Low-pH insertion type compound targeting CXCR4 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 CXCR4 as well as a preparation method and application of the low-pH insertion type compound. The existing CXCR4 targeting probe has the problems of low tumor uptake and short residence time. The invention provides a CXCR4 targeting low-pH insertion type compound which is formed by connecting a CXCR4 targeting group, a low-pH insertion group and a bifunctional chelating agent, and provides a CXCR4 targeting low-pH insertion type radiolabeled complex which is used for preparing a human or animal tumor radiodiagnosis probe or treatment probe. The brand-new CXCR4 targeting probe is designed by adopting a mode of combining CXCR4 targeting small molecules with the low-pH insertion peptide, the uptake and retention of the CXCR4 targeting small molecules in tumors are improved by utilizing the anchoring characteristic of the low-pH insertion peptide in a cell membrane, and the CXCR4 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 in particular to a low-pH insertion compound targeting CXCR4, and a preparation method and application thereof. Background Art

[0002] The chemokine receptor CXCR4, a receptor for the chemokine CXCL12 / SDF-1 (stromal cell-derived factor-1), is the most studied chemokine receptor. It has a seven-transmembrane structure with seven helical regions connected by six extracellular loops. CXCR4 is overexpressed in over 30 human cancers, including uterine carcinosarcoma, lung squamous cell carcinoma, colorectal adenocarcinoma, pancreatic cancer, bladder urothelial carcinoma, lung adenocarcinoma, breast cancer, melanoma, and lymphoid neoplasms such as diffuse large B-cell lymphoma. CXCR4 expression is associated with tumor invasion, metastasis, and invasiveness.

[0003] Imaging and treating tumors using positron emission tomography (PET) probes or radionuclide therapy probes targeting CXCR4 have received extensive attention and show great potential to improve patient management. 68 Ga-Pentixafor is used for non-invasive imaging of CXCR4 expression in tumors and has been widely used in hematological malignancies to help select patients whose tumors show CXCR4 overexpression, who can benefit from new therapies targeting CXCR4 to increase the chemotherapy sensitivity of the tumor and inhibit tumor metastasis and invasiveness. In addition, 177 Lu-He 90 Y-Pentixather has been studied in patients with advanced hematologic malignancies, and preliminary studies have shown a favorable therapeutic response in metabolically active lesions. However, existing CXCR4-targeted probes still suffer from low tumor uptake and short tumor retention times due to their small molecular weight and easy clearance, which compromises the effectiveness of radionuclide therapy.

[0004] Therefore, it is necessary to design new CXCR4 targeting probes to overcome the above defects. Summary of the Invention

[0005] The purpose of the present invention is to provide a low-pH insertion compound targeting CXCR4 and its preparation method and application, so as to at least solve the problems of low tumor uptake and short retention time of existing CXCR4 targeting probes.

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

[0007] Provided is a low-pH insertion compound targeting CXCR4, which is composed of a CXCR4 targeting group, a low-pH insertion group and a bifunctional chelating agent.

[0008] Furthermore, the structure of the low pH insertion compound targeting CXCR4 is:

[0009]

[0010] in:

[0011] R1 is a CXCR4 targeting group, and its structure is:

[0012]

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

[0014]

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

[0016]

[0017] In another aspect, a method for preparing the low-pH insertion compound targeting CXCR4 is provided, the method comprising:

[0018]

[0019] On the other hand, a low-pH insertion-type radiolabeled complex targeting CXCR4 is provided. The low-pH insertion-type radiolabeled complex targeting CXCR4 is obtained by labeling the low-pH insertion-type compound targeting CXCR4 with a radionuclide.

[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 CXCR4 is:

[0022]

[0023] in:

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

[0025]

[0026] Alternatively, the structure of the low pH insertion type radiolabeled complex targeting CXCR4 is:

[0027]

[0028] Among them, R3' is a radionuclide 161 Tb-labeled bifunctional chelator, 161 Tb-DO3A, 161 Tb-DO3A-NCS or 161 Tb-DOTA-NCS, the structure is:

[0029]

[0030] Alternatively, the structure of the low pH insertion type radiolabeled complex targeting CXCR4 is:

[0031]

[0032] R3' is a radionuclide 177 Lu-labeled bifunctional chelator, 177 Lu-DO3A, 177 Lu-DO3A-NCS or 177 Lu-DOTA-NCS, the structure is:

[0033]

[0034] In another aspect, the present invention provides a use of the low-pH intercalation radiolabeled complex targeting CXCR4 in preparing a radioactive diagnostic probe or therapeutic probe for human or animal tumors.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] The present invention provides a low-pH insertion compound targeting CXCR4, a preparation method, and an application thereof. The low-pH insertion compound targeting CXCR4 is labeled with a radionuclide via a bifunctional chelating agent to construct a PET molecular imaging probe for use as a tumor positron tracer; or to construct a radionuclide therapy probe for use as a tumor radionuclide therapy. Experiments have shown that it has suitable physicochemical and radiological properties, as well as relatively ideal biological characteristics, and can be used for radioactive diagnosis or treatment of tumors. Compared with existing CXCR4-targeted radioactive probes, the present invention constructs a CXCR4-targeted low-pH insertion probe with higher tumor uptake and longer retention time, which is beneficial to improving the effect of radionuclide therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, without paying any creative work, they can also obtain drawings of other embodiments based on these drawings.

[0038] Figure 1 This is the HPLC identification result of the chemical purity of the CXCR4-targeted low-pH insertion compound prepared in Example 1.

[0039] Figure 2 This is the MS identification result of the chemical purity of the CXCR4-targeted low-pH insertion compound prepared in Example 1.

[0040] Figure 3 Prepared in Example 2 68 Ga and 177 Results of radiochemical purity characterization of Lu-labeled CXCR4-targeted low-pH intercalation radiolabeled complex.

[0041] Figure 4 Prepared in Example 2 68 Ga(A) and 177 In vitro stability HPLC identification results of Lu(B)-labeled CXCR4-targeted low-pH insertion-type radiolabeled complexes. In vitro stability HPLC identification results.

[0042] Figure 5 Prepared in Example 2 68 Micro-PET imaging results of Ga-DO3A-Pentixavar in CHO cell tumor-bearing mice. DETAILED DESCRIPTION

[0043] To facilitate understanding of the present invention, the present invention will be described more fully below with reference to the accompanying drawings. The accompanying drawings illustrate preferred embodiments of the present invention. However, the present invention may be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and comprehensive understanding of the present disclosure.

[0044] In the description of the present invention, it is to be understood that all technologies and scientific terms used have the same meaning as those of ordinary skill in the art to which the present invention belongs. When there is a contradiction, the definition in this specification shall prevail. If not otherwise specified, the technical means used in the embodiment are conventional means well known to those skilled in the art, the reagent used in the embodiment is a commercially available product, and the device used in the embodiment is an existing device, and the limitation of means, reagent or device can not be interpreted as limitation of the present invention, and the means, reagent or device for solving the same technical problems of the same type are within protection scope of the present invention.

[0045] 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 limited by a series of upper preferred values and lower preferred values, this should be understood to specifically disclose all 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 separately. When a numerical range is described in this specification, unless otherwise stated, the range is intended to include its end values and all integers and fractions within the range.

[0046] In the description of the present invention, it should be understood that multiple steps are involved in the description of the method, which should not be understood as a limitation on the order of the method steps. Technical solutions obtained by simply changing the order of the steps when solving the same technical problem are also within the scope of protection of the present invention.

[0047] Positron Emission Computed Tomography (PET) is a clinical imaging technology in the field of nuclear medicine. The examination involves markers that, after being injected into the human body, reflect the state of life metabolic activities by monitoring the accumulation of the substances during metabolism, thereby achieving the purpose of diagnosis.

[0048] 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, making it 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 vector can mediate CXCR4 aggregation in tumor tissues, effectively enhancing the efficacy of positron-ionization diagnostics or radionuclide therapy for tumors.

[0049] The coupling design method can greatly preserve the biological activity of small molecule probes on the target receptor. Introducing low-pH insertion groups into small molecule probes can greatly enhance tumor uptake and retention. Based on this, the present invention constructs a probe structure with high affinity and selectivity for CXCR4. Through further structural modification using the coupling design method, a radioactive complex targeting CXCR4 with low-pH insertion properties is prepared, which has clinical application potential and provides an alternative solution for non-invasive and precise tumor diagnosis and treatment.

[0050] Specifically, the present invention provides a low-pH insertion compound targeting CXCR4, which is composed of a CXCR4 targeting group, a low-pH insertion group, and a bifunctional chelating agent, and has the structure:

[0051]

[0052] in:

[0053] R1 is a CXCR4 targeting group, and its structure is:

[0054]

[0055] R2 is a low pH insertion group Var3, whose structure is:

[0056]

[0057] R3 is a bifunctional chelating agent, which is DO3A, DO3A-NCS or DOTA-NCS, and its structure is:

[0058]

[0059] The present invention uses Wang resin as a carrier and a peptide synthesizer to prepare a low-pH insertion compound targeting CXCR4 through solid-phase synthesis. The compound is then purified by preparative HPLC (high performance liquid chromatography). The specific synthetic route is as follows:

[0060]

[0061] The specific preparation process includes the following steps:

[0062] Step 1: Preparation of low pH insertion group compd 1.

[0063] Wang resin was used as a support and cyclically reacted with amino acids such as Fmoc-Ala-OH in a peptide synthesizer under the conditions of DIC, DMAP, and DCM, and deprotected using 20% Pip / DMF. After the cyclic reaction, deprotection was performed using 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.

[0064] Step 2: Prepare the low pH insertion compound FAPI-Var3 targeting FAP.

[0065] Compd 3, Compd 4, and Compd 5 were sequentially reacted with Compd 2 in the presence of EDCH, HOBt, NMM, and DMF, followed by deprotection in TFA. The product was then reacted with tert-butyl-protected DO3A-tBu, DO3A-NCS-tBu, or DOTA-NCS-tBu in the presence of HATU, DIEA, and DMF, followed by deprotection using 20% Pip / DMF. The product was further reacted with adipic anhydride in DIEA and DMF. Finally, the product was reacted with Compd 1 obtained in step 1 in the presence of DCC, HOSu, DIPEA, and DMF, followed by deprotection in TFA to yield the target product, Pentixavar. The final product was purified by preparative HPLC and identified by mass spectrometry.

[0066] On the other hand, based on the above-mentioned low pH insertion type compound targeting CXCR4, the present invention further provides a radiolabeled complex, i.e., a low pH insertion type radiolabeled complex targeting CXCR4, obtained by labeling the above-mentioned low pH insertion type compound targeting CXCR4 with a radionuclide, wherein the radionuclide is selected from 68 Ga, 161 Tb, 177A kind of road.

[0067] 1. The structure is:

[0068]

[0069] in:

[0070] R3' is a radionuclide 68 Ga-labeled bifunctional chelator, 68 Ga-DO3A, 68 Ga-DO3A-NCS or 68 Ga-DOTA-NCS, the structure is:

[0071]

[0072] 2. The structure is:

[0073]

[0074] Among them, R3' is a radionuclide 161 Tb-labeled bifunctional chelator, 161 Tb-DO3A, 161 Tb-DO3A-NCS or 161 Tb-DOTA-NCS, the structure is:

[0075]

[0076] 3. The structure is:

[0077]

[0078] R3' is a radionuclide 177 Lu-labeled bifunctional chelator, 177 Lu-DO3A, 177 Lu-DO3A-NCS or 177 Lu-DOTA-NCS, the structure is:

[0079]

[0080] The low pH insertion type radiolabeled complex targeting CXCR4 can be used to prepare a radioactive diagnostic probe or therapeutic probe for human or animal tumors. Specifically, it can be prepared as an injection containing the low pH insertion type radioactive probe targeting CXCR4, which can be injected into the patient. 68 Ga is obtained by wet labeling method. The specific preparation process is as follows:

[0081] Step 1: Dissolve the low pH insertion compound targeting CXCR4 in a small amount of dimethyl sulfoxide and add an appropriate amount of sodium acetate solution or other buffer solution, then add the freshly washed 68 GaCl3 hydrochloric acid solution, sealed at 100℃ for 10 minutes, the reaction solution was diluted with water for injection and separated and purified by C18 reverse phase solid phase extraction column, and the extraction column was rinsed with buffer or water for injection;

[0082] Step 2: Elute the adsorbate on the C18 reverse phase solid phase extraction column with ethanol and water for injection in sequence, and then filter through a sterilizing filter to obtain the adsorbate containing the 68 Injection of Ga-labeled complexes.

[0083] Of course, when other radioactive nuclides are selected, the above preparation process can also be used.

[0084] In the wet labeling method, the buffer solution is a substance that stabilizes the pH of the reaction solution and can be any one of acetate, lactate, tartrate, malate, maleate, succinate, ascorbate, carbonate or phosphate, or a mixture of two or more thereof.

[0085] Example 1: Preparation of low pH insertion compound DO3A-Pentixavar targeting CXCR4

[0086] The synthetic route is:

[0087]

[0088] Specifically, Wang resin was used as a carrier, and a peptide synthesizer was used to prepare a low-pH insertion compound targeting CXCR4 through solid-phase synthesis, and then purified by preparative HPLC.

[0089] Identified by high performance liquid chromatography ( Figure 1 ), DO3A-Pentixavar chemical purity were 99.23%, respectively, under the following conditions: binary gradient elution, initial B phase concentration 45%, to 65% at 20 minutes, mobile phase A is water (containing 0.1% TFA), B is acetonitrile (containing 0.1% TFA). Identified by mass spectrometry ( Figure 2 ), [M+3H] + / 3 is 1675.5, and the calculated value (m / z) is 5019.57.

[0090] Example 2: 68 Ga and 177 Preparation of Lu-labeled CXCR4-targeted low-pH intercalation radioactive complexes

[0091] 68The Ga-DO3A-Pentixavar wet labeling method is as follows:

[0092] 40 μg of the compound DO3A-Pentixavar prepared in Example 1 was dissolved in 40 μl of dimethyl sulfoxide, and about 18.5 to 1850 MBq of 68 GaCl3 hydrochloric acid solution (eluted from the gallium germanium generator) was added, and then 0.25 mol / L sodium acetate solution was added to adjust the pH to 3.0-4.0, and the mixture was reacted at 100°C for 10 minutes.

[0093] Take a C18 reverse phase solid phase extraction column and slowly elute it with 5 mL of anhydrous ethanol and 10 mL of injection water in sequence. After the reaction is completed, cool it to room temperature, dilute the reaction solution with 5 mL of injection water, load it onto the C18 reverse phase solid phase extraction column, rinse the purification column with 5 mL of injection water, and then elute the adsorbent on the C18 reverse phase solid phase extraction column with 1.0 mL of 60% ethanol and 6.0 mL of injection water in sequence, and filter it through a sterilizing filter to obtain the product containing the 68 The uncorrected labeling rates of Ga-DO3A-Pentixavar injection were 53.3±5.8% (n=5).

[0094] 177 The Lu-DO3A-Pentixavar wet labeling method is as follows:

[0095] The compound DO3A-Pentixavar prepared in Example 1 was dissolved in 40 μl of dimethyl sulfoxide and added 177 LuCl3 hydrochloric acid solution, the ratio of precursor to radioactivity is: 3.7 to 5.0 megabecquer / microgram. Then add 0.25 mol / L sodium acetate solution to adjust the pH to 4.0-5.0, and place it at 100°C for 20 minutes. Take a C18 reverse phase solid phase extraction column and slowly rinse it with 5 mL of anhydrous ethanol and 10 mL of injection water in turn. After the reaction is completed, cool it to room temperature, load it onto the C18 reverse phase solid phase extraction column, rinse the purification column with 5 mL of injection water, and then use 1.0 mL of 60% ethanol and 6.0 mL of injection water to elute the adsorbent on the C18 reverse phase solid phase extraction column in turn, and filter it through a sterilizing filter to obtain the substance containing the 177 Lu-DO3A-Pentixavar injection: The uncorrected labeling rate was 94.5±3.3% (n=5).

[0096] Example 3: Analysis and application effects:

[0097] The radioactive 68 Ga and 177 Taking Lu labeled probe as an example, its performance determination is described as follows:

[0098] 1. Radio-HPLC radiochemical purity identification:

[0099] Identification conditions: binary gradient elution, initial phase B concentration 5%, increasing to 95% from 5 minutes to 12 minutes and continuing to 20 minutes, mobile phase A is water (containing 0.1% TFA), B is acetonitrile (containing 0.1% TFA).

[0100] After identification, 68 Ga and 177 The radiochemical purity of Lu-labeled probes was 93.5% and 92.8%, respectively, which is higher than that of Lu-labeled probes in pharmacopoeia. 18 The radiochemical purity of F-deoxyglucose is greater than 90% (Chinese Pharmacopoeia 2020 Edition, Part II). Figure 3 .

[0101] 2. Inspection:

[0102] 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 (i.e., the amount of the product that can be injected after filtering through a sterilizing filter). 68 Ga and 177 Lu-labeled probe solution) was diluted 60-fold with bacterial endotoxin test water and tested according to the standard method (Chinese Pharmacopoeia 2020 edition, Part II, Appendix XI E). The endotoxin content of this product per 1mL was less than 15EU. Sterility test: Take an appropriate amount of this product and test according to the standard method (Chinese Pharmacopoeia 2020 edition, Part II, Appendix XI H). This product meets the requirements.

[0103] 3. Radioactivity concentration:

[0104] Accurately measure a certain volume of this product and place it in an activity meter to measure the activity. Calculate the radioactivity concentration based on the sample volume and activity. The radioactivity concentration of this product is 1.50-150MBq / mL.

[0105] 4. Validity period:

[0106] 3h is calculated from the calibration time. The results of in vitro stability test show that 68 The radiochemical purity of Ga-DO3A-Pentixavar was still higher than 90% after incubation in normal saline and mouse serum for 3 hours. 177 The radiochemical purity of Lu-DO3A-Pentixavar remained above 90% after 24 hours of incubation in normal saline and mouse serum, indicating that the probes have high in vitro stability. Figure 4 )

[0107] 5. Fat Solubility

[0108] Measured by shake bottle method 68Ga-DO3A-Pentixavar and 177 The lipid solubility log D of Lu-DO3A-Pentixavar were -2.36±0.18 and -2.33±0.12, respectively.

[0109] 6. 68 Ga-DO3APentixavar and 68 Comparison of Ga-Pentixafor micro-PET imaging in CHO cell tumor-bearing mice:

[0110] A tumor-bearing mouse model was established using ovarian cancer cells (CHO) with high CXCR4 expression, and a low-pH intercalating radiolabeled complex targeting CXCR4 was injected via the tail vein. 68 Ga-DO3A-Pentixavar (0.1 mL, approximately 10 MBq) in saline (containing 7% ethanol) or radiolabeled complex targeting CXCR4 68 Ga-DO3A-Pentixafor (0.1 mL, approximately 10 MBq) was injected into normal saline (containing 7% ethanol). Dynamic imaging was performed using micro-PET 1 hour after injection. Figure 5 The results show that 68 Ga-DO3A-Pentixavar with 68 Ga-DO3A-Pentixafor can image CXCR4-highly expressed tumors. Both are primarily metabolized in the kidneys and excreted through the ureters to the bladder. 68 Ga-DO3A-Pentixavar can be physiologically absorbed by the liver due to its large molecular weight. 68 Ga-DO3A-Pentixavar with 68 Ga-DO3A-Pentixafor showed a higher uptake ratio between tumor and normal organs. 68 Ga-DO3A-Pentixavar has a strong tumor retention, indicating 68 Ga-DO3A-Pentixavar is beneficial for tumor diagnosis.

[0111] The above performance measurements demonstrate that the present invention employs a CXCR4-targeting small molecule combined with a low-pH insertion peptide to design a novel CXCR4-targeting probe. This probe utilizes the anchoring properties of the low-pH insertion peptide on the cell membrane to enhance the uptake and retention of the CXCR4-targeting small molecule in tumors, effectively overcoming the problems of low tumor uptake and short retention time in the prior art. The probe possesses suitable physicochemical and radiological properties, as well as relatively ideal biological characteristics, and can be used for radioactive diagnosis or treatment of tumors, facilitating clinical applications.

[0112] The above examples are used to illustrate the present invention, which are only used to help understand the present invention and are not intended to limit the present invention. Those skilled in the art can make several simple deductions, modifications or substitutions based on the concept of the present invention.

Claims

1. A low pH insertion compound targeting CXCR4, characterized in that: The low pH insertion compound targeting CXCR4 is composed of a CXCR4 targeting group, a low pH insertion group and a bifunctional chelating agent.

2. The low pH insertion compound targeting CXCR4 according to claim 1, characterized in that: The structure of the low pH insertion compound targeting CXCR4 is: in: R1 is a CXCR4 targeting group, and its structure is: R2 is a low pH insertion group Var3, whose structure is: R3 is a bifunctional chelating agent, which is DO3A, DO3A-NCS or DOTA-NCS, and its structure is:

3. The method for preparing the low-pH insertion compound targeting CXCR4 according to claim 2, wherein: The method comprises:

4. A low-pH insertion-type radiolabeled complex targeting CXCR4, characterized in that: The low-pH insertion-type radiolabeled complex targeting CXCR4 is obtained by labeling the low-pH insertion-type compound targeting CXCR4 according to claim 2 with a radionuclide.

5. The low-pH insertion-type radiolabeled complex targeting CXCR4 according to claim 4, characterized in that: The radionuclide is selected from 68 Ga, 161 Tb, 177 Lu.

6. The low-pH intercalation radiolabeled complex targeting CXCR4 according to claim 4, characterized in that: The structure of the low pH insertion type radiolabeled complex targeting CXCR4 is: in: R3' is a radionuclide 68 Ga-labeled bifunctional chelator, 68 Ga-DO3A, 68 Ga-DO3A-NCS or 68 Ga-DOTA-NCS, the structure is:

7. The low-pH insertion-type radiolabeled complex targeting CXCR4 according to claim 4, characterized in that: The structure of the low pH insertion type radiolabeled complex targeting CXCR4 is: Among them, R3' is a radionuclide 161 Tb-labeled bifunctional chelator, 161 Tb-DO3A, 161 Tb-DO3A-NCS or 161 Tb-DOTA-NCS, the structure is:

8. The low-pH intercalation radiolabeled complex targeting CXCR4 according to claim 4, characterized in that: The structure of the low pH insertion type radiolabeled complex targeting CXCR4 is: R3' is a radionuclide 177 Lu-labeled bifunctional chelator, 177 Lu-DO3A, 177 Lu-DO3A-NCS or 177 Lu-DOTA-NCS, the structure is:

9. Use of the low-pH intercalation radiolabeled complex targeting CXCR4 as claimed in claim 4 in the preparation of radioactive diagnostic probes or therapeutic probes for human or animal tumors.

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