Double-target targeted polypeptide compound as well as preparation method and application thereof

Abstract

The invention belongs to the field of nuclear medicine radiopharmaceuticals and relates to a double-target targeted polypeptide compound as well as a preparation method and application thereof. The structure of the compound or the pharmaceutically acceptable salt thereof comprises a TATE cyclic peptide structure, an FAPI-46 structure and a DOTA complexing group, wherein DOTA is used for complexing radionuclide; the DOTA complexing group is connected with two symmetrical phenylalanine through pentanic acid, so that the fat solubility of the DOTA complexing group is improved; the phenylalanine is respectively connected with the FAPI-46 and the TATE through the two hexanes, so that the steric hindrance of the FAPI-46 and the TATE is reduced. A radiopharmaceutical prepared from the double-target targeted polypeptide compound can be simultaneously combined with two targets, namely a somatostatin receptor and a fibroblast active protein, and has higher receptor binding affinity and higher tumor uptake through adjustment of lipid solubility and steric hindrance. Development of tumor-bearing animals shows that on SSTR2 / FAP < + > double-expression-bearing tumors, the double-target polypeptide drug is 4.8 times that of single-target TATE and 7 times that of single-target FAPI.

Description

Technical Field

[0001] The present invention belongs to the field of nuclear medicine radiopharmaceuticals, and specifically relates to a dual-target targeted polypeptide compound, a preparation method and an application thereof. Background Art

[0002] Somatostatin receptors are overexpressed on a wide range of neuroendocrine tumor (NET) cells. To date, five human somatostatin receptor subtypes have been discovered, including SSTR1-5. Among them, SSTR2 is the main expression subtype in NET, which has always been a popular target for somatostatin-based imaging and therapy. There are currently three SSTR PET radiotracers available: 68 Ga-DOTA-TATE, approved by the European Medicines Agency (EMA) in 2016 and the FDA in 2019 68 Ga-DOTA-TOC, and FDA-approved in 2020 64 Cu-DOTA-TATE. 68 Although Ga-DOTA-NOC has not been approved by the FDA or EMA, its use is similar to that of 68Ga-DOTA-TOC and 68 Ga-DOTA-TATE was used in much the same way and had similar accuracy in detecting SSTR-positive disease. 177 Lu-DOTA-TATE (Luta Thera) was recently approved by the FDA, although 177 Lu-DOTA-TATE is effective in patients with neuroendocrine tumors, but the therapy is limited by the relatively low dose (23-29 Gy) that can be delivered to the tumor, due to the rapid clearance of the peptide from the blood and the low absolute amount of radioactive drug uptake by the tumor.

[0003] Fibroblast activation protein (FAP) is a type II transmembrane serine protease that is highly expressed in cancer-associated fibroblasts (CAFs) and is closely related to tumor growth, invasion, metastasis, immunosuppression, and prognosis. Because it is expressed in a wide range of tumor types, it has become a promising target for cancer imaging and radionuclide therapy in recent years. In recent years, a variety of quinoline-based FAP inhibitors have been developed, such as FAPI-02, FAPI-04, and FAPI-46. However, all of the above radiopharmaceuticals have a short tumor retention time, which is good for imaging but not ideal for radionuclide therapy. Therefore, it is necessary to modify FAPI to enhance its binding within the tumor target and prolong its retention time within the tumor to improve the therapeutic efficiency of the tumor.

[0004] In recent years, single radiotracers targeting TATE or FAP for tumor imaging have been widely studied, and some of them have been used clinically. However, due to tumor heterogeneity and multicellular systems with complex tumor-stroma interactions, the diagnostic efficiency of typical single-specific radiotracers is limited. Dual targeting is a new imaging and treatment technology proposed in recent years to improve the diagnosis and treatment of tumors, such as TATA-RGD, TATE-PSMA and TATE-FAP, but due to the integration of dual targets, there are many technical difficulties. Therefore, the use of dual targets improves the detection sensitivity of tumors, but the absolute uptake of dual-target tracers by tumors is not significantly increased, and the retention time in the tumor is not long, which affects the actual use of dual-target radiopharmaceuticals. Summary of the invention

[0005] The purpose of the present invention is to address the defects of the prior art and provide a dual-target targeted polypeptide compound, preparation method and application. The compound is used as a diagnostic and therapeutic radiopharmaceutical, which can not only improve the detection sensitivity of tumors, but also prolong the tumor uptake and intratumoral retention time of the tracer.

[0006] To achieve the above object, the technical solution of the present invention is as follows:

[0007] A dual-target targeted polypeptide compound, wherein the compound or a pharmaceutically acceptable salt thereof comprises a TATE cyclic peptide structure, a FAPI-46 structure and a DOTA complexing group, wherein DOTA is used for complexing a radioactive nuclide; the TATE cyclic peptide structure, the FAPI-46 structure and the DOTA complexing group are respectively connected via amino acids to form a DOTA-TATE-F46 compound, and a dual-target targeted radioactive drug is formed by complexing the DOTA-TATE-F46 compound with the radioactive nuclide.

[0008] Furthermore, in the dual-target targeted polypeptide compound as described above, the DOTA complexing group is connected to two symmetrical phenylalanines via valeric acid, thereby improving the lipid solubility of the drug through phenylalanine and increasing the circulation time of the drug in the body.

[0009] Furthermore, in the dual-target targeted polypeptide compound as described above, the phenylalanine is connected to FAPI-46 and TATE respectively through two hexanoines, and the hexanoine reduces the steric hindrance between FAPI-46 and TATE, thereby increasing the affinity of the two targets to the tumor.

[0010] Further, in the dual-target targeting polypeptide compound as described above, the structural formula of the DOTA-TATE-F46 compound is as follows:

[0011]

[0012] Further, in the dual-target targeting polypeptide compound as described above, the radionuclide complexed with DOTA includes 68 Ga, 64 Cu, 161 Tb, 225 Ac, 211 Pb or 177 Any one of the following.

[0013] A method for preparing the above dual-target targeting polypeptide compound comprises:

[0014] (1) adding an appropriate amount of a precursor compound of FAPI-46 and N-benzyloxycarbonyl-6-aminohexanoic acid to a DMF solution, adding an appropriate amount of DIPEA, and reacting at room temperature to obtain hexanoic acid-46; repeating the operation again to obtain two 6-aminohexanoated FAPI-46; then adding CBZ-L-alanine, and reacting at room temperature to obtain compound A;

[0015] (2) OBz-valeric acid and DOTA-Tris (tBu) lipid NHS lipid are reacted under triethylamine conditions at room temperature for a period of time, and then appropriate amounts of compound A and DIPEA are added and reacted at room temperature to obtain compound B;

[0016] (3) Take an appropriate amount of threonine resin, remove Fmoc and couple it with Boc-protected TATE peptide, then connect it with two Fmoc-6-aminohexanoic acids in sequence, and then connect it with an appropriate amount of compound B. Finally, remove the resin to obtain DOTA-TATE-F46 compound.

[0017] The above dual-target targeted polypeptide compound is used for the preparation of dual-target tumor diagnosis or treatment radioactive drugs.

[0018] Further, the DOTA-TATE-F46 compound complexes the radionuclide 68 Ga or 64 Cu can be used for the preparation of radiopharmaceuticals for the diagnosis and therapeutic efficacy evaluation of tumors expressing neuroendocrine receptors or fibroblast activity proteins alone or simultaneously;

[0019] DOTA-TATE-F46 compound complexed with radionuclides 161 Tb, 177 Lu, 225 Ac or 211 Pb can be used to prepare radioactive drugs for treating tumors expressing neuroendocrine receptors or fibroblast activity proteins alone or simultaneously.

[0020] Furthermore, the method for preparing the above dual-target targeted polypeptide compound into a radiopharmaceutical is as follows:

[0021] Under acidic and heating conditions, the DOTA-TATE-F46 compound reacts with a salt containing a radioactive metal ion to become a radioactive drug for diagnosis or treatment. The reaction formula is as follows:

[0022]

[0023] M is a radioactive metal ion: 68 Ga, 64 Cu, 161 Tb, 225 Ac, 211 Pb or 177 Lu.

[0024] The beneficial effects of the present invention are as follows: the present invention provides a new type of radioactive drug for dual targets, which aims at the problem that TATE has a low tumor uptake value and FAPI has a short tumor retention time. By adding phenylalanine, the drug's lipid solubility is increased, the drug's circulation time in the body is increased, and the tumor uptake is increased; and by adding two hexanoines, the spatial steric hindrance between FAPI-46 and TATE is reduced, the mutual interference is reduced, and the affinity of the two targets to the tumor is maintained to achieve multiple superposition of affinity. Compared with the existing TATE and FAP single imaging agents, it can be combined with somatostatin receptors and fibroblast activation protein at the same time, and has higher receptor binding affinity and higher tumor uptake; on SSTR2 / FAP+ tumors, the dual-target peptide drug is 4.8 times that of the single target TATE and 7 times that of the single target FAPI. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the mass spectrum of the DOTA-TATE-F46 compound in the embodiment of the present invention;

[0026] Figure 2 In the embodiment of the present invention 68 Results of Ga-DOTA-TATE-F46 uptake and blocking experiments in NCL-H727 cells;

[0027] Figure 3 In the embodiment of the present invention, three 68 Distribution of Ga-labeled drugs in mice bearing NCI-H727 tumors for 1 hour;

[0028] Figure 4 In the embodiment of the present invention 68 PET imaging of Ga-DOTA-TATE-F46 in tumor-bearing mice, T: tumor, L: liver, B: bladder.

[0029] Figure 5 In the embodiment of the present invention 177Distribution results of Lu-DOTA-TATE-F46 in mice;

[0030] Figure 6 In the embodiment of the present invention 225 Distribution results of Ac-DOTA-TATE-F46 in mice. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0032] If no specific techniques or conditions are specified in the following examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0033] The present invention provides a dual-target targeting polypeptide compound, wherein the compound or a pharmaceutically acceptable salt thereof comprises a TATE cyclic peptide structure, a FAPI-46 structure and a DOTA complexing group, wherein the TATE cyclic peptide structure, the FAPI-46 structure and the DOTA complexing group are respectively connected through amino acids to form a DOTA-TATE-F46 compound.

[0034] Among them, DOTA can complex radioactive metal nuclides for diagnosis or treatment, TATE is an inhibitor of somatostatin receptor subtype SSTR2; F46 is the abbreviation of FAPI-46, which is a fibroblast activation protein inhibitor; it can bind to tumor targets independently or simultaneously.

[0035] The DOTA complex group is connected to two symmetrical phenylalanines through valeric acid, and the phenylalanine is connected to FAPI-46 and TATE respectively through two hexanes. The dual-target somatostatin and fibroblast activation protein inhibitors increase their lipid solubility by adding phenylalanine, and the two hexanes reduce the steric hindrance between the two inhibitors, and form a radioactive drug after combining with radioactive metal ions, wherein the combined radioactive metal ions can be: 68 Ga, 64 Cu, 161 Tb, 225 Ac, 211 Pb or 177 Lu et al. The structural formula of DOTA-TATE-F46 compound is as follows:

[0036]

[0037] Under acidic and heating conditions, the DOTA-TATE-F46 compound reacts with a salt containing a radioactive metal ion to become a radioactive drug for diagnosis or treatment. The reaction formula is as follows:

[0038]

[0039] M is a radioactive metal ion: 68 Ga, 64 Cu, 161 Tb, 225 Ac, 211 Pb or 177 Lu.

[0040] The above radionuclide-labeled DOTA-TATE-F46 salt is used for targeted imaging of neuroendocrine tumors or other tumors expressing FAP, and is used for tumor diagnosis, staging or efficacy evaluation; while the use of β or α nuclides can achieve targeted treatment of multiple tumors.

[0041] Example 1: Synthesis of DOTA-TATE-F46 compound

[0042] (1) Synthesis of Compound A

[0043]

[0044] 100 mg of the precursor compound of FAPI-46 was mixed with N-benzyloxycarbonyl-6-aminohexanoic acid in a DMF solution, and 10 μL of DIPEA was added to react at room temperature (a, b: DIPEA, DMF) to obtain hexanoic acid-46; the operation was repeated again (c, d: DIPEA, DMF) to obtain two 6-aminohexanoated FAPI-46; CBZ-L-alanine was added and reacted at room temperature under the same conditions (e, f: DIPEA, DMF, MeOH, Pd / C) to obtain 30 mg of compound A.

[0045] (2) Synthesis of Compound B

[0046]

[0047] OBz-valeric acid and DOTA-Tris (tBu) lipid NHS lipid were reacted at room temperature for 24 hours under triethylamine conditions (g: DMF), and then compound A was added, and 10 μL of DIPEA was added and reacted at room temperature (h, i: DIPEA, DMF, MeOH, Pd / C) to obtain 22 mg of compound B.

[0048] (3) Synthesis of DOTA-TATE-F46

[0049]

[0050] Take 100 mg of threonine resin, remove Fmoc (K: 20% piperidine, DMF), couple with Boc-protected TATE peptide (l, DIPEA, DMF), then connect with two Fmoc-6-aminohexanoic acids in sequence, and then connect with 25 mg of compound B (m: DIPEA, DMF), and finally remove the resin (n, o: 20% piperidine, DMF, HPLC purification) to obtain 18 mg of DOTA-TATE-F46 compound. Its mass spectrum is as follows Figure 1 shown.

[0051] Embodiment 2: 68 Labeling and pharmaceutical properties of Ga-DOTA-TATE-F46

[0052] This embodiment is used to obtain 68 Ga-DOTA-TATE-F46, the reaction formula is as follows:

[0053]

[0054] Take 40 μg of DOTA-TATE-F46, add 130 μL of 1M sodium acetate, and then add 0.05M hydrochloric acid to elute 370 MBq of 68 GaCl3 solution was heated at 85℃ for 5 minutes. Cooled and filtered through a sterile filter membrane. The radiochemical purity was greater than 95% by TLC analysis. Labeled in the same way 68 Ga-DOTA-TATE, 68 Ga-FAPI-46, for biological research control.

[0055] Measured by octanol method 68 The lipid-water partition coefficient of Ga-DOAT-TATE-F46 was calculated as log P = log (n-octanol CPM / water CPM). The experiment was repeated three times. 68 The Log P value of Ga-DOTA-TATE-F46 was -0.20±0.05, while that of the control 68 Ga-DOTA-TATE and 68 The Log P values ​​of Ga-FAPI-46 were -3.02±0.08 and -3.05±0.04, respectively. 68 The hydrophilicity of Ga-DOTA-TATE-F46 is lower than 68 Ga-DOTA-TATE and 68 Ga-FAPI-46.

[0056] Embodiment 3: 68 Uptake of Ga-DOTA-TATE-F46 in NCI-H727 cells expressing both neuroendocrine and fibroblast activity proteins

[0057] In the 24-well plate method, NCI-H727 cells were incubated for 24 h, the original culture medium was discarded, and then each well was added 68 Ga-DOTA-TATE-F46, 68 Ga-DOTA-TATE, 68 Ga-FAPI-46 (1.48×104Bq) was incubated for 30min, 1h, 2h and 4h. Then, the culture medium was removed and the cells were washed twice with cold PBS (pH 7.4), followed by lysis of the cells with 0.5mL (1M) NaOH. In the blocking study, excess unlabeled FAPI-46, DOTA-TATE, and FAPI-46+DOTA-TATE (10μg / well) were used as inhibitors and 68 Ga-DOTA-TATE-F46 was added to the cells and treated with the same method 1 hour later. The cell lysate was collected and the radioactivity was measured using a γ counter. Mc3 cells were used as negative control and only Ga-DOTA-TATE-F46 was added. 68 Ga-DOTA-TATE-F46 (1.48×104 Bq / well, 100 μL), and the rest of the procedures were carried out as described above.

[0058] 68 The results of Ga-DOTA-TATE-F46 uptake and blocking experiments in NCL-H727 cells are shown in Figure 2 As shown, at all time points, 68 The cellular uptake of Ga-DOTA-TATE-F46 in NCI-H727 cells was significantly higher than 68 Ga-DOTA-TATE and 68 Ga-FAPI-46 (all p<0.001, Figure 2 When compared with 1000 times 68 When Ga-DOTA-TATE-F46 was co-incubated with unlabeled TATE, FAPI-46 or TATE+FAPI-46 in molar amounts, 68 The cellular uptake of Ga-DOTA-TATE-F46 in NCI-H727 cells was significantly reduced (all p < 0.01, Figure 2 (as shown in the figure on the right).

[0059] Embodiment 4: 68 Pharmacokinetics of Ga-DOTA-TATE-F46

[0060] Nine healthy BALB / c mice were injected via tail vein 68 Ga-DOTA-TATE-F46, 68 Ga-DOTA-TATE, 68Ga-FAPI-46 (0.37MBq, 100μL) was injected, and blood was collected by tail cutting (5μl×3) at 2, 5, 10, 15, 30, 60, 90, and 120min after injection. The radioactivity in the blood was measured using a γ counter and converted into blood radioactivity concentration (kBq / ml). The two-compartment model in the pharmacokinetic software WinNonlin was used to analyze the time-blood radioactivity concentration data of mice.

[0061] 68 The distribution half-life and elimination half-life of Ga-DOTA-TATE-F46 were 1.79 min and 37.75 min, respectively. 68 Ga-DOTA-TATE, 68 The corresponding values ​​for Ga-FAPI-46 are 1.67 min and 18.92 min, and 0.30 min and 21.37 min, respectively. 68 The pharmacokinetic of Ga-DOTA-TATE-F46 conforms to the two-compartment model.

[0062] To further evaluate 68 The pharmacokinetic properties of Ga-DOTA-TATE-F46 in vivo were investigated by biodistribution studies of the three tracers in tumor-bearing (NCI-H727) mice, such as Figure 3 At 0.5, 1, 2, and 4 hp.i, the tumor 68 The uptake of Ga-DOTA-TATE-F46 was 3.56±0.69, 7.53±1.13, 7.08±0.88, and 6.48±1.82% ID / g, respectively, and the tracer showed good uptake and retention in tumors. 68 Ga-DOTA-TATE-F46 has a high uptake in the liver and kidneys, but as time goes by, the uptake gradually decreases, indicating that the tracer is mainly excreted through the liver and kidneys. 68 Ga-DOTA-TATE and 68 The biodistribution of Ga-FAPI-46 in NCI-H727 tumor-bearing mice was studied; 68 The tumor uptake rate of Ga-DOTA-TATE was 1.57±0.17% ID / g. 68 The tumor uptake rate of Ga-FAPI-46 was 1.07±0.01% ID / g, which was lower than 68 Ga-DOTA-TATE-F46 (p < 0.001). At 1 hour, the tumor was responsive to the dual-target tracer 68 Ga-DOTA-TATE-F46 uptake is 68 4.8 times that of Ga-DOTA-TATE, 687 times that of Ga-FAPI-46.

[0063] Embodiment 6: 68 PET imaging of Ga-DOTA-TATE-F46 in tumor-bearing mice

[0064] The NCI-H727 tumor xenograft model (n=3) was used as the research subject. 68 Ga-DOTA-TATE-F46, 68 Ga-DOTA-TATE, 68 Ga-FAPI-46 (5.55-7.4MBq, 150μL / mouse). PET scans were performed at 1 hour and 4 hours after injection. Images were reconstructed using the three-dimensional ordered subset maximum expectation value (3D-OSEM) algorithm and processed and analyzed on a Recon / Avator-s-10 workstation.

[0065] Figure 4 The results show that in the 1-hour A, B, and C graphs, 68 Ga-DOTA-TATE-F46, 68 Ga-DOTA-TATE, 68 Ga-FAPI-46 was obviously uptaken by the tumor (T) at 4 hours. 68 Ga-DOTA-TATE-F46 still showed obvious tumor imaging (A, right). 68 Ga-FAPI-46 (B, right) and 68 The tumor of Ga-DOTA-TATE (C, right) is barely visible. L is the liver, K is the kidney, B is the bladder, and T is the tumor (the area in the circle in the figure).

[0066] The above is 68 The pharmaceutical properties of Ga-DOTA-TATE-F46 and animal experimental research data have proved that DOTA-TATE-F46 compounds can increase the circulation time of drugs in the body and improve tumor uptake. 64 Cu and 68 Ga has similar characteristics. 64 Cu-DOTA-TATE-F46 can also refer to the above experimental data.

[0067] The experimental results show that DOTA-TATE-F46 compounds complex radionuclides 68 Ga or 64 Cu can be used as dual-target tumor diagnostic radiopharmaceuticals and can be used for the diagnosis and efficacy evaluation of tumors that express neuroendocrine receptors or fibroblast activity proteins alone or simultaneously.

[0068] Embodiment 7:177 Distribution of Lu-DOTA-TATE-F46 in normal mice

[0069] Take 20 μg of DOTA-TATE-F46, add 65 μL of 1M sodium acetate, and then add 0.05M hydrochloric acid to elute 74 MBq of 177 The LuCl3 solution was heated at 85°C for 30 minutes, cooled, filtered through a sterile filter membrane, and the radiochemical purity was greater than 98% by TLC analysis.

[0070] Twenty healthy BALB / c mice were randomly divided into four groups (5 mice in each group) and injected via the tail vein. 177 Lu-DOTA-TATE-F46 (740KBq, 100μL)) was injected and the animals were killed 1 and 24 hours after injection. The blood, heart, liver, spleen, lung, kidney, bone and muscle were collected and the radioactivity count was measured and weighed to calculate %ID / g. 177 The distribution results of Lu-DOTA-TATE-F46 in mice are shown in Figure 5 shown.

[0071] It can be seen that radioactivity is quickly cleared from the blood, mainly metabolized by the kidneys. Due to its high fat solubility, a high level of radioactivity remains in the stomach after 24 hours.

[0072] Due to radionuclides 161 Tb and 177 Lu has similar characteristics. 161 Tb-DOTA-TATE-F46 can also refer to the above experimental data.

[0073] Embodiment 8: 225 Distribution of Ac-DOTA-TATE-F46 in normal mice

[0074] Take 10 μg of DOTA-TATE-F46, add 65 μL of 1M sodium acetate, and then add 0.05M hydrochloric acid to elute 370KBq of 225 AcCl3 solution was heated at 85°C for 5 minutes, cooled, filtered through a sterile filter membrane, and the radiochemical purity was greater than 95% by TLC analysis.

[0075] Twenty healthy BALB / c mice were randomly divided into four groups (5 mice in each group) and injected via the tail vein. 225 Ac-DOTA-TATE-F46 (18KBq, 100μL)) was injected and the animals were killed 1, 4, 24, and 48 hours after injection. The blood, brain, heart, liver, spleen, lung, kidney, bone, and muscle were collected and the radioactivity counts were measured and weighed to calculate %ID / g. 225 The distribution results of Ac-DOTA-TATE-F46 in mice are as follows Figure 6 shown.

[0076] It can be seen that the radioactivity is cleared from the blood quickly, and there is a rebound after 48 hours, which may be related to the radioactivity in the liver; it is mainly metabolized by the kidneys, and the radioactivity in the bones and muscles shows a gradual downward trend.

[0077] Due to radionuclides 211 Pb and 225 Ac has similar characteristics. 211 Pb-DOTA-TATE-F46 can also refer to the above experimental data.

[0078] The experimental results show that DOTA-TATE-F46 compounds complex radionuclides 161 Tb, 177 Lu or 225 Ac, 211 Pb can be used as a dual-target tumor therapy radiopharmaceutical and can be used for radionuclide therapy of tumors expressing either neuroendocrine receptors or fibroblast activity proteins alone or simultaneously.

[0079] Those skilled in the art will readily conceive of other embodiments of the present invention after considering the specification and practicing the invention disclosed herein. This application is intended to cover any variations, uses or adaptations of the present invention that follow the general principles of the present invention and include common knowledge or customary techniques in the art that are not disclosed by the present invention. Thus, if these variations and use adaptations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and use adaptations.

[0080] The above embodiments are merely illustrative of the present invention, and the present invention may also be implemented in other specific ways or other specific forms without departing from the gist or essential features of the present invention. Therefore, the described embodiments should be considered illustrative rather than restrictive in any respect. The scope of protection of the present invention should be described by the claims, and any changes equivalent to the intent and scope of the claims should also be included within the scope of the present invention.

Claims

1. A dual-target targeting polypeptide compound, characterized in that: The structure of the compound or its pharmaceutically acceptable salt comprises a TATE cyclic peptide structure, a FAPI-46 structure and a DOTA complexing group, wherein DOTA is used for complexing radioactive nuclides; the TATE cyclic peptide structure, the FAPI-46 structure and the DOTA complexing group are respectively connected through amino acids to form a DOTA-TATE-F46 compound, and a dual-target targeted radioactive drug is formed by complexing the DOTA-TATE-F46 compound with the radioactive nuclides.

2. The dual-target targeting polypeptide compound according to claim 1, characterized in that: The DOTA complexing group is connected to two symmetrical phenylalanines through valeric acid, and the lipid solubility of the drug is improved through phenylalanine, thereby increasing the circulation time of the drug in the body.

3. The dual-target targeting polypeptide compound according to claim 2, characterized in that: The phenylalanine is connected to FAPI-46 and TATE respectively through two hexanoines, and the hexanoine reduces the steric hindrance between FAPI-46 and TATE, thereby increasing the affinity of the two targets to the tumor.

4. The dual-target targeting polypeptide compound according to claim 3, characterized in that: The structural formula of the DOTA-TATE-F46 compound is as follows:

5. The dual-target targeting polypeptide compound according to any one of claims 1 to 4, characterized in that: Radionuclides complexed with DOTA include 68 Ga, 64 Cu, 161 Tb, 225 Ac, 211 Pb or 177 Any one of the following.

6. A method for preparing a dual-target targeting polypeptide compound according to any one of claims 1 to 5, characterized in that: include: (1) adding an appropriate amount of a precursor compound of FAPI-46 and N-benzyloxycarbonyl-6-aminohexanoic acid to a DMF solution, adding an appropriate amount of DIPEA, and reacting at room temperature to obtain hexanoic acid 46; repeating the operation again to obtain two 6-aminohexanoated FAPI-46; then adding CBZ-L-alanine, and reacting at room temperature to obtain compound A; (2) OBz-valeric acid and DOTA-Tris (tBu) lipid NHS lipid are reacted under triethylamine conditions at room temperature for a period of time, and then appropriate amounts of compound A and DIPEA are added and reacted at room temperature to obtain compound B; (3) Take an appropriate amount of threonine resin, remove Fmoc and couple it with Boc-protected TATE peptide, then connect it with two Fmoc-6-aminohexanoic acids in sequence, and then connect it with an appropriate amount of compound B. Finally, remove the resin to obtain DOTA-TATE-F46 compound.

7. Use of a dual-target targeting polypeptide compound according to any one of claims 1 to 5, characterized in that: Preparation of radiopharmaceuticals for dual-target tumor diagnosis or treatment.

8. The use of the dual-target targeting polypeptide compound according to claim 7, characterized in that: DOTA-TATE-F46 compound complexed with radionuclides 68 Ga or 64 Cu can be used in the preparation of radiopharmaceuticals for the diagnosis and therapeutic efficacy evaluation of tumors expressing neuroendocrine receptors or fibroblast activity proteins alone or simultaneously.

9. The use of the dual-target targeting polypeptide compound according to claim 7, characterized in that: DOTA-TATE-F46 compound complexed with radionuclides 161 Tb, 177 Lu, 225 Ac or 211 Pb can be used to prepare radioactive drugs for treating tumors expressing neuroendocrine receptors or fibroblast activity proteins alone or simultaneously.

10. A method for preparing a radiopharmaceutical from the dual-target targeting polypeptide compound according to any one of claims 1 to 5, characterized in that: Under acidic and heated conditions, the DOTA-TATE-F46 compound reacts with a salt containing a radioactive metal ion to produce a diagnostic or therapeutic radiopharmaceutical. The reaction formula is as follows: M is a radioactive metal ion: 68 Ga, 64 Cu, 161 Tb, 225 Ac, 211 Pb or 177 Lu.

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