy. Experiments show that 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. Compared with the existing PSMA-targeted radioactive probes, the present invention constructs a low-pH insertable probe targeting PSMA with higher tumor uptake and longer retention time, which is beneficial to improving the effect of radionuclide therapy. Description of the Drawings

[0038] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the accompanying drawings required in the description of the embodiments or the prior art. Obviously, the accompanying drawings in the following description 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 HPLC identification result of the chemical purity of the PSMA-targeted low pH insertable compound prepared in Example 1.

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

[0041] Figure 3 For the preparation in Example 2 68 Ga-labeled PSMA-targeted low pH insertable radiocomplex 68 Radiochemical purity identification result of Ga-DO3A-PSMA-Var3.

[0042] Figure 4 For the preparation in Example 2 68 Ga-DO3A-PSMA-Var3 (A) and 177 HPLC identification result of the in vitro stability of Lu-DO3A-PSMA-Var3 (B).

[0043] Figure 5 For the preparation in Example 2 68 Micro-PET imaging result of Ga-DO3A-PSMA-Var in nude mice bearing 22RV1 tumors.

[0044] Figure 6 For the preparation in Example 2 68 Bar graph of organ uptake-time of Ga-DO3A-PSMA-Var3 in nude mice bearing 22RV1 tumors.

[0045] Figure 7 For the preparation in Example 2 177 In vivo distribution result of Lu-DO3A-PSMA-Var3 in nude mice bearing 22RV1 tumors 24 hours after injection. Specific embodiments

[0046] 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.

[0047] In the description of the present invention, it should be understood that all the technologies and scientific terms used have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains. When there is a contradiction, the definition 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 should not be construed as a limitation of the present invention. Means, reagents, or devices of the same type that solve the same technical problems are within the protection scope of the present invention.

[0048] In the description of the present invention, it should be understood that when a quantity, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper limit preferred values and lower limit preferred values, this should be understood to specifically disclose all the ranges formed by any pairing of any range upper limit or preferred value and 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.

[0049] 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. Technical solutions obtained only by changing the step order when solving the same technical problem are also within the protection scope of the present invention.

[0050] Positron Emission Computed Tomography (PET) is a clinical imaging technique 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, the situation of life metabolic activities can be reflected, thereby achieving the purpose of diagnosis.

[0051] 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 PSMA aggregation in tumor tissues, effectively enhancing the efficacy of positron-ionization diagnostics or radionuclide therapy for tumors.

[0052] The conjugation design method can greatly preserve the biological activity of small molecule probes for their target receptors. Introducing low-pH insertion groups into small molecule probes can significantly enhance their uptake and retention in tumors. Based on this, the present invention constructs a probe structure with high affinity and selectivity for PSMA. Further structural modification is performed through the conjugation design method to prepare a low-pH insertion-type PSMA-targeting radioactive complex with clinical potential, providing an alternative solution for non-invasive and precise tumor diagnosis and treatment.

[0053] Specifically, the present invention provides a low-pH insertion compound targeting PSMA, which is composed of a PSMA targeting group, a low-pH insertion group, and a bifunctional chelating agent, and has the structure:

[0054]

[0055] in:

[0056] R1 is a PSMA targeting group, and its structure is:

[0057]

[0058] R2 is a low pH insertion group Var3, whose structure is:

[0059]

[0060] R3 is a bifunctional chelating agent, which is DO3A, DO3A-NCS or DOTA-NCS, and its structure is:

[0061]

[0062] The present invention uses Wang resin as a carrier and prepares a low pH insertable compound targeting PSMA by solid-phase synthesis method using a peptide synthesizer, and purifies it by preparative HPLC (high performance liquid chromatograph). The specific synthesis route is as follows:

[0063]

[0064] The specific preparation process includes the following steps:

[0065] Step 1: Prepare the low pH insertion group compd 1.

[0066] 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 and uses 20% Pip / DMF for deprotection. After the cyclic reaction ends, it is deprotected under the conditions of acetic anhydride, DIEA, DMF and 4% hydrazine hydrate, DMF to obtain the target product Ac-Ala-Lys-Asp(OtBu)-Asp(OtBu)-Gln(Trt)-Asn(Trt)-Pro-Trp(Boc)-Arg(Pbf)-Ala-Tyr(tBu)-Leu-Asp(OtBu)-Leu-Leu-Phe-Pro-Thr(tBu)-Asp(OtBu)-Thr(tBu)-Leu-Leu-Leu-Asp(OtBu)-Leu-Leu-Trp(Boc)-Ala-WangResin.

[0067] Step 2: Prepare the low pH insertable compound FAPI-Var3 targeting FAP.

[0068] Compd 2 first reacts with Compd 3 under the conditions of EDCH, HOBt, NMM, and DMF and is deprotected in 20% Pip / DMF; 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 is deprotected using 4% hydrazine hydrate / DMF; 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, HATU, DIPEA, and DMF and is deprotected in TFA to obtain the target product PSMA-Var3. The final product is purified by preparative HPLC (high performance liquid chromatograph) and identified by mass spectrometry.

[0069] On the other hand, based on the above-mentioned low-pH insertable compound targeting PSMA, the present invention also provides a radiolabeled complex, namely a low-pH insertable radiolabeled complex targeting PSMA, which is obtained by radiolabeling the above-mentioned low-pH insertable compound targeting PSMA, and the radionuclide is selected from 68 Ga, 161 Tb, 177 one of Lu.

[0070] For example, the following several low-pH insertable radiolabeled complexes targeting PSMA:

[0071] 1. The structure is:

[0072]

[0073] Wherein:

[0074] R3’ is a radionuclide 68 a bifunctional chelating agent labeled with Ga, which is 68 Ga-DO3A, 68 Ga-DO3A-NCS or 68 Ga-DOTA-NCS, and the structure is:

[0075]

[0076] 2. The structure is:

[0077]

[0078] Wherein, R3’ is a radionuclide 161 a bifunctional chelating agent labeled with Tb, which is 161 Tb-DO3A, 161 Tb-DO3A-NCS or 161 Tb-DOTA-NCS, and the structure is:

[0079]

[0080] 3. The structure is:

[0081]

[0082] R3’ is a radionuclide 177 a bifunctional chelating agent labeled with Lu, which is 177 Lu-DO3A, 177 Lu-DO3A-NCS or 177 Lu-DOTA-NCS, and the structure is:

[0083]

[0084] The above-mentioned low pH insertable radiolabeled complex targeting PSMA can be used to prepare radioactive diagnostic probes or therapeutic probes for human or animal tumors. Specifically, it can be prepared into an injection solution containing the above-mentioned low pH insertable radioactive probe targeting PSMA, which can be obtained by 68 the wet labeling method of

[0085] Step 1: Dissolve the low pH insertable compound targeting PSMA 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 minutes. Dilute the reaction solution with water for injection and then separate and purify it through a C18 reversed-phase solid-phase extraction column, and rinse the extraction column with the buffer solution or water for injection;

[0086] Step 2: Then elute the adsorbate on the C18 reversed-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.

[0087] Of course, when other radionuclides are selected, the above preparation process method can also be adopted.

[0088] 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.

[0089] Example 1: Preparation of the low pH insertable compound DO3A-PSMA-Var3 targeting PSMA

[0090] The synthesis route is as follows:

[0091]

[0092] Specifically: Using Wang resin as a carrier, through solid-phase synthesis method, use a peptide synthesizer to prepare the low pH insertable compound targeting PSMA, and purify it by preparative HPLC.

[0093] Identified by high performance liquid chromatography ( Figure 1 ), the chemical purities of DO3A-PSMA-Var3 are 97.14% respectively. The conditions are: binary gradient elution, the initial concentration of phase B is 45%, and it is 65% 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-PSMA-Var3 + / 3 was 1547.59, and the calculated value (m / z) was 4637.36.

[0094] Example 2: 68 Ga and 177 Preparation of PSMA-targeted low pH insertable radiolabeled complex labeled with Lu

[0095] 68 The wet labeling method of Ga-DO3A-PSMA-Var3 is as follows:

[0096] Dissolve 20 micrograms of the compound DO3A-PSMA-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.

[0097] 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 it 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-PSMA-Var3. The uncorrected labeling rates were: 60.3 ± 3.8% (n = 5).

[0098] 177 The wet labeling method of Lu-DO3A-PSMA-Var3 is as follows:

[0099] Dissolve the compound DO3A-PSMA-Var3 prepared in Example 1 in 40 microliters of dimethyl sulfoxide, add 177 LuCl3 hydrochloric acid solution, and the ratio of precursor to radioactivity is: 3.7 - 5.0 megabecquerels / μg. 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 it 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-PSMA-Var3. The uncorrected labeling rate was 93.5 ± 1.8% (n = 5).

[0100] Example 3: Analysis and application effects:

[0101] Taking the radioactive 68 Ga and 177 Lu-labeled probes prepared in Example 2 below as an example, their performance measurements are described as follows:

[0102] 1. Radio-HPLC radiochemical purity identification

[0103] Identification conditions: Binary gradient elution, the initial concentration of phase B is 5%, increasing to 95% from 5 minutes to 12 minutes and continuing to 20 minutes. Mobile phase A is water (containing 0.1% TFA), and B is acetonitrile (containing 0.1% TFA).

[0104] After identification, 68 Ga and 177 the radiochemical purities of the Lu-labeled probes are 98.8% and 98.5% respectively, higher than the specified standard in the pharmacopoeia for 18 F-deoxyglucose with a radiochemical purity greater than 90% (Chinese Pharmacopoeia 2020 Edition, Volume II). The results are shown in Figure 3 .

[0105] 2. Inspection

[0106] The pH value is 4.0 - 7.0 (Chinese Pharmacopoeia 2020 Edition, Volume 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, Volume 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, Volume II, Appendix XI H). This product meets the requirements.

[0107] 3. Radioactive concentration: Accurately measure a certain volume of this product, place it in a dose calibrator 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.

[0108] 4. Shelf life: Calculated from the calibration time for 3 h. Through in vitro stability experiments, the results show that 68 the radiochemical purity of Ga-DO3A-PSMAVar3 is still higher than 98% after incubation in normal saline and mouse serum for 3 h, 177The radiochemical purity of Lu-DO3A-PSMA-Var3 remained higher than 98% after incubation in saline and mouse serum for 24 h, indicating that the probes had high in vitro stability.( Figure 4 )

[0109] 5. Lipophilicity: Measured by the shake-flask method 68 The lipophilicity logD of Ga-DO3A-PSMA-Var3 and 177 Lu-DO3A-PSMA-Var3 were -2.86 ± 0.13 and -2.57 ± 0.15, respectively.

[0110] 6. 68 Micro-PET imaging of Ga-PSMA-Var3 in tumor-bearing mice with 22RV1 cells

[0111] For tumor-bearing mice with 22RV1 cells, through tail vein injection 68 Saline (containing 7% ethanol) of Ga-DO3A-PSMA-Var3 (0.1 mL, about 10 MBq). Dynamic imaging was performed using micro-PET after injection. Figure 5 The results showed that 68 Ga-DO3A-PSMA-Var3 could image tumors. The uptake of the heart, liver, kidney, muscle, and tumor at 30, 60, 120, and 240 min after injection was outlined respectively, and the uptake-time bar graph of each organ was drawn( Figure 6 ). Compared with the existing PSMA-targeted probes, 68 The uptake of Ga-PSMA-Var3 in tumors gradually increased with time, reached the highest at 240 min after injection, the retention time was significantly enhanced, the uptake in normal organs gradually decreased with time, and the tumor-to-normal organ uptake ratio gradually increased with time, which was beneficial for tumor diagnosis.

[0112] 7. 177 Distribution of Lu-DO3A-PSMA-Var3 in tumor-bearing mice with 22RV1 cells

[0113] For tumor-bearing mice with 22RV1 cells, through tail vein injection 177 Lu-DO3A-PSMA-Var3. The mice were anesthetized and sacrificed 24 hours after injection, and blood, whole brain, heart, liver, spleen, lung, kidney, muscle, bone and other organs, as well as tumors, were taken, weighed and their radioactivity counts (CPM) were measured with a γ-counter. The radioactive percentage dose in each organ was expressed as the radioactive percentage dose per gram of organ (%ID / g), and the tail count was measured for data correction. The results are as Figure 7 shown 177 The distribution of Lu-DO3A-PSMA-Var3 in mice was similar to that of 68Ga-DO3A-PSMA-Var3 is similar, mainly metabolized by the kidneys in mice, with high uptake in tumors and low uptake in normal organs. Therefore, 177 Lu-DO3A-PSMA-Var3 has a high tumor-to-normal organ uptake ratio, which is beneficial to radionuclide therapy for tumors.

[0114] The above performance measurements prove that the PSMA-targeted probe with a new structure designed by the present invention by combining a PSMA-targeted small molecule with a low-pH insertion peptide utilizes the anchoring property of the low-pH insertion peptide in the cell membrane to enhance the uptake and retention of the PSMA-targeted small molecule in tumors, 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 radio-diagnosis or therapy, especially for prostate cancer, which is conducive to clinical application.

[0115] The above uses specific examples to illustrate 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 belongs, several simple deductions, deformations or substitutions can also be made according to the idea of the present invention.

Claims

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

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

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

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

5. The radiolabeled complex of a low pH insertable compound targeting PSMA according to claim 4, characterized in that: The radionuclide is selected from 68 Ga,[[]] 161 Tb,[[]] 177 Lu.[[]] 6. The radiolabeled complex of a low pH insertable compound targeting PSMA according to claim 4, characterized in that: The structure of the radiolabeled complex of the low pH insertable compound targeting PSMA 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 as follows:

7. The radiolabeled complex of a low pH insertable compound targeting PSMA according to claim 4, characterized in that: The structure of the radiolabeled complex of the low pH insertable compound targeting PSMA is: Among them, 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 radiolabeled complex of a low pH insertable compound targeting PSMA according to claim 4, characterized in that: The structure of the radiolabeled complex of the low pH insertable compound targeting PSMA is: 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. Use of the radiolabeled complex of a low pH insertable compound targeting PSMA according to claim 4 in the preparation of a radioactive diagnostic probe or a therapeutic probe for human or animal tumors.

10. Use of the radiolabeled complex of a low pH insertable compound targeting PSMA according to claim 4 in the preparation of a radioactive diagnostic probe or a therapeutic probe for human or animal prostate cancer.

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