Radiolabeled derivatives of risedronic acid, precursor compounds thereof, and methods of making and using

Abstract

The application discloses a radioactive marker of risedronate derivative, a precursor compound, a preparation method and application, and belongs to the technical field of nuclear medicine. The application provides a precursor compound of a radioactive marker of a risedronate derivative or a pharmaceutically acceptable salt thereof, and a radioactive marker of a compound of formula I, and the structure is shown as formula II. The application creatively combines risedronate with a chelating agent to obtain NOTA-risedronate and DOTA-risedronate, and then labels the compounds with a radionuclide. The radioactive marker product of the application has larger water solubility, better in-vitro stability at room temperature, higher plasma protein binding rate, and shows higher and longer bone uptake in imaging and in-vivo distribution in mice. Compared with Ga-DOTA-ibandronate, the compound of the application has twice the uptake amount at a lesion site. 68 Compared with Ga-DOTA-ibandronate, the compound of the application has twice the uptake amount at a lesion site.

Description

Technical Field

[0001] This invention belongs to the field of nuclear medicine technology, specifically relating to radiolabeled derivatives of ritidiazoline, their precursor compounds, their preparation methods, and their applications. Background Technology

[0002] Bone is a common site of distant metastasis for prostate cancer, breast cancer, and lung cancer, with the spine being the most frequent site of bone metastasis. Studies report that 65%–75% of breast and prostate cancers, and 30%–40% of lung cancers, will develop bone metastases. Early diagnosis and treatment of metastatic bone tumors can effectively improve patients' prognosis and quality of life. Bone metastasis is often considered an advanced stage of the disease, and treatment options are mostly palliative. Meanwhile, bone-related events (SREs) caused by bone metastasis, such as bone pain, spinal cord compression, pathological fractures, and hypercalcemia, are major factors affecting patients' ability to move independently and their quality of life.

[0003] Currently, the main treatments for metastatic bone tumors include chemotherapy, radiotherapy, endocrine therapy, surgery, bisphosphonate therapy, and radionuclide therapy. Radionuclide therapy can significantly relieve bone pain, kill tumor cells, and has few side effects, making it an effective and safe treatment. Current medications include... 223 RaCl2, 89 SrCl2, 153 Sm-EDTMPs can significantly relieve bone pain and reduce the incidence of bone-related events.

[0004] 68 Ga、 111 In、 89 Zr、 177 Lu、 225 Ac、 64 Cu、 211 At are medical isotopes with excellent nuclear properties. 68 Ga is through 68 Ge / 68 Ga generators are obtained, are simple to prepare, and have low cost; they can emit β-rays. + X-rays are used for PET imaging. 111 In、 89 Zr、 177 Lu、 225 Ac、 64 Cu、 211 All AT products can be purchased from overseas, ensuring stable supply channels and ample supply.

[0005] 177 Lu emits three types of energy, β -The particles emit 497 keV (78.6%), 384 keV (9.1%), and 176 keV (12.2%) for therapeutic purposes, while also emitting gamma rays at 113 keV (6.4%) and 208 keV (11%). The half-life (T1 / 2) is 6.7 days, making it suitable for in vivo localization imaging. 111 In has a half-life (T1 / 2) of 2.3 days, and the emitted rays can be used for both in vivo imaging and radionuclide therapy. 89 Zr is a novel positron-emitting nuclide with a half-life of 78.4 hours. It first decays into an intermediate nuclide through 22.3% positron emission and 76.6% electron capture. 89m Y then rapidly (15.6 s) decays into a stable nuclide. 89 Y emits 909 keV of gamma photons, making it suitable for in vivo localization imaging. 225 Ac emits alpha rays; alpha ions have a higher energy transfer linear density, resulting in higher ray energy, shorter range, and a greater relative biological effect. It has the strongest killing effect on tumor cells, with a half-life (T1 / 2) of 9.9 days. Its daughter nuclides... 213 The half-life (T1 / 2) of Bi is 46 min. 64 Cu nuclides are valued for their suitable half-life (12.7 h) and unique decay properties (β-decay). + decay, β - With its characteristics of decay, electron capture, and the ability to form complexes with various ligands, it has become a research hotspot in the fields of nuclear medicine molecular probes and therapeutic drugs. 211 The alpha rays released by the decay of At have an average energy of 6.8 MeV and a half-life of 7.2 h. Their range in tissues is 55-88 μm and their half-life is 7.2 h, which makes them highly valuable for clinical applications.

[0006] 99m Tc-MDP is currently the most commonly used bone imaging agent in clinical practice. However, as a single-photon imaging agent, its ability to localize and visualize lesions is far inferior to that of positron emission tomography (PET) imaging agents. HEDP (hexamethylenetetrafluoroethylene) bisphosphonates are commonly used in clinical research for imaging and targeted therapy of metastatic bone tumors. However, as a first-generation nitrogen-free bisphosphonate, HEDP's potency is significantly lower than that of second- and third-generation nitrogen-containing bisphosphonates, such as alendronate and risedronate. Therefore, exploring drugs with better imaging quality, better therapeutic effects, and combined imaging and treatment of bone metastases has become an urgent problem for those skilled in the art. Summary of the Invention

[0007] One of the objectives of this invention is to provide a precursor compound of a radiolabeled ritidiadronate derivative of Formula I or a pharmaceutically acceptable salt thereof, which, after radionuclide labeling, exhibits good imaging effects and can treat bone tumors.

[0008] A second objective of this invention is to provide a radiolabeled form of the ritidiadronic acid derivative of Formula II or a pharmaceutically acceptable salt thereof, which is prepared by radiolabeling of a compound of Formula I.

[0009] A third objective of this invention is to provide a method for preparing compounds of formula I.

[0010] The fourth objective of this invention is to provide a method for preparing compounds of formula II.

[0011] The fifth objective of this invention is to provide applications of compounds of formula I.

[0012] The sixth object of the present invention is to provide the application of the compound of formula II.

[0013] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0014] The present invention provides a precursor compound of a radiolabeled ritidiaphosphonate derivative with the structure shown in Formula I, or a pharmaceutically acceptable salt thereof.

[0015] ,

[0016] Where R1 is ,or ,

[0017] or .

[0018] The radiolabeled compound of formula I or a pharmaceutically acceptable salt thereof provided by this invention has the structure shown in formula II.

[0019] ,

[0020] Where R2 is ,or ,

[0021] or ;

[0022] A is a radioactive nuclide, preferably... 68 Ga、 111 In、 89 Zr、 177 Lu、 225 Ac、 64 Cu、 211 At.

[0023] In some embodiments of the present invention, the radiochemical purity of the compound of formula II or its pharmaceutically acceptable salt is greater than or equal to 95%.

[0024] The present invention provides a method for preparing a precursor compound of the radiolabeled compound of Formula I or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0025] Step 1. Compound 1 reacts with N-Boc glycine to generate compound 2;

[0026] Step 2. Compound 2 reacts with LiOH to form compound 3;

[0027] Step 3. Add chlorobenzene, H3PO3 and POCl3 to compound 3, heat to react, and compound 4 is generated;

[0028] ;

[0029] Step 4. When R1 is When compound 4 reacts with NOA-NHS-ester, it generates compound I-1, as shown in the following reaction equation:

[0030] ;

[0031] When R1 is When compound 4 reacts with DOTA-NHS-ester, compound I-2 is formed, and the reaction equation is as follows:

[0032] ;

[0033] When R1 is At that time, compound 4 reacts with DOTA-p-Bn-NCS to generate compound I-3; the reaction formula is:

[0034] .

[0035] The method for preparing the radiolabeled substance of Formula II provided by the present invention includes: reacting a compound of Formula I with a radioactive nuclide salt solution to obtain the radiolabeled substance of Formula II.

[0036] In some embodiments of the present invention, the radioactive nuclide is 68 Ga、 111 In、 89 Zr、 177 Lu or 64 When Cu is used, the solution of compound I, sodium acetate solution, and radioactive nuclide salt solution are mixed evenly, the pH value of the mixed solution is adjusted, the reaction is carried out, the pH value is adjusted again, sterilized, and filtered to obtain Cu.

[0037] When the radioactive nuclide is 225When Ac is used, the solution of compound I, sodium citrate solution, sodium ascorbate solution and radioactive nuclide salt solution are mixed evenly, the pH value of the mixed solution is adjusted, the reaction is carried out, the pH value is adjusted again, sterilized and filtered to obtain the product;

[0038] When radioactive nuclides 211 At, the solution of compound I, sodium borate solution, and radioactive nuclide salt solution are mixed evenly, the pH value of the mixed solution is adjusted, the reaction is carried out, the pH value is adjusted again, sterilized, and filtered to obtain the final product.

[0039] In some embodiments of the present invention, the reaction of compound I-1 with a radioactive nuclide salt solution includes the following steps:

[0040] When the radioactive nuclide is 68 At Ga, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5; react at 80-100℃, preferably 95℃; react for 10-30 min, preferably 15 min; adjust the pH to 5 after the reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 68 The concentration of Ga salt solution is 5 mCi / ml to 10 mCi / ml;

[0041] When the radioactive nuclide is 111 In the infusion process, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of a 0.25 M sodium acetate solution; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5.5; react at 80-100℃, preferably 95℃; react for 10-30 min, preferably 15 min; adjust the pH to 5 after the reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 111 The concentration of the In salt solution is 10 mCi / ml to 20 mCi / ml;

[0042] When the radioactive nuclide is 89 For Zr, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5; react at 80-100℃, preferably 80℃; react for 10-30 min, preferably 15 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 89The concentration of the Zr salt solution is 10 mCi / ml to 20 mCi / ml;

[0043] When the radioactive nuclide is 177 At time Lu, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution, followed by the addition of a solution with an activity of 20 mCi. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5; react at 80-100℃, preferably 95℃; react for 10-30 min, preferably 15 min; adjust the pH to 4.5 after reaction; the concentration of the Formula I-1 solution is 1 mg / ml; 177 The concentration of Lu salt solution is 20 mCi / ml to 30 mCi / ml;

[0044] When the radioactive nuclide is 225 During Ac, 20-30 μg of compound I-1 was added to 0.8-1.5 ml of 0.1 M sodium ascorbate solution and 0.8-1.5 ml of 0.1 M sodium citrate solution, followed by the addition of a solution with an activity of 0.01 mCi. 225 Ac salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5; react at 80-100℃, preferably 95℃; react for 10-30 min, preferably 15 min; adjust the pH to 5.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 225 The concentration of the Ac salt solution is 0.01 mCi / ml to 0.02 mCi / ml;

[0045] When the radioactive nuclide is 64 For Cu, add 30-40 μg of compound I to 0.8-1.5 ml of 0.25 M sodium acetate solution; then add a solution with an activity of 5 mCi. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5; react at 80-100℃, preferably 95℃; react for 10-30 min, preferably 15 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml;

[0046] When the radioactive nuclide is 211 At 1, 30-40 μg of compound I was added to 0.8-1.5 ml of a 0.25 M sodium borate solution; subsequently, a solution with an activity of 1 mCi was added. 211At salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5; react at 80-100℃, preferably 95℃; react for 10-30 min, preferably 15 min; adjust the pH to 6.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 211 The concentration of the At salt solution is 1.0 mCi / ml to 2.0 mCi / ml.

[0047] In some embodiments of the present invention, the reaction of compound I-2 with a radioactive nuclide salt solution includes the following steps:

[0048] When the radioactive nuclide is 68 At Ga, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 4.5; react at 80-100℃, preferably 95℃; react for 10-30 min, preferably 15 min; adjust the pH to 5 after the reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 68 The concentration of Ga salt solution is 5 mCi / ml to 10 mCi / ml;

[0049] When the radioactive nuclide is 111 In the infusion process, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of a 0.25 M sodium acetate solution; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5.5; react at 80-100℃, preferably 95℃; react for 10-30 min, preferably 15 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 111 The concentration of the In salt solution is 10 mCi / ml to 20 mCi / ml;

[0050] When the radioactive nuclide is 89 For Zr, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5; react at 80-100℃, preferably 80℃; react for 10-30 min, preferably 15 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 89 The concentration of the Zr salt solution is 10 mCi / ml to 20 mCi / ml;

[0051] When the radioactive nuclide is 177 At time Lu, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution, followed by the addition of a solution with an activity of 20 mCi. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5; react at 80-100℃, preferably 85℃; react for 10-30 min, preferably 15 min; adjust the pH to 5 after the reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 177 The concentration of Lu salt solution is 20 mCi / ml to 30 mCi / ml;

[0052] When the radioactive nuclide is 225 For Ac, 20-30 μg of compound I-2 is added to 0.8-1.5 ml of 0.1 M sodium ascorbate solution and 0.8-1.5 ml of 0.1 M sodium citrate solution, followed by the addition of 225Ac salt solution with an activity of 0.01 mCi; the mixture is thoroughly mixed, and the pH of the mixed solution is adjusted to 4-7, preferably 5; the reaction is carried out at 80-100℃, preferably 90℃; the reaction time is 10-30 min, preferably 15 min; the pH is adjusted to 5.5 after the reaction; the concentration of compound I-2 solution is 1 mg / ml; 225 The concentration of the Ac salt solution is 0.01 mCi / ml to 0.02 mCi / ml;

[0053] When the radioactive nuclide is 64 For Cu, add 30-40 μg of compound I-2 to 0.8-1.5 ml of 0.25 M sodium acetate solution; then add a solution with an activity of 5 mCi. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5.5; react at 80-100℃, preferably 90℃; react for 10-30 min, preferably 15 min; adjust the pH to 4.5 after the reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml;

[0054] When the radioactive nuclide is 211 At, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium borate solution; subsequently, a solution with an activity of 1 mCi was added. 211At salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5; react at 80-100℃, preferably 95℃; react for 10-30 min, preferably 15 min; adjust the pH to 6.5 after reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 211 The concentration of the At salt solution is 1.0 mCi / ml to 2.0 mCi / ml.

[0055] In some embodiments of the present invention, the reaction of compound I-3 with a radioactive nuclide salt solution includes the following steps:

[0056] When the radioactive nuclide is 68 At Ga, 20-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5; react at 80-100℃, preferably 85℃; react for 10-30 min, preferably 15 min; adjust the pH to 5 after the reaction; the concentration of the compound solution of Formula 1 is 1 mg / ml; 68 The concentration of Ga salt solution is 5 mCi / ml to 10 mCi / ml;

[0057] When the radioactive nuclide is 111 In the infusion process, 30-40 μg of compound I-3 was added to 0.7-1.4 ml of a 0.25 M sodium acetate solution; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5.5; react at 80-100℃, preferably 90℃; react for 10-30 min, preferably 15 min; adjust the pH to 5 after the reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 111 The concentration of the In salt solution is 10 mCi / ml to 20 mCi / ml;

[0058] When the radioactive nuclide is 89 For Zr, 30-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5; react at 80-100℃, preferably 80℃; react for 10-30 min, preferably 15 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 89 The concentration of the Zr salt solution is 10 mCi / ml to 20 mCi / ml;

[0059] When the radioactive nuclide is 177 At time Lu, 30-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution, followed by the addition of a solution with an activity of 20 mCi. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5; react at 80-100℃, preferably 95℃; react for 10-30 min, preferably 15 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 177 The concentration of Lu salt solution is 20 mCi / ml to 30 mCi / ml;

[0060] When the radioactive nuclide is 225 For Ac, 20-30 μg of compound I-3 is added to 0.8-1.5 ml of 0.1 M sodium ascorbate solution and 0.8-1.5 ml of 0.1 M sodium citrate solution, followed by the addition of 225 Ac salt solution with an activity of 0.01 mCi; the mixture is thoroughly mixed, and the pH of the mixed solution is adjusted to 4-7, preferably 5; the reaction is carried out at 80-100℃, preferably 95℃; the reaction time is 10-30 min, preferably 15 min; the pH is adjusted to 5.5 after the reaction; the concentration of compound I-3 solution is 1 mg / ml; 225 The concentration of the Ac salt solution is 0.01 mCi / ml to 0.02 mCi / ml;

[0061] When the radioactive nuclide is 64 For Cu, add 30-40 μg of compound I-3 to 0.8-1.5 ml of 0.25 M sodium acetate solution; then add a solution with an activity of 5 mCi. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5; react at 80-100℃, preferably 95℃; react for 10-30 min, preferably 15 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml;

[0062] When the radioactive nuclide is 211 At, 30-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium borate solution; subsequently, a solution with an activity of 1 mCi was added. 211At salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5; react at 80-100℃, preferably 95℃; react for 10-30 min, preferably 15 min; adjust the pH to 6.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 211 The concentration of the At salt solution is 1.0 mCi / ml to 2.0 mCi / ml.

[0063] The use of the compound of Formula I or a pharmaceutically acceptable salt thereof, or the compound of Formula II or a pharmaceutically acceptable salt thereof, provided by this invention, in the preparation of a medicament that combines imaging and treatment of metastatic bone tumors.

[0064] Compared with the prior art, the present invention has the following beneficial effects:

[0065] The method of this invention is simple and rationally designed. This invention creatively combines risedronic acid with a chelating agent to obtain NOTA-risedronic acid and DOTA-risedronic acid, and then uses a radionuclide... 68 Ga、 111 In、 89 Zr、 177 Lu、 225 Ac、 64 Cu、 211 At-labeled NOTA-risedronic acid and DOTA-risedronic acid, we obtain 68 Ga、 111 In、 89 Zr、 177 Lu、 225 Ac、 64 Cu、 211 At-NOTA-risedronic acid and 68 Ga、 111 In、 89 Zr、 177 Lu、 225 Ac、 64 Cu、 211 At-DOTA-risedronic acid.

[0066] The radiolabeled product of this invention has high water solubility, good in vitro stability at room temperature, and high plasma protein binding rate. In mice, it shows high and long-lasting bone uptake in imaging and in vivo distribution. It is a bone imaging agent and a radiopharmaceutical for the treatment of metastatic bone tumors with excellent performance.

[0067] Preparation of the present invention 68 Ga、 111 In、 89 Zr、 177 Lu、 225 Ac、64 Cu、 211 At-labeled nota-risedronate and doa-risedronate have simple labeling methods, high labeling yields, short reaction times, low prodrug dosage (microgram level), and very high target-to-non-target ratios (T / N ratios), reaching up to 10 times or more. According to literature reports, T / N ratios greater than 4-5 indicate high potential therapeutic value. Furthermore, [the text abruptly ends here, likely due to an incomplete sentence or missing information]. 68 Compared to Ga-DOTA-ibandronic acid, the compounds of this invention have twice the uptake at the lesion site, resulting in unexpected technical effects.

[0068] The abbreviations corresponding to the names in this invention are:

[0069] DCM: Dichloromethane

[0070] PyBOP: Benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate

[0071] DIPEA: N-ethyldiisopropylamine

[0072] NOTA-NHS-ester: NOTA-succinimide ester

[0073] DMF: N,N-Dimethylformamide

[0074] DOTA-NHS-ester: DOTA-succinimide ester

[0075] DOTA-p-Bn-NCS: 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid Attached Figure Description

[0076] Appendix Figure 1 Here is the LC-MS chromatogram of compound I-1;

[0077] Appendix Figure 2 Here is the LC-MS chromatogram of compound I-2;

[0078] Appendix Figure 3 The LC-MS chromatogram of compound I-3;

[0079] Appendix Figure 4 for 68 TLC image of Ga-labeled compound II-1;

[0080] Appendix Figure 5 for 177 TLC chromatogram of Lu-labeled compound II-1;

[0081] Appendix Figure 6 for 68TLC image of Ga-labeled compound II-2;

[0082] Appendix Figure 7 for 177 TLC chromatogram of Lu-labeled compound II-2;

[0083] Appendix Figure 8 for 68 TLC image of Ga-labeled compound II-3;

[0084] Appendix Figure 9 for 177 TLC chromatogram of Lu-labeled compound II-3;

[0085] Appendix Figure 10 Injected into the tail vein of nude mice in Experiment 1 68 Ga-DOTA-risedronic acid ( 68 PET / CT image of Ga-labeled compound (formula II-1) 2 hours later.

[0086] Appendix Figure 11 For example 2 68 PET / CT image of Ga-labeled compound formula II-1 tumor-bearing mice.

[0087] Appendix Figure 12 For example 2 68 PET / CT images of Ga-DOTA-ibandronic acid tumor-bearing mice. Detailed Implementation

[0088] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Where the manufacturers of reagents or instruments used in the embodiments are not specified, they are all conventional products that can be purchased commercially.

[0089] Example 1

[0090] This embodiment discloses a method for preparing compound 4, specifically as follows:

[0091] S1. Take 180 mg (1 mmol) of compound 1, 210 mg (1.2 mmol) of N-Boc glycine, add 5 mL of DCM and stir well. Add 780 mg (1.5 mmol) of PyBOP and 260 mg (2 mmol) of DIPEA. Stir the mixture at room temperature for 24 hours. TLC detection showed that compound 1 had reacted completely. Dilute the reaction solution with DCM, wash successively with water and saturated brine, dry with anhydrous sodium sulfate, concentrate to dryness, and separate by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 300 mg of target compound 2.

[0092] S2. Take 168 mg (0.5 mmol) of compound 2, add 1 mL of ethanol, 0.5 mL of water, and 24 mg (1 mmol) of LiOH. React at room temperature for 5 hours. TLC was used to determine if the reaction of compound 2 was complete. The pH was adjusted to 6 with 2 M HCl, and the mixture was extracted with dichloromethane. The extract was concentrated to dryness to obtain the target compound 3, which can be used for the next reaction without purification.

[0093] S3. Take 100 mg (0.33 mmol) of compound 3, add 5 mL of chlorobenzene and 270 mg (3.3 mmol) of phosphorous acid, heat to 90 °C, stir for 30 min, and add 1 g (6.6 mmol) of phosphorus oxychloride dropwise. React for 8 h, decant the supernatant, add 5 mL of water to the solid, heat to 90 °C and react for 12 h, filter while hot, add 10 mL of methanol to the filtrate, filter, dry, and obtain a white solid as target compound 4, whose reaction formula is as follows:

[0094] .

[0095] Example 2

[0096] This embodiment discloses a method for synthesizing compound I-1, specifically as follows:

[0097] Take 35 mg (0.1 mmol) of compound 4, add 99 mg (0.15 mmol) of NOTA-NHS-ester, 0.5 mL of DMF, 0.5 mL of water, and 78 mg (0.6 mmol) of DIPEA, and react at room temperature for 24 h. LC-MS monitoring showed the presence of product mass. The reaction solution was filtered and concentrated, and the residue was purified by prep-HPLC. A white solid compound, the target compound I-1, was obtained. Its reaction formula is as follows:

[0098] .

[0099] The LC-MS chromatogram of compound I-1 is attached. Figure 1 As shown.

[0100] Example 3

[0101] This embodiment discloses a method for synthesizing compound I-2, specifically as follows:

[0102] Take 35 mg (0.1 mmol) of compound 4, add 115 mg (0.15 mmol) of DOTA-NHS-ester, 0.5 mL of DMF, 0.5 mL of water, and 78 mg (0.6 mmol) of DIPEA, and react at room temperature for 24 h. LC-MS monitoring showed the presence of product mass. The reaction solution was filtered and concentrated, and the residue was purified by prep-HPLC. A white solid compound, the target compound I-2, was obtained. Its reaction formula is as follows:

[0103]

[0104] The LC-MS chromatogram of compound I-2 is attached. Figure 2 As shown.

[0105] In this embodiment, DOTA-NHS-ester can be replaced with an equimolar amount of DOTA-p-Bn-NCS.

[0106] Example 4

[0107] This embodiment discloses a method for synthesizing compound I-3, specifically as follows:

[0108] Compound 4 (35 mg, 0.1 mmol) was mixed with 83 mg (0.15 mmol) of DOTA-p-Bn-NCS, 0.5 mL of DMF, 0.5 mL of water, and 78 mg (0.6 mmol) of DIPEA. The mixture was reacted at room temperature for 24 h, and LC-MS showed the presence of product mass. The reaction solution was filtered and concentrated, and the residue was purified by prep-HPLC. A white solid compound, the target compound I-3, was obtained. Its reaction formula is as follows:

[0109] .

[0110] The LC-MS chromatogram of compound I-3 is attached. Figure 3 As shown.

[0111] Example 5

[0112] This embodiment discloses the reaction of compound I-1 with a radioactive nuclide salt solution to generate compound II-1, the reaction formula being:

[0113]

[0114] 1. Radioactive nuclides are 68 Ga

[0115] 30 μg of compound I-1 was added to 1.0 mL of a 0.25 M sodium acetate solution; subsequently, a solution with an activity of 10 mCi was added. 68Ga salt solution; mix thoroughly, adjust the pH of the mixture to 5; react at 80-100℃ for 15 min; after the reaction, adjust the pH to 5 to generate... 68 The TLC chromatogram of the Ga-labeled compound, formula II-1, is attached. Figure 4 As shown.

[0116] 2. Radioactive nuclides are 111 In

[0117] 30 μg of compound I-1 was added to 1.0 mL of a 0.25 M sodium acetate solution; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixture to 5.5; react at 95℃ for 15 min; adjust the pH to 5 after the reaction; generate 111 In-labeled compound formula II-1.

[0118] 3. Radioactive nuclides are 89 Zr

[0119] 30 μg of compound I-1 was added to 1.0 mL of a 0.25 M sodium acetate solution; subsequently, a solution with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixture to 5; react at 80℃ for 15 min; adjust the pH to 4.5 after the reaction; generate 89 The Zr-labeled compound is of formula II-1.

[0120] 4. Radioactive nuclides are 177 Lu

[0121] 30 μg of compound I-1 was added to a 1.0 M sodium acetate solution with a concentration of 0.25 M, followed by the addition of a solution with an activity of 20 mCi. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixture to 5; react at 95℃ for 15 min; adjust the pH to 4.5 after the reaction; generate 177 The TLC chromatogram of the Lu-labeled compound, formula II-1, is attached. Figure 5 As shown.

[0122] 5. Radioactive nuclides are 225 Ac

[0123] 30 μg of compound I-1 was added to 1.0 ml of 0.1 M sodium ascorbate solution and 1.0 ml of 0.1 M sodium citrate solution, followed by the addition of a solution with an activity of 0.01 mCi. 225 Ac salt solution; mix thoroughly, adjust the pH of the mixture to 5; react at 95℃ for 15 min; adjust the pH to 5.5 after the reaction; generate 225 The Ac-labeled compound is of formula II-1.

[0124] 6. Radioactive nuclides are 64 Cu

[0125] 30 μg of compound I-1 was added to 1.0 mL of a 0.25 M sodium acetate solution; subsequently, a solution with an activity of 5 mCi was added. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixture to 5; react at 95℃ for 15 min; adjust the pH to 4.5 after the reaction; generate 64 The Cu-labeled compound is of formula II-1.

[0126] 7. Radioactive nuclides are 211 At

[0127] 30 μg of compound I-1 was added to 1.0 mL of a 0.25 M sodium borate solution; subsequently, a solution with an activity of 1 mCi was added. 211 At salt solution; mix thoroughly, adjust the pH of the mixture to 5; react at 95℃ for 15 min; adjust the pH to 6.5 after the reaction; generate 211 Compound II-1 labeled with At.

[0128] The radiochemical purity of compound II-1 in this embodiment is greater than or equal to 95%.

[0129] Example 6

[0130] This embodiment discloses the reaction of compound I-2 with a radioactive nuclide salt solution to generate compound II-2, the reaction formula being:

[0131] .

[0132] 1. Radioactive nuclides are 68 Ga

[0133] 30 μg of compound I-2 was added to 1.0 mL of a 0.25 M sodium acetate solution; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixture to 4.5; react at 95℃ for 15 min; adjust the pH to 5 after the reaction; generate 68 The TLC chromatogram of the Ga-labeled compound, formula II-2, is attached. Figure 6 As shown.

[0134] 2. Radioactive nuclides are 111 In

[0135] 30 μg of compound I-2 was added to 1.0 mL of a 0.25 M sodium acetate solution; subsequently, a solution with an activity of 10 mCi was added. 111In salt solution; mix thoroughly, adjust the pH of the mixture to 5.5; react at 95℃ for 15 min; adjust the pH to 4.5 after the reaction; generate 111 The compound with the In label is of formula II-2.

[0136] 3. Radioactive nuclides are 89 Zr

[0137] 30 μg of compound I-2 was added to 1.0 mL of a 0.25 M sodium acetate solution; subsequently, a solution with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixture to 5; react at 80℃ for 15 min; adjust the pH to 4.5 after the reaction; generate 89 The Zr-labeled compound is of formula II-2.

[0138] 4. Radioactive nuclides are 177 Lu

[0139] 30 μg of compound I-2 was added to 1.0 mL of 0.25 M sodium acetate solution, followed by the addition of a solution with an activity of 20 mCi. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixture to 5; react at 85℃ for 15 min; adjust the pH to 5 after the reaction; generate 177 The TLC chromatogram of the Lu-labeled compound, formula II-2, is attached. Figure 7 As shown.

[0140] 5. Radioactive nuclides are 225 Ac

[0141] 30 μg of compound I-2 was added to 1.0 mL of 0.1 M sodium ascorbate solution and 1.0 mL of 0.1 M sodium citrate solution, followed by the addition of a 225Ac salt solution with an activity of 0.01 mCi; the mixture was thoroughly mixed, and the pH of the solution was adjusted to 5; the reaction was carried out at 90 °C for 15 min; the pH was then adjusted to 5.5; the product was generated. 225 The Ac-labeled compound is of formula II-2.

[0142] 6. Radioactive nuclides are 64 Cu

[0143] 30 μg of compound I-2 was added to 1.0 mL of a 0.25 M sodium acetate solution; subsequently, a solution with an activity of 5 mCi was added. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 5.5; react at 90℃ for 15 min; adjust the pH to 4.5 after the reaction; generate 64 The Cu-labeled compound is of formula II-2.

[0144] 7. When the radioactive nuclide is211 At

[0145] 30 μg of compound I-2 was added to 1.0 mL of a 0.25 M sodium borate solution; subsequently, a solution with an activity of 1 mCi was added. 211 At salt solution; mix thoroughly, adjust the pH of the mixture to 5; react at 95℃ for 15 min; adjust the pH to 6.5 after the reaction; generate 211 Compound II-2 labeled with At.

[0146] The radiochemical purity of compound II-2 in this embodiment is greater than or equal to 95%.

[0147] Example 7

[0148] This embodiment discloses the reaction of compound I-3 with a radioactive nuclide salt solution to generate compound II-3, the reaction formula being:

[0149] .

[0150] 1. Radioactive nuclides are 68 Ga

[0151] 40 μg of compound II-3 was added to 1.0 mL of 0.25 M sodium acetate solution; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixture to 5; react at 85℃ for 15 min; adjust the pH to 5 after the reaction; generate 68 The TLC chromatogram of the Ga-labeled compound, formula II-3, is attached. Figure 8 As shown.

[0152] 2. Radioactive nuclides are 111 In

[0153] 40 μg of compound II-3 was added to 1.0 mL of 0.25 M sodium acetate solution; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixture to 5.5; react at 90℃ for 15 min; adjust the pH to 5 after the reaction; generate 111 The compound with the In label is of formula II-3.

[0154] 3. Radioactive nuclides are 89 Zr

[0155] 40 μg of compound II-3 was added to 1.0 mL of 0.25 M sodium acetate solution; subsequently, a solution with an activity of 2 mCi was added. 89Zr salt solution; mix thoroughly, adjust the pH of the mixture to 5; react at 80℃ for 15 min; adjust the pH to 4.5 after the reaction; generate 89 The Zr-labeled compound has the formula II-3.

[0156] 4. Radioactive nuclides are 177 Lu

[0157] Add 40 μg of compound II-3 to 0.8–1.5 mL of 0.25 M sodium acetate solution, followed by the addition of a solution with an activity of 20 mCi. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7, preferably 5; react at 80-100℃, preferably 95℃ for 15 min; adjust the pH to 4.5 after the reaction; generate 177 The TLC chromatogram of the Lu-labeled compound, formula II-3, is attached. Figure 9 As shown.

[0158] 5. Radioactive nuclides are 225 Ac

[0159] Add 30 μg of compound II-3 to 1.0 mL of 0.1 M sodium ascorbate solution and 1.0 mL of 0.1 M sodium citrate solution, followed by the addition of a solution with an activity of 0.01 mCi. 225 Ac salt solution; mix thoroughly, adjust the pH of the mixture to 5; react at 95℃ for 15 min; adjust the pH to 5.5 after the reaction; 225 The Ac-labeled compound has the formula II-3.

[0160] 6. Radioactive nuclides are 64 Cu

[0161] 40 μg of compound II-3 was added to 1.0 mL of 0.25 M sodium acetate solution; subsequently, a solution with an activity of 5 mCi was added. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixture to 5; react at 95℃ for 15 min; adjust the pH to 4.5 after the reaction; generate 64 The Cu-labeled compound is of formula II-3.

[0162] 7. Radioactive nuclides are 211 At

[0163] 40 μg of compound II-3 was added to 1.0 mL of a 0.25 M sodium borate solution; subsequently, a solution with an activity of 1 mCi was added. 211 At salt solution; mix thoroughly, adjust the pH of the mixture to 5; react at 95℃ for 15 min; adjust the pH to 6.5 after the reaction; generate 211 Compound II-3 labeled with At.

[0164] The radiochemical purity of compound II-3 in this embodiment is greater than or equal to 95%.

[0165] Experimental Example 1

[0166] This experimental example discloses the present invention. 68 PET / CT imaging of Ga-labeled compound formula II-1 in tumor-bearing mice.

[0167] (1) Establishment of tumor-bearing mouse model: Twelve SPF-grade female nude mice were anesthetized with isoflurane. The skin around the left knee joint was disinfected, and the left hind limb was flexed. Using an insulin needle (29G needle), the needle was inserted perpendicularly to the femur from the glenoid fossa of the femoral head, and slowly rotated to enter the medullary cavity. 25 μl (approximately 2 × 10⁻⁶) was injected. 6 MDA-MB-231 cell culture medium (for 12 females); then sterilized, sealed with sterile bone wax, and placed the animals on a 37°C hot plate for rewarming. After recovery, they were returned to their cages for continued rearing.

[0168] (2) Detection of tumor-bearing mouse model: Four weeks after inoculation, Micro-CT was used to scan 12 nude mice. It was observed that each nude mouse had different degrees of bone destruction and different degrees of soft tissue swelling, indicating that the bone transfer model was successfully established.

[0169] (3) Imaging of tumor-bearing mice: One successfully modeled tumor-bearing mouse was injected with freshly prepared imaging via the tail vein. 68 Approximately 0.1 mCi / 0.1 ml of Ga-labeled compound II-1 was injected, followed by a whole-body PET / CT scan 2 hours later. The results are shown in the attached image. Figure 10 As shown. Two hours after injection, whole-body bone scintigraphy was clearer, with obvious imaging at the joints of the limbs, and significant uptake of imaging agent in the bone metastases of the left knee joint.

[0170] Experimental Example 2

[0171] This experimental example discloses the present invention. 68 Ga-labeled compound formula II-1 and 68 Comparative experiment of Ga-DOTA-ibandronic acid in tumor-bearing mice using PET / CT imaging. 68 Ga-DOTA-ibandronic acid was prepared according to the method in Example 2, Table 1, No. 5 of the patent specification with application number CN202111419244X.

[0172] Four tumor-bearing mice that had successfully developed the tumor model were each injected with freshly prepared [treatment] via the tail vein. 68 Ga-labeled compound formula II-1, 68Two animals were injected with approximately 0.1 mCi / 0.1 ml of Ga-DOTA-ibandronic acid. Whole-body PET / CT imaging was performed 2 hours after injection. The results are shown in Table 1 and Appendix. Figure 11 Appendix Figure 12 As shown. Among them. Figure 11 for 68 Ga-labeled compound formula II-1 tumor-bearing mouse imaging Figure 12 for 68 Ga-DOTA-ibandronic acid tumor-bearing mouse imaging.

[0173] Table 1 Imaging results of tumor-bearing mice

[0174]

[0175] The results show that the present invention 68 The Ga-labeled compound, formula II-1, showed significantly higher uptake rates in both the head and lesion sites compared to other compounds. 68 Ga-DOTA-ibandronic acid, in which uptake at the lesion site is 68 Twice that of Ga-DOTA-ibandronic acid. This invention... 68 Ga-labeled compound II-1 exhibits unexpectedly better imaging performance.

[0176] Finally, it should be noted that the above embodiments are merely preferred embodiments of the present invention used to illustrate the technical solutions of the present invention, and are not intended to limit the invention, nor are they intended to limit the scope of the patent. Any modifications or refinements made to the main design concept and spirit of the present invention that are not of substantial significance, but which still solve the same technical problem as the present invention, should be included within the scope of protection of the present invention. In addition, the direct or indirect application of the technical solutions of the present invention to other related technical fields are similarly included within the scope of patent protection of the present invention.

Claims

1. A precursor compound of a radiolabeled picaridin derivative with the structure shown in Formula I, or a pharmaceutically acceptable salt thereof. ， in, R1 is ,or , or .

2. A radiolabeled picaridin derivative of formula I or a pharmaceutically acceptable salt thereof, characterized in that, The structure is shown in Equation II. ， Where R2 is ,or , or ; A is a radioactive nuclide.

3. The radiolabeled substance or its pharmaceutically acceptable salt according to claim 2, characterized in that, A is 68 Ga、 111 In、 89 Zr、 177 Lu、 225 Ac、 64 Cu or 211 At.

4. The radiolabeled substance or a pharmaceutically acceptable salt thereof according to claim 2 or 3, characterized in that, Its radiochemical purity is greater than or equal to 95%.

5. A method for preparing the precursor compound of the radiolabeled substance of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Includes the following steps: Step 1. Compound 1 reacts with N-Boc glycine to generate compound 2; Step 2. Compound 2 reacts with LiOH to form compound 3; Step 3. Add chlorobenzene, H3PO3 and POCl3 to compound 3, heat to react, and compound 4 is generated; ； Step 4. When R1 is When compound 4 reacts with NOA-NHS-ester, it generates compound I-1, as shown in the following reaction equation: ； When R1 is When compound 4 reacts with DOTA-NHS-ester, compound I-2 is formed, and the reaction equation is as follows: ； When R1 is At that time, compound 4 reacts with DOTA-p-Bn-NCS to generate compound I-3; the reaction formula is: 。 6. The method for preparing the radiolabeled substance according to any one of claims 2 to 4, characterized in that, include: The compound of Formula I is reacted with a solution of radioactive nuclide salt to obtain the radiolabeled substance shown in Formula II.

7. The method for preparing radiolabeled substances according to claim 6, characterized in that, Radioactive nuclides are 68 Ga、 111 In、 89 Zr、 177 Lu or 64 When Cu is used, the solution of compound I, sodium acetate solution, and radioactive nuclide salt solution are mixed evenly, the pH value of the mixed solution is adjusted, the reaction is carried out, the pH value is adjusted again, sterilized, and filtered to obtain Cu. When the radioactive nuclide is 225 When Ac is used, the solution of compound I, sodium citrate solution, sodium ascorbate solution and radioactive nuclide salt solution are mixed evenly, the pH value of the mixed solution is adjusted, the reaction is carried out, the pH value is adjusted again, sterilized and filtered to obtain the product; When radioactive nuclides 211 At, the solution of compound I, sodium borate solution, and radioactive nuclide salt solution are mixed evenly, the pH value of the mixed solution is adjusted, the reaction is carried out, the pH value is adjusted again, sterilized, and filtered to obtain the final product.

8. The method for preparing radiolabeled substances according to claim 7, characterized in that, The reaction of compound I-1 with a radioactive nuclide salt solution includes the following steps: When the radioactive nuclide is 68 At Ga, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 68 The concentration of Ga salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 111 In step I, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5 after the reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 111 The concentration of the In salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 89 To obtain a solution of compound I-1, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution of compound I-1 with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 89 The concentration of the Zr salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 177 Lu, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 20 mCi was added. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 177 The concentration of Lu salt solution is 20 mCi / ml to 30 mCi / ml; When the radioactive nuclide is 225 During the Ac process, 20-30 μg of compound I-1 was added to 0.8-1.5 ml of 0.1 M sodium ascorbate solution and 0.8-1.5 ml of 0.1 M sodium citrate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 0.01 mCi was added. 225 Ac salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 225 The concentration of the Ac salt solution is 0.01 mCi / ml to 0.02 mCi / ml; When the radioactive nuclide is 64 In Cu, 30-40 μg of compound I is added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 5 mCi is added. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 211 At 100°C, 30-40 μg of compound I was added to 0.8-1.5 ml of 0.25 M sodium borate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 1 mCi was added. 211 At salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 6.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 211 The concentration of the At salt solution is 1.0 mCi / ml to 2.0 mCi / ml.

9. The method for preparing radiolabeled substances according to claim 8, characterized in that, When the radioactive nuclide is 68 At Ga, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 68 The concentration of Ga salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 111 In step I, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixed solution to 5.5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5 after the reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 111 The concentration of the In salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 89 To obtain a solution of compound I-1, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution of compound I-1 with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 89 The concentration of the Zr salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 177 Lu, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 20 mCi was added. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 177 The concentration of Lu salt solution is 20 mCi / ml to 30 mCi / ml; When the radioactive nuclide is 225 During the Ac process, 20-30 μg of compound I-1 was added to 0.8-1.5 ml of 0.1 M sodium ascorbate solution and 0.8-1.5 ml of 0.1 M sodium citrate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 0.01 mCi was added. 225 Ac salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 225 The concentration of the Ac salt solution is 0.01 mCi / ml to 0.02 mCi / ml; When the radioactive nuclide is 64 In Cu, 30-40 μg of compound I is added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 5 mCi is added. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 211 At 100°C, 30-40 μg of compound I was added to 0.8-1.5 ml of 0.25 M sodium borate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 1 mCi was added. 211 At salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 6.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 211 The concentration of the At salt solution is 1.0 mCi / ml to 2.0 mCi / ml.

10. The method for preparing the radiolabeled substance according to claim 8, characterized in that, When the radioactive nuclide is 68 At Ga, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 95℃; reaction time is 10-30 min; adjust the pH to 5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 68 The concentration of Ga salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 111 In step I, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 95℃; reaction time is 10-30 min; adjust the pH to 5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 111 The concentration of the In salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 89 To obtain a solution of compound I-1, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution of compound I-1 with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 89 The concentration of the Zr salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 177 Lu, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 20 mCi was added. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 95℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 177 The concentration of Lu salt solution is 20 mCi / ml to 30 mCi / ml; When the radioactive nuclide is 225 During the Ac process, 20-30 μg of compound I-1 was added to 0.8-1.5 ml of 0.1 M sodium ascorbate solution and 0.8-1.5 ml of 0.1 M sodium citrate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 0.01 mCi was added. 225 Ac salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 95℃; reaction time is 10-30 min; adjust the pH to 5.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 225 The concentration of the Ac salt solution is 0.01 mCi / ml to 0.02 mCi / ml; When the radioactive nuclide is 64 In Cu, 30-40 μg of compound I is added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 5 mCi is added. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 95℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 211 At 100°C, 30-40 μg of compound I was added to 0.8-1.5 ml of 0.25 M sodium borate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 1 mCi was added. 211 At salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 95℃; reaction time is 10-30 min; adjust the pH to 6.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 211 The concentration of the At salt solution is 1.0 mCi / ml to 2.0 mCi / ml.

11. The method for preparing radiolabeled substances according to claim 8, characterized in that, When the radioactive nuclide is 68 At Ga, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 68 The concentration of Ga salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 111 In step I, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 111 The concentration of the In salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 89 To obtain a solution of compound I-1, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution of compound I-1 with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 89 The concentration of the Zr salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 177 Lu, 30-40 μg of compound I-1 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 20 mCi was added. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 177 The concentration of Lu salt solution is 20 mCi / ml to 30 mCi / ml; When the radioactive nuclide is 225 During the Ac process, 20-30 μg of compound I-1 was added to 0.8-1.5 ml of 0.1 M sodium ascorbate solution and 0.8-1.5 ml of 0.1 M sodium citrate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 0.01 mCi was added. 225 Ac salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 5.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 225 The concentration of the Ac salt solution is 0.01 mCi / ml to 0.02 mCi / ml; When the radioactive nuclide is 64 In Cu, 30-40 μg of compound I is added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 5 mCi is added. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 211 At 100°C, 30-40 μg of compound I was added to 0.8-1.5 ml of 0.25 M sodium borate solution to obtain a solution of compound I-1; subsequently, a solution with an activity of 1 mCi was added. 211 At salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 6.5 after reaction; the concentration of the compound solution of formula I-1 is 1 mg / ml; 211 The concentration of the At salt solution is 1.0 mCi / ml to 2.0 mCi / ml.

12. The method for preparing the radiolabeled substance according to claim 7, characterized in that, The reaction of compound I-2 with a radioactive nuclide salt solution includes the following steps: When the radioactive nuclide is 68 At Ga, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5 after the reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 68 The concentration of Ga salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 111 In step I, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 111 The concentration of the In salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 89 To obtain a solution of compound I-2, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution of compound I-2 with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of compound I-2 solution is 1 mg / ml; 89 The concentration of the Zr salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 177 Lu, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 20 mCi was added. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5 after the reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 177 The concentration of Lu salt solution is 20 mCi / ml to 30 mCi / ml; When the radioactive nuclide is 225 During Ac, 20-30 μg of compound I-2 was added to 0.8-1.5 ml of 0.1 M sodium ascorbate solution and 0.8-1.5 ml of 0.1 M sodium citrate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 0.01 mCi was added. 225 Ac salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5.5 after reaction; the concentration of compound I-2 solution is 1 mg / ml; 225 The concentration of the Ac salt solution is 0.01 mCi / ml to 0.02 mCi / ml; When the radioactive nuclide is 64 In Cu, 30-40 μg of compound I-2 is added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 5 mCi is added. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 211 At 100°C, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium borate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 1 mCi was added. 211 At salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 6.5 after reaction; the concentration of compound I-2 solution is 1 mg / ml; 211 The concentration of the At salt solution is 1.0 mCi / ml to 2.0 mCi / ml.

13. The method for preparing the radiolabeled substance according to claim 12, characterized in that, When the radioactive nuclide is 68 At Ga, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixed solution to 4.5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5 after reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 68 The concentration of Ga salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 111 In step I, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixed solution to 5.5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of compound I-2 solution is 1 mg / ml; 111 The concentration of the In salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 89 To obtain a solution of compound I-2, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution of compound I-2 with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 89 The concentration of the Zr salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 177 Lu, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 20 mCi was added. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5 after the reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 177 The concentration of Lu salt solution is 20 mCi / ml to 30 mCi / ml; When the radioactive nuclide is 225 During Ac, 20-30 μg of compound I-2 was added to 0.8-1.5 ml of 0.1 M sodium ascorbate solution and 0.8-1.5 ml of 0.1 M sodium citrate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 0.01 mCi was added. 225 Ac salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5.5 after reaction; the concentration of compound I-2 solution is 1 mg / ml; 225 The concentration of the Ac salt solution is 0.01 mCi / ml to 0.02 mCi / ml; When the radioactive nuclide is 64 In Cu, 30-40 μg of compound I-2 is added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 5 mCi is added. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 5.5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 211 At 100°C, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium borate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 1 mCi was added. 211 At salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 6.5 after reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 211 The concentration of the At salt solution is 1.0 mCi / ml to 2.0 mCi / ml.

14. The method for preparing the radiolabeled substance according to claim 12, characterized in that, When the radioactive nuclide is 68 At Ga, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 95℃; reaction time is 10-30 min; adjust the pH to 5 after reaction; the concentration of compound I-2 solution is 1 mg / ml; 68 The concentration of Ga salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 111 In step I, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 95℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of compound I-2 solution is 1 mg / ml; 111 The concentration of the In salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 89 To obtain a solution of compound I-2, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution of compound I-2 with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of compound I-2 solution is 1 mg / ml; 89 The concentration of the Zr salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 177 Lu, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 20 mCi was added. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 85℃; reaction time is 10-30 min; adjust the pH to 5 after reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 177 The concentration of Lu salt solution is 20 mCi / ml to 30 mCi / ml; When the radioactive nuclide is 225 During Ac, 20-30 μg of compound I-2 was added to 0.8-1.5 ml of 0.1 M sodium ascorbate solution and 0.8-1.5 ml of 0.1 M sodium citrate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 0.01 mCi was added. 225 Ac salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 90℃; reaction time is 10-30 min; adjust the pH to 5.5 after reaction; the concentration of compound I-2 solution is 1 mg / ml; 225 The concentration of the Ac salt solution is 0.01 mCi / ml to 0.02 mCi / ml; When the radioactive nuclide is 64 In Cu, 30-40 μg of compound I-2 is added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 5 mCi is added. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 90℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 211 At 100°C, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium borate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 1 mCi was added. 211 At salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 95℃; reaction time is 10-30 min; adjust the pH to 6.5 after reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 211 The concentration of the At salt solution is 1.0 mCi / ml to 2.0 mCi / ml.

15. The method for preparing the radiolabeled substance according to claim 12, characterized in that, When the radioactive nuclide is 68 At Ga, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 5 after reaction; the concentration of compound I-2 solution is 1 mg / ml; 68 The concentration of Ga salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 111 In step I, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 4.5 after reaction; the concentration of compound I-2 solution is 1 mg / ml; 111 The concentration of the In salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 89 To obtain a solution of compound I-2, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution of compound I-2 with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 4.5 after reaction; the concentration of compound I-2 solution is 1 mg / ml; 89 The concentration of the Zr salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 177 Lu, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 20 mCi was added. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 5 after the reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 177 The concentration of Lu salt solution is 20 mCi / ml to 30 mCi / ml; When the radioactive nuclide is 225 During Ac, 20-30 μg of compound I-2 was added to 0.8-1.5 ml of 0.1 M sodium ascorbate solution and 0.8-1.5 ml of 0.1 M sodium citrate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 0.01 mCi was added. 225 Ac salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 5.5 after reaction; the concentration of compound I-2 solution is 1 mg / ml; 225 The concentration of the Ac salt solution is 0.01 mCi / ml to 0.02 mCi / ml; When the radioactive nuclide is 64 In Cu, 30-40 μg of compound I-2 is added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 5 mCi is added. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 211 At 100°C, 30-40 μg of compound I-2 was added to 0.8-1.5 ml of 0.25 M sodium borate solution to obtain a solution of compound I-2; subsequently, a solution with an activity of 1 mCi was added. 211 At salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 6.5 after reaction; the concentration of the compound solution of formula I-2 is 1 mg / ml; 211 The concentration of the At salt solution is 1.0 mCi / ml to 2.0 mCi / ml.

16. The method for preparing the radiolabeled substance according to claim 7, characterized in that, The reaction of compound I-3 with a radioactive nuclide salt solution includes the following steps: When the radioactive nuclide is 68 At Ga, 20-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 68 The concentration of Ga salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 111 In step I, 30-40 μg of compound I-3 was added to 0.7-1.4 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 111 The concentration of the In salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 89 To obtain a solution of compound I-3, 30-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution of compound I-3 with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 89 The concentration of the Zr salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 177 Lu, 30-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 20 mCi was added. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 177 The concentration of Lu salt solution is 20 mCi / ml to 30 mCi / ml; When the radioactive nuclide is 225 During the Ac process, 20-30 μg of compound I-3 was added to 0.8-1.5 ml of 0.1 M sodium ascorbate solution and 0.8-1.5 ml of 0.1 M sodium citrate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 0.01 mCi was added. 225 Ac salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 225 The concentration of the Ac salt solution is 0.01 mCi / ml to 0.02 mCi / ml; When the radioactive nuclide is 64 In Cu, 30-40 μg of compound I-3 is added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 5 mCi is added. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 211 At 100°C, 30-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium borate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 1 mCi was added. 211 At salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 6.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 211 The concentration of the At salt solution is 1.0 mCi / ml to 2.0 mCi / ml.

17. The method for preparing a radiolabeled substance according to claim 16, characterized in that, When the radioactive nuclide is 68 At Ga, 20-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5 after the reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 68 The concentration of Ga salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 111 In step I, 30-40 μg of compound I-3 was added to 0.7-1.4 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixed solution to 5.5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 111 The concentration of the In salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 89 To obtain a solution of compound I-3, 30-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution of compound I-3 with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 89 The concentration of the Zr salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 177 Lu, 30-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 20 mCi was added. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 177 The concentration of Lu salt solution is 20 mCi / ml to 30 mCi / ml; When the radioactive nuclide is 225 During the Ac process, 20-30 μg of compound I-3 was added to 0.8-1.5 ml of 0.1 M sodium ascorbate solution and 0.8-1.5 ml of 0.1 M sodium citrate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 0.01 mCi was added. 225 Ac salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 5.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 225 The concentration of the Ac salt solution is 0.01 mCi / ml to 0.02 mCi / ml; When the radioactive nuclide is 64 In Cu, 30-40 μg of compound I-3 is added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 5 mCi is added. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 211 At 100°C, 30-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium borate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 1 mCi was added. 211 At salt solution; mix thoroughly, adjust the pH of the mixed solution to 5; react at 80-100℃; reaction time is 10-30 min; adjust the pH to 6.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 211 The concentration of the At salt solution is 1.0 mCi / ml to 2.0 mCi / ml.

18. The method for preparing a radiolabeled substance according to claim 16, characterized in that, When the radioactive nuclide is 68 At Ga, 20-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 85℃; reaction time is 10-30 min; adjust the pH to 5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 68 The concentration of Ga salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 111 In step I, 30-40 μg of compound I-3 was added to 0.7-1.4 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 90℃; reaction time is 10-30 min; adjust the pH to 5 after reaction; the concentration of compound I-3 solution is 1 mg / ml; 111 The concentration of the In salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 89 To obtain a solution of compound I-3, 30-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution of compound I-3 with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of compound I-3 solution is 1 mg / ml; 89 The concentration of the Zr salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 177 Lu, 30-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 20 mCi was added. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 95℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 177 The concentration of Lu salt solution is 20 mCi / ml to 30 mCi / ml; When the radioactive nuclide is 225 During the Ac process, 20-30 μg of compound I-3 was added to 0.8-1.5 ml of 0.1 M sodium ascorbate solution and 0.8-1.5 ml of 0.1 M sodium citrate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 0.01 mCi was added. 225 Ac salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 95℃; reaction time is 10-30 min; adjust the pH to 5.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 225 The concentration of the Ac salt solution is 0.01 mCi / ml to 0.02 mCi / ml; When the radioactive nuclide is 64 In Cu, 30-40 μg of compound I-3 is added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 5 mCi is added. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 95℃; reaction time is 10-30 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 211 At 100°C, 30-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium borate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 1 mCi was added. 211 At salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 95℃; reaction time is 10-30 min; adjust the pH to 6.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 211 The concentration of the At salt solution is 1.0 mCi / ml to 2.0 mCi / ml.

19. The method for preparing a radiolabeled substance according to claim 16, characterized in that, When the radioactive nuclide is 68 At Ga, 20-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 10 mCi was added. 68 Ga salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 68 The concentration of Ga salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 111 In step I, 30-40 μg of compound I-3 was added to 0.7-1.4 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 10 mCi was added. 111 In salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 111 The concentration of the In salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 89 To obtain a solution of compound I-3, 30-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution; subsequently, a solution of compound I-3 with an activity of 2 mCi was added. 89 Zr salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 4.5 after reaction; the concentration of compound I-3 solution is 1 mg / ml; 89 The concentration of the Zr salt solution is 10 mCi / ml to 20 mCi / ml; When the radioactive nuclide is 177 Lu, 30-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 20 mCi was added. 177 Lu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 177 The concentration of Lu salt solution is 20 mCi / ml to 30 mCi / ml; When the radioactive nuclide is 225 During the Ac process, 20-30 μg of compound I-3 was added to 0.8-1.5 ml of 0.1 M sodium ascorbate solution and 0.8-1.5 ml of 0.1 M sodium citrate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 0.01 mCi was added. 225 Ac salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 5.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 225 The concentration of the Ac salt solution is 0.01 mCi / ml to 0.02 mCi / ml; When the radioactive nuclide is 64 In Cu, 30-40 μg of compound I-3 is added to 0.8-1.5 ml of 0.25 M sodium acetate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 5 mCi is added. 64 Cu salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 4.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml; When the radioactive nuclide is 211 At 100°C, 30-40 μg of compound I-3 was added to 0.8-1.5 ml of 0.25 M sodium borate solution to obtain a solution of compound I-3; subsequently, a solution with an activity of 1 mCi was added. 211 At salt solution; mix thoroughly, adjust the pH of the mixed solution to 4-7; react at 80-100℃; reaction time is 15 min; adjust the pH to 6.5 after reaction; the concentration of the compound solution of formula I-3 is 1 mg / ml; 211 The concentration of the At salt solution is 1.0 mCi / ml to 2.0 mCi / ml.

20. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the radiolabeled substance of any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for both imaging and treatment of metastatic bone tumors.

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