Radiolabeled risedronate derivatives, precursor compounds thereof, and methods for producing and using them

Abstract

The present invention discloses radiolabeled risedronate derivatives, their precursor compounds, and preparation and application methods, and belongs to the technical field of nuclear medicine. The present invention provides a precursor compound of a radiolabeled risedronate derivative represented by Formula I or a pharmaceutically acceptable salt thereof, and a radiolabeled risedronate derivative represented by Formula II or a pharmaceutically acceptable salt thereof. The present invention creatively combines risedronate with a chelating agent to obtain NOTA-risedronate or DOTA-risedronate, which are then labeled with a radionuclide. The radiolabeled products of the present invention have higher water solubility, better in vitro stability at room temperature, high plasma protein binding rate, and exhibit imaging in mice, higher in vivo distribution, and longer-lasting bone uptake. 68 Compared to Ga-DOTA-ibandronic acid, the compounds of the present invention have twice the uptake at the lesion site. JPEG2026505959000048.jpg45147

Description

[Technical Field]

[0001] This application claims priority from Chinese patent application bearing application number 202310140015.7 and filed on February 21, 2023, the contents of which are hereby incorporated in their entirety into this application.

[0002] The present invention relates to the technical field of nuclear medicine, and specifically to a radiolabeled risedronate derivative, its precursor compound, and its preparation method and use. [Background technology]

[0003] Bones are a common site of distant metastasis for prostate, breast, and lung cancer, with the spine being the most common site of bone metastasis. Studies have shown that bone metastasis occurs in 65% to 75% of breast and prostate cancer patients and 30% to 40% of lung cancer patients. Early diagnosis and treatment of metastatic bone tumors can effectively improve patient prognosis and quality of life. Bone metastasis is often considered a sign of terminal disease, and palliative care is often the preferred treatment regimen. However, skeletal-related events (SREs) caused by bone metastasis, such as bone pain, spinal cord compression, pathological fractures, and hypercalcemia, are major factors that affect patients' ability to function independently and their quality of life.

[0004] Currently, the main treatment methods for metastatic bone tumors include chemotherapy, radiation therapy, endocrine therapy, surgery, bisphosphonate therapy, and radionuclide therapy. Radionuclide therapy can significantly relieve bone pain and kill tumor cells, while also having minimal toxicity and side effects, making it an effective and safe treatment method. Currently, drugs used in radionuclide therapy can significantly relieve bone pain and reduce the incidence of skeletal-related events. 223 RaCl2, 89 SrCl2, 153 Contains Sm-EDTMP.

[0005] 68 Ga, 111 In, 89 Zr, 177Lu, 225 Ac, 64 Cu, 221 At is a medical isotope with excellent nuclear properties. 68 Ga 68 Ge / 68 Ga generator, which is easy to manufacture and low cost, and it is suitable for PET imaging. + It can emit rays. 111 In, 89 Zr, 177 Lu, 225 Ac, 64 Cu, 221 Both At can be purchased from overseas, the supply route is stable, and there is a sufficient supply.

[0006] 177 Lu is a therapeutically useful β - It emits particles of three different energies: 497 keV (78.6%), 384 keV (9.1%), and 176 keV (12.2%), as well as gamma rays of 113 keV (6.4%) and 208 keV (11%). Its half-life (T1 / 2) is 6.7 days, making it suitable for in vivo stereotactic imaging. 111 In has a half-life (T1 / 2) of 2.3 days, and the emitted radiation can be used for both in vivo imaging and nuclide therapy. 89 Zr has a half-life of 78.4 hours, and first decays into intermediate nuclides by 22.3% positron emission and 76.6% electron capture. 89m decays further rapidly (15.6s) to stable nuclides 89m It is a novel positronic nuclide that decays to Y and emits a 909 keV gamma photon, making it suitable for in vivo stereotactic imaging. 225 Ac emits α-particles, has higher α-ion energy transfer, higher energy, shorter range, higher relative biological effect, and the strongest killing effect on tumor cells. Its half-life (T1 / 2) is 9.9 days, and its daughter nuclides 213 The half-life (T1 / 2) of Bi is 46 min. 64 The Cu nuclide has a favorable half-life (12.7 h), unique decay characteristics (β + Decay, beta -Due to its characteristics such as its ability to undergo decay and electron capture, and the ability to form complexes with various ligands, it has already become a hot research topic in the fields of nuclear medicine molecular probes and integrated medical treatment drugs. 211 At decays and emits alpha rays with an average energy of 6.8 MeV, a half-life of 7.2 hours, and a range in tissue of 55 to 88 μm, making it highly valuable for clinical applications.

[0007] 99m Tc-MDP is currently the most commonly used bone imaging agent in clinical practice. However, as a single-photon imaging agent, it is far inferior to positron imaging agents in terms of lesion localization and visualization. Phosphonates (HEDP) are commonly used in clinical studies 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, the search for a drug with better imaging quality and therapeutic efficacy that can both image and treat tumor bone metastases has become an urgent issue for those skilled in the art. Summary of the Invention

[0008] The first object of the present invention is to provide a precursor compound of a radiolabeled risedronate derivative represented by formula I or a pharmaceutically acceptable salt thereof, which has good imaging effect after being labeled with a nuclide and can treat bone tumors.

[0009] A second object of the present invention is to provide a radiolabeled risedronate derivative represented by formula II or a pharmaceutically acceptable salt thereof, which is prepared by labeling the compound of formula I with a nuclide.

[0010] A third object of the present invention is to provide methods for preparing compounds of formula I.

[0011] A fourth object of the present invention is to provide a method for preparing compounds of formula II.

[0012] A fifth object of the present invention is to provide uses for the compounds of formula I.

[0013] A sixth object of the present invention is to provide uses for compounds of formula II.

[0014] In order to achieve the above object, the present invention adopts the following technical solutions.

[0015] A first aspect of the present invention provides a precursor compound of a radiolabeled risedronate derivative having a structure represented by formula I or a pharmaceutically acceptable salt thereof, [ka] Among them, R1 is [ka] or [ka] or [ka] is.

[0016] A second aspect of the present invention provides a radiolabeled risedronate derivative represented by formula II or a pharmaceutically acceptable salt thereof: [ka] Of these, R2 is [ka] or [ka] or [ka] and A is a radionuclide, preferably 68 Ga,111 In, 89 Zr, 177 Lu, 225 Ac, 64 Cu or 221 At.

[0017] In some embodiments of the present invention, the compound of formula II or a pharmaceutically acceptable salt thereof has a radiochemical purity of 95% or greater.

[0018] A third aspect of the present invention provides a method for producing a precursor compound of a radiolabel represented by formula I or a pharmaceutically acceptable salt thereof, the method comprising the following steps: Step 1. Reacting compound 1 with N-Boc glycine to form compound 2; Step 2. Producing compound 3 from compound 2 under the action of LiOH; Step 3. Adding chlorobenzene, H3PO3 and POCl3 to compound 3 and heating to react to produce compound 4; [ka] , Step 4. R1 [ka] Then, compound 4 is reacted with NOTA-NHS-ester to produce compound I-1, the reaction scheme being: [ka] and R1 is [ka] Then, compound 4 is reacted with DOTA-NHS-ester to produce compound I-2, the reaction scheme being: [ka] and Preferably, [ka] and R1 is [ka] Then, compound 4 is reacted with DOTA-p-Bn-NCS to produce compound I-3, the reaction scheme being: [ka] And, Includes.

[0019] A fourth aspect of the present invention provides a method for preparing a radiolabel of formula II, which comprises reacting a compound of formula I with a radionuclide salt solution to obtain a radiolabel of formula II.

[0020] In some embodiments of the present invention, the radiolabel of Formula II is obtained by mixing a solution of the compound of Formula I, a sodium salt solution, and a radionuclide salt solution, adjusting the pH, reacting, adjusting the pH, and filtering.

[0021] In some embodiments of the present invention, the radionuclide 68 Ga, 111 In, 89 Zr, 177 Lu or 64 In the case of Cu, the radiolabel is obtained by mixing a solution of the compound of formula I, a sodium acetate solution and a radionuclide salt solution, adjusting the pH of the mixed solution, reacting, adjusting the pH again, sterilizing, and filtering; Radionuclides 225 In the case of Ac, the solution of the compound of formula I, the sodium citrate solution, the sodium ascorbate solution and the radionuclide salt solution are mixed, the pH value of the mixed solution is adjusted, the mixture is reacted, the pH value is adjusted again, sterilized and filtered to obtain a radiolabeled product; radionuclides 211In the case of At, the radiolabel is obtained by mixing a solution of the compound of formula I, a sodium borate solution and a radionuclide salt solution, adjusting the pH value of the mixed solution, reacting, adjusting the pH value again, sterilizing, and filtering.

[0022] In some embodiments of the present invention, reacting compound Formula I-1 with a radionuclide salt solution specifically comprises the following steps: [ka] Radionuclides 68 In the case of Ga, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of compound formula I-1 containing 30 to 40 μg of solute, and then the activity of 68 Add Ga salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 minutes, preferably 15 minutes, and adjust the pH value to 5 after the reaction, wherein the concentration of compound formula I-1 solution is 1 mg / mL; 68 The concentration of the Ga salt solution is 5 to 10 mCi / mL. Radionuclides 111 In the case of In, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of compound formula I-1 containing 30 to 40 μg of solute, and then the activity of 111 Add In salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5.5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 minutes, preferably 15 minutes, and adjust the pH value to 5 after the reaction, wherein the concentration of compound formula I-1 solution is 1 mg / mL; 111 The concentration of the In salt solution is 10 to 20 mCi / mL. Radionuclides 89 In the case of Zr, 0.8-1.5 mL of a 0.25 M sodium acetate solution is added to a solution of compound formula I-1 containing 30-40 μg of solute, and then the activity of the solution is 2 mCi. 89Add Zr salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 80°C, the reaction time is 10-30 min, preferably 15 min, and after the reaction, adjust the pH value to 4.5, wherein the concentration of compound formula I-1 solution is 1 mg / mL; 89 The concentration of the Zr salt solution is 10 to 20 mCi / mL. Radionuclides 177 In the case of Lu, 0.8-1.5 mL of a 0.25 M sodium acetate solution is added to a solution of compound formula I-1 containing 30-40 μg of solute, and then the activity of the solution is 20 mCi. 177 Add Lu salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 4.5 after the reaction, wherein the concentration of compound formula I-1 solution is 1 mg / mL; 177 The concentration of the Lu salt solution is 20-30 mCi / mL. Radionuclides 225 In the case of Ac, 0.8 to 1.5 mL of a 0.1 M sodium ascorbate solution and 0.8 to 1.5 mL of a 0.1 M sodium citrate solution are added to a solution of compound formula I-1 containing 20 to 30 μg of solute, and then a solution having an activity of 0.01 mCi is added. 225 Add Ac salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 minutes, preferably 15 minutes, and adjust the pH value to 5.5 after the reaction, wherein the concentration of compound formula I-1 solution is 1 mg / mL; 225 The concentration of Ac salt solution is 0.01-0.02 mCi / mL; Radionuclides 64 In the case of Cu, 0.8-1.5 mL of a 0.25 M sodium acetate solution is added to a solution of compound formula I-1 containing 30-40 μg of solute, and then the activity of the solution is 5 mCi. 64Add Cu salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and after the reaction, adjust the pH value to 4.5, wherein the concentration of compound formula I-1 solution is 1 mg / mL; 64 The concentration of the Cu salt solution is 5 to 10 mCi / mL. Radionuclides 211 In the case of At, 0.8-1.5 mL of a 0.25 M sodium borate solution is added to a solution of compound formula I-1 containing 30-40 μg of solute, and then the activity of the solution is 1 mCi. 211 Add At salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 6.5 after the reaction, wherein the concentration of compound formula I-1 solution is 1 mg / mL; 211 The concentration of the At salt solution is 1.0 to 2.0 mCi / mL. Includes.

[0023] In some embodiments of the present invention, reacting compound Formula I-2 with a radionuclide salt solution specifically comprises the following steps: [ka] Radionuclides 68 In the case of Ga, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of compound I-2 containing 30 to 40 μg of solute, and then the activity of the solution is 10 mCi. 68 Add Ga salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 4.5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 minutes, preferably 15 minutes, and adjust the pH value to 5 after the reaction, wherein the concentration of compound formula I-2 solution is 1 mg / mL; 68 The concentration of the Ga salt solution is 5 to 10 mCi / mL. Radionuclides 111In the case of In, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of compound formula I-2 containing 30 to 40 μg of solute, and then the activity of 111 Add In salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5.5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 minutes, preferably 15 minutes, and after the reaction, adjust the pH value to 4.5, wherein the concentration of compound formula I-2 solution is 1 mg / mL; 111 The concentration of the In salt solution is 10-20 mCi / mL. Radionuclides 89 In the case of Zr, 0.8-1.5 mL of 0.25 M sodium acetate solution is added to a solution of compound formula I-2 containing 30-40 μg of solute, and then the activity of the solution is 2 mCi. 89 Add Zr salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 80°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 4.5 after the reaction, wherein the concentration of compound formula I-2 solution is 1 mg / mL; 89 The concentration of the Zr salt solution is 10 to 20 mCi / mL. Radionuclides 177 In the case of Lu, 0.8-1.5 mL of a 0.25 M sodium acetate solution is added to a solution of compound I-2 containing 30-40 μg of solute, and then the activity of the solution is 20 mCi. 177 Add Lu salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 85°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 5 after the reaction, wherein the concentration of compound formula I-2 solution is 1 mg / mL; 177 The concentration of the Lu salt solution is 20-30 mCi / mL. Radionuclides 225 In the case of Ac, 0.8 to 1.5 mL of a 0.1 M sodium ascorbate solution and 0.8 to 1.5 mL of a 0.1 M sodium citrate solution are added to a solution of compound formula I-2 containing 20 to 30 μg of solute, and then the activity of the solution is 0.01 mCi.225 Add Ac salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 90°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 5.5 after the reaction, wherein the concentration of compound formula I-2 solution is 1 mg / mL; 225 The concentration of Ac salt solution is 0.01-0.02 mCi / mL; Radionuclides 64 In the case of Cu, 0.8-1.5 mL of 0.25 M sodium acetate solution is added to a solution of compound formula I-2 containing 30-40 μg of solute, and then the activity of the solution is 5 mCi. 64 Add Cu salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5.5, react at 80-100°C, preferably 90°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 4.5 after the reaction, wherein the concentration of compound formula I-2 solution is 1 mg / mL; 64 The concentration of the Cu salt solution is 5 to 10 mCi / mL. Radionuclides 211 In the case of At, 0.8-1.5 mL of a 0.25 M sodium borate solution is added to a solution of compound I-2 containing 30-40 μg of solute, and then the activity of the solution is 1 mCi. 211 Add At salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 6.5 after the reaction, wherein the concentration of compound formula I-2 solution is 1 mg / mL; 211 The concentration of the At salt solution is 1.0 to 2.0 mCi / mL. Includes.

[0024] In some embodiments of the present invention, reacting compound of formula I-3 with a radionuclide salt solution specifically comprises the following steps: [ka] Radionuclides 68In the case of Ga, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of compound I-3 containing 20 to 40 μg of solute, and then the activity of the solution is 10 mCi. 68 Add Ga salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 85°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 5 after the reaction, wherein the concentration of compound formula I-3 solution is 1 mg / mL; 68 The concentration of the Ga salt solution is 5 to 10 mCi / mL. Radionuclides 111 In the case of In, 0.7 to 1.4 mL of a 0.25 M sodium acetate solution is added to a solution of compound formula I-3 containing 30 to 40 μg of solute, and then the activity of 111 Add In salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5.5, react at 80-100°C, preferably 90°C, the reaction time is 10-30 minutes, preferably 15 minutes, and adjust the pH value to 5 after the reaction, wherein the concentration of compound formula I-3 solution is 1 mg / mL; 111 The concentration of the In salt solution is 10 to 20 mCi / mL. Radionuclides 89 In the case of Zr, 0.8-1.5 mL of 0.25 M sodium acetate solution is added to a solution of compound I-3 containing 30-40 μg of solute, and then the activity of the solution is 2 mCi. 89 Add Zr salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 80°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 4.5 after the reaction, wherein the concentration of compound formula I-3 solution is 1 mg / mL; 89 The concentration of the Zr salt solution is 10 to 20 mCi / mL. Radionuclides 177 In the case of Lu, 0.8-1.5 mL of a 0.25 M sodium acetate solution is added to a solution of compound I-3 containing 30-40 μg of solute, and then the activity of the solution is 20 mCi. 177Add Lu salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 4.5 after the reaction, wherein the concentration of compound formula I-3 solution is 1 mg / mL; 177 The concentration of the Lu salt solution is 20-30 mCi / mL. Radionuclides 225 In the case of Ac, 0.8 to 1.5 mL of a 0.1 M sodium ascorbate solution and 0.8 to 1.5 mL of a 0.1 M sodium citrate solution are added to a solution of compound formula I-3 containing 20 to 30 μg of solute, and then a solution having an activity of 0.01 mCi is added. 225 Add Ac salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 5.5 after the reaction, wherein the concentration of compound formula I-3 solution is 1 mg / mL; 225 The concentration of Ac salt solution is 0.01-0.02 mCi / mL; Radionuclides 64 In the case of Cu, 0.8-1.5 mL of 0.25 M sodium acetate solution is added to a solution of compound I-3 containing 30-40 μg of solute, and then the activity of the solution is 5 mCi. 64 Add Cu salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 4.5 after the reaction, wherein the concentration of compound formula I-3 solution is 1 mg / mL; 64 The concentration of the Cu salt solution is 5 to 10 mCi / mL. Radionuclides 211 In the case of At, 0.8-1.5 mL of a 0.25 M sodium borate solution is added to a solution of compound I-3 containing 30-40 μg of solute, and then the activity of the solution is 1 mCi. 211Add At salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 6.5 after the reaction, wherein the concentration of compound formula I-3 solution is 1 mg / mL; 211 The concentration of the At salt solution is 1.0 to 2.0 mCi / mL. Includes.

[0025] A fifth aspect of the present invention provides the use of a precursor compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, or a radiolabeled compound according to the second aspect of the present invention or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament, particularly the use in the manufacture of a medicament for imaging and / or treating metastatic bone tumours.

[0026] A sixth aspect of the present invention provides a method for imaging and / or treating metastatic bone tumours, comprising administering to a subject in need thereof an effective amount of the radiolabel of the second aspect of the present invention or a pharmaceutically acceptable salt thereof.

[0027] A precursor compound or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention, or a radiolabeled compound or a pharmaceutically acceptable salt thereof according to the second aspect of the present invention, which is used for imaging and / or treating metastatic bone tumors.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] The present invention is simple in method and rational in design. The present invention creatively combines risedronate with a chelating agent to obtain NOTA-risedronate, DOTA-risedronate, and then combines the two to obtain radionuclides. 68 Ga, 111 In, 89 Zr, 177 Lu, 225 Ac, 64 Cu, 221 NOTA-risedronic acid and DOTA-risedronic acid were labeled with At. 68 Ga, 111In, 89 Zr, 177 Lu, 225 Ac, 64 Cu, 221 At-NOTA-risedronic acid and 68 Ga, 111 In, 89 Zr, 177 Lu, 225 Ac, 64 Cu, 221 At-DOTA-risedronic acid is obtained.

[0030] The radiolabeled product of the present invention has high water solubility, good in vitro stability at room temperature, high plasma protein binding rate, and exhibits excellent imaging properties in mice, as well as higher in vivo distribution and longer-lasting bone uptake, making it an excellent bone imaging agent and radiopharmaceutical for the treatment of metastatic bone tumors.

[0031] The present invention 68 Ga, 111 In, 89 Zr, 177 Lu, 225 Ac, 64 Cu, 221 The labeling method for producing At-labeled NOTA-risedronic acid and DOTA-risedronic acid is simple, with high labeling yields, shorter reaction times, and low precursor usage (microgram levels). The target / non-target ratio (T / N value) is very high, reaching up to 10 times or more. According to literature reports, a T / N ratio greater than 4-5 has very high therapeutic potential. 68 Compared with Ga-DOTA-ibandronic acid, the compound of the present invention has twice the uptake at the lesion site, and the present invention has an unexpected technical effect.

[0032] The names corresponding to the English abbreviations in the present invention are as follows: DCM: dichloromethane PyBOP: Benzotriazol-1-yl-oxytrispyrrolidinylphosphohexafluorophosphate DIPEA: N-ethyldiisopropylamine NOTA-NHS-ester: NOTA-succinimidyl ester DMF: N,N-dimethylformamide DOTA-NHS-ester: DOTA-succinimidyl ester DOTA-p-Bn-NCS: 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [Brief explanation of the drawings]

[0033] [Figure 1] FIG. 1 is an LC-MS diagram of compound formula I-1. [Figure 2] FIG. 1 is the LC-MS profile of compound formula I-2. [Figure 3] FIG. 1 is the LC-MS profile of compound I-3. [Figure 4] FIG. 1 is a TLC diagram of compound formula II-1 labeled with 68Ga. [Figure 5] FIG. 1 is a TLC diagram of compound formula II-1 labeled with 177Lu. [Figure 6] FIG. 1 is a TLC diagram of compound formula II-2 labeled with 68Ga. [Figure 7] FIG. 1 is a TLC diagram of compound formula II-2 labeled with 177Lu. [Figure 8] FIG. 1 is a TLC diagram of compound formula II-3 labeled with 68Ga. [Figure 9] FIG. 1 is a TLC diagram of compound formula II-3 labeled with 177Lu. [Figure 10] FIG. 1 is a PET / CT imaging image taken 2 hours after tail vein injection of 68Ga-DOTA-risedronic acid (compound II-1 labeled with 68Ga) into nude mice in Test Example 1. [Figure 11] 1 is a PET / CT imaging image of 68Ga-labeled compound formula II-1 in tumor-bearing mice in Test Example 2. FIG. [Figure 12] FIG. 1 shows PET / CT imaging images of 68Ga-DOTA-ibandronic acid in tumor-bearing mice in Test Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0034] In order to clarify the purpose, technical solutions and advantages of the following examples of the present invention, the technical solutions in the following examples are clearly and completely explained. Unless specific conditions are specified in the examples, the procedures are carried out according to standard conditions or manufacturer's recommendations. Reagents or equipment used in the examples, unless specified by manufacturer, are all commercially available products.

[0035] Example 1 This example discloses a method for preparing compound 4, which is specifically as follows:

[0036] S1. Compound 1 (180 mg, 1 mmol) and N-Boc glycine (210 mg, 1.2 mmol) were added to 5 mL of DCM and stirred until homogeneous. PyBOP (780 mg, 1.5 mmol) and DIPEA (260 mg, 2 mmol) were added and stirred at room temperature for 24 hours. TLC showed that compound 1 had completely reacted. The reaction mixture was diluted with DCM, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and separated by column chromatography (petroleum ether:ethyl acetate volume ratio = 2:1) to obtain 300 mg of the target compound 2.

[0037] S2. Compound 2 (168 mg, 0.5 mmol) was added to 1 mL of ethanol, 0.5 mL of water, and 24 mg of LiOH (1 mmol). The mixture was allowed to react at room temperature for 5 hours. TLC showed that compound 2 had completely reacted. 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 target compound 3. This product can be used for the next reaction without further purification.

[0038] S3. Compound 3 (100 mg, 0.33 mmol) was taken, chlorobenzene (5 mL) and phosphorous acid (270 mg, 3.3 mmol) were added, the mixture was heated to 90°C, and stirred for 30 minutes. Phosphorus oxychloride (1 g, 6.6 mmol) was added dropwise and reacted for 8 hours. The supernatant was discarded, and 5 mL of water was added to the remaining solid. The mixture was heated to 90°C and reacted for 12 hours. The mixture was filtered while still hot. 10 mL of methanol was added to the filtrate, and the mixture was filtered. The filter cake was dried to obtain the target compound 4 as a white solid. The reaction scheme was as follows: [ka]

[0039] Example 2 This example discloses a method for synthesizing compound formula I-1, specifically: 35 mg (0.1 mmol) of compound 4 was added to 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. The reaction was allowed to proceed at room temperature for 24 hours, and the product was monitored by LC-MS. The reaction mixture was filtered, and the filtrate was concentrated. The concentrate was purified by prep-HPLC to obtain the target compound, Formula I-1, as a white solid. The prep-HPLC operating conditions were a YMC-Actus Triart Diol-HILIC column with a 150 mm x 30 mm, 5 μm, 120 Å diameter column, and an acetonitrile solution containing 0.2% acetic acid by volume as the mobile phase. The reaction scheme was as follows: [ka]

[0040] The LC-MS pattern of compound I-1 is shown in FIG.

[0041] Example 3 This example discloses a method for synthesizing compound I-2, specifically: 35 mg (0.1 mmol) of compound 4 was taken, and 115 mg (0.15 mmol) of DOTA-NHS-ester was added. 0.5 mL of DMF, 0.5 mL of water, and 78 mg (0.6 mmol) of DIPEA were added. The reaction was allowed to proceed at room temperature for 24 hours, and the product was monitored by LC-MS. The reaction mixture was filtered, and the filtrate was concentrated. The concentrate was purified by prep-HPLC to obtain the target compound, Formula I-2, as a white solid. The prep-HPLC operating conditions were a YMC-Actus Triart Diol-HILIC column with a 150 mm x 30 mm, 5 μm, 120 Å diameter column, and a 0.2% acetic acid solution by volume mobile phase. The reaction scheme was as follows: [ka]

[0042] The LC-MS profile of compound I-2 is shown in FIG.

[0043] The DOTA-NHS-ester in this example can be replaced with an equimolar amount of DOTA-p-Bn-NCS.

[0044] Example 4 This example discloses a method for synthesizing compound I-3, specifically: 35 mg (0.1 mmol) of compound 4 was taken, and 83 mg (0.15 mmol) of DOTA-p-Bn-NCS was added. 0.5 mL of DMF, 0.5 mL of water, and 78 mg (0.6 mmol) of DIPEA were added. The reaction was allowed to proceed at room temperature for 24 hours, and the product was monitored by LC-MS. The reaction mixture was filtered, and the filtrate was concentrated. The concentrate was purified by prep-HPLC to obtain the target compound, Formula I-3, as a white solid. The prep-HPLC operating conditions were a YMC-Actus Triart Diol-HILIC column with a 150 mm x 30 mm, 5 μm, 120 Å diameter, and a 0.2% (vol.) acetic acid solution as the mobile phase. The reaction scheme was as follows: [ka]

[0045] The LC-MS profile of compound I-3 is shown in FIG.

[0046] Example 5 This example discloses reacting compound I-1 with a radionuclide salt solution to produce compound II-1, the reaction scheme being: [ka] It was.

[0047] 1. Radionuclides 68 Ga 30 μg of compound formula I-1 was dissolved in sterile water to obtain a compound formula I-1 solution with a concentration of 1 mg / mL. 1.0 mL of sodium acetate solution with a concentration of 0.25 M was added to the compound formula I-1 solution, and then a solution with an activity of 10 mCi was added. 68 Add 2 mL of Ga salt solution, mix evenly, adjust the pH of the mixture to 5, react at 80-100°C for 15 minutes, and adjust the pH of the reaction product to 5 after the reaction. 68 Ga-labeled compound II-1 was obtained, the TLC diagram of which is shown in Figure 4.

[0048] 2. Radionuclides 111 In 30 μg of compound formula I-1 was dissolved in sterile water to obtain a compound formula I-1 solution with a concentration of 1 mg / mL. 1.0 mL of sodium acetate solution with a concentration of 0.25 M was added to the compound formula I-1 solution, and then a solution with an activity of 10 mCi was added. 111 Add 1 mL of In salt solution, mix evenly, adjust the pH of the mixture to 5.5, and react at 95°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 5. 111 The In-labeled compound of formula II-1 was obtained.

[0049] 3. Radionuclides 89 Zr 30 μg of compound formula I-1 was dissolved in sterile water to obtain a compound formula I-1 solution with a concentration of 1 mg / mL. 1.0 mL of sodium acetate solution with a concentration of 0.25 M was added to the compound formula I-1 solution, and then a solution with an activity of 2 mCi was added.89 Add 1 mL of Zr salt solution, mix evenly, adjust the pH of the mixture to 5, and react at 80°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 4.5. 89 Zr-labeled compound formula II-1 was obtained.

[0050] 4. Radionuclides 177 Lu 30 μg of compound formula I-1 was dissolved in sterile water to obtain a compound formula I-1 solution with a concentration of 1 mg / mL. 1.0 mL of sodium acetate solution with a concentration of 0.25 M was added to the compound formula I-1 solution, and then a solution with an activity of 20 mCi was added. 177 Add 2 mL of Lu salt solution, mix evenly, adjust the pH of the mixture to 5, and react at 95°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 4.5. 177 Lu-labeled compound II-1 was obtained, the TLC diagram of which is shown in Figure 5.

[0051] 5. Radionuclides 225 Ac 30 μg of compound formula I-1 was dissolved in sterile water to obtain a compound formula I-1 solution with a concentration of 1 mg / mL. 1.0 mL of 0.1 M sodium ascorbate solution and 1.0 mL of 0.1 M sodium citrate solution were added to the compound formula I-1 solution, and then a 0.01 mCi solution was added. 225 Add 1 mL of Ac salt solution, mix evenly, adjust the pH of the mixture to 5, and react at 95°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 5.5. 225 Ac-labeled compound formula II-1 was obtained.

[0052] 6. Radionuclides 64 Cu 30 μg of compound formula I-1 was dissolved in sterile water to obtain a compound formula I-1 solution with a concentration of 1 mg / mL. 1.0 mL of sodium acetate solution with a concentration of 0.25 M was added to the compound formula I-1 solution, and then a solution with an activity of 5 mCi was added. 64Add 1 mL of Cu salt solution, mix evenly, adjust the pH of the mixture to 5, and react at 95°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 4.5. 64 Cu-labeled compound formula II-1 was obtained.

[0053] 7. Radionuclides 211 At 30 μg of compound formula I-1 was dissolved in sterile water to obtain a compound formula I-1 solution with a concentration of 1 mg / mL. 1.0 mL of sodium borate solution with a concentration of 0.25 M was added to the compound formula I-1 solution, and then a 1 mCi sodium borate solution was added. 211 Add 1 mL of At salt solution, mix evenly, adjust the pH of the mixture to 5, and react at 95°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 6.5. 211 The At-labeled compound of formula II-1 was obtained.

[0054] The radiochemical purity of the compound of formula II-1 in this example was 95% or more.

[0055] Example 6 This example discloses the reaction of compound I-2 with a radionuclide salt solution to produce compound II-2, the reaction scheme being: [ka] It was.

[0056] 1. Radionuclides 68 Ga 30 μg of compound formula I-2 was dissolved in sterile water to obtain a compound formula I-2 solution with a concentration of 1 mg / mL. 1.0 mL of sodium acetate solution with a concentration of 0.25 M was added to the compound formula I-2 solution, and then a solution with an activity of 10 mCi was added. 68 Add 2 mL of Ga salt solution, mix evenly, adjust the pH of the mixture to 4.5, and react at 95°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 5. 68 Ga-labeled compound II-2 was obtained, and its TLC diagram is shown in Figure 6.

[0057] 2. Radionuclides 111 In 30 μg of compound formula I-2 was dissolved in sterile water to obtain a compound formula I-2 solution with a concentration of 1 mg / mL. 1.0 mL of sodium acetate solution with a concentration of 0.25 M was added to the compound formula I-2 solution, and then a solution with an activity of 10 mCi was added. 111 Add 1 mL of In salt solution, mix evenly, adjust the pH of the mixture to 5.5, and react at 95°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 4.5. 111 The In-labeled compound of formula II-2 was obtained.

[0058] 3. Radionuclides 89 Zr 30 μg of compound I-2 was dissolved in sterile water to obtain a compound I-2 solution with a concentration of 1 mg / mL. 1.0 mL of sodium acetate solution with a concentration of 0.25 M was added to the compound I-2 solution, and then a solution with an activity of 2 mCi was added. 89 Add 1 mL of Zr salt solution, mix evenly, adjust the pH of the mixture to 5, and react at 80°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 4.5. 89 Zr-labeled compound formula II-2 was obtained.

[0059] 4. Radionuclides 177 Lu 30 μg of compound I-2 was dissolved in sterile water to obtain a compound I-2 solution with a concentration of 1 mg / mL. 1.0 mL of sodium acetate solution with a concentration of 0.25 M was added to the compound I-2 solution, and then a solution with an activity of 20 mCi was added. 177 Add 2 mL of Lu salt solution, mix evenly, adjust the pH of the mixture to 5, and react at 85°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 5. 177 Lu-labeled compound II-2 was obtained, the TLC diagram of which is shown in Figure 7.

[0060] 5. Radionuclides 225 Ac 30 μg of compound I-2 was dissolved in sterile water to obtain a compound I-2 solution with a concentration of 1 mg / mL. 1.0 mL of 0.1 M sodium ascorbate solution and 1.0 mL of 0.1 M sodium citrate solution were added to the compound I-2 solution. Then, a 0.01 mCi solution was added. 225 Add 1 mL of Ac salt solution, mix evenly, adjust the pH value of the mixed solution to 5, react at 90 ° C for 15 min, and after the reaction, adjust the pH value of the reaction product to 5.5. 225 Ac-labeled compound formula II-2 was obtained.

[0061] 6. Radionuclides 64 Cu 30 μg of compound I-2 was dissolved in sterile water to obtain a compound I-2 solution with a concentration of 1 mg / mL. 1.0 mL of sodium acetate solution with a concentration of 0.25 M was added to the compound I-2 solution, and then a solution with an activity of 5 mCi was added. 64 Add 1 mL of Cu salt solution, mix evenly, adjust the pH value of the mixed solution to 5.5, react at 90 °C for 15 min, and after the reaction, adjust the pH value of the reaction product to 4.5. 64 Cu-labeled compound formula II-2 was obtained.

[0062] 7. Radionuclides 211 At 30 μg of compound I-2 was dissolved in sterile water to obtain a compound I-2 solution with a concentration of 1 mg / mL. 1.0 mL of sodium borate solution with a concentration of 0.25 M was added to the compound I-2 solution, and then a 1 mCi solution was added. 211 Add 1 mL of At salt solution, mix evenly, adjust the pH of the mixture to 5, and react at 95°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 6.5. 211 The At-labeled compound of formula II-2 was obtained.

[0063] The radiochemical purity of the compound of formula II-2 in this example was 95% or more.

[0064] Example 7 This example discloses the reaction of compound I-3 with a radionuclide salt solution to produce compound II-3, the reaction scheme being: [ka] It was.

[0065] 1. Radionuclides 68 Ga 40 μg of compound I-3 was dissolved in sterile water to obtain a compound I-3 solution with a concentration of 1 mg / mL. 1.0 mL of sodium acetate solution with a concentration of 0.25 M was added to the compound I-3 solution, and then a solution with an activity of 10 mCi was added. 68 Add 2 mL of Ga salt solution, mix evenly, adjust the pH of the mixture to 5, react at 85°C for 15 minutes, and adjust the pH of the reaction product to 5 after the reaction. 68 Ga-labeled compound II-3 was obtained, and its TLC diagram is shown in Figure 8.

[0066] 2. Radionuclides 111 In 40 μg of compound I-3 was dissolved in sterile water to obtain a compound I-3 solution with a concentration of 1 mg / mL. 1.0 mL of sodium acetate solution with a concentration of 0.25 M was added to the compound I-3 solution, and then a solution with an activity of 10 mCi was added. 111 Add 1 mL of In salt solution, mix evenly, adjust the pH value of the mixed solution to 5.5, react at 90 °C for 15 min, and after the reaction, adjust the pH value of the reaction product to 5. 111 The In-labeled compound of formula II-3 was obtained.

[0067] 3. Radionuclides 89 Zr 40 μg of compound I-3 was dissolved in sterile water to obtain a compound I-3 solution with a concentration of 1 mg / mL. 1.0 mL of sodium acetate solution with a concentration of 0.25 M was added to the compound I-3 solution, and then a solution with an activity of 2 mCi was added. 89 Add 1 mL of Zr salt solution, mix evenly, adjust the pH of the mixture to 5, and react at 80°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 4.5. 89Zr-labeled compound formula II-3 was obtained.

[0068] 4. Radionuclides 177 Lu 40 μg of compound I-3 was dissolved in sterile water to obtain a compound I-3 solution with a concentration of 1 mg / mL. 1 mL of sodium acetate solution with a concentration of 0.25 M was added to the compound I-3 solution, and then a solution with an activity of 20 mCi was added. 177 Add 2 mL of Lu salt solution, mix evenly, adjust the pH of the mixture to 5, and react at 95°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 4.5. 177 Lu-labeled compound II-3 was obtained, the TLC diagram of which is shown in Figure 9.

[0069] 5. Radionuclides 225 Ac 30 μg of compound I-3 was dissolved in sterile water to obtain a compound I-3 solution with a concentration of 1 mg / mL. 1.0 mL of 0.1 M sodium ascorbate solution and 1.0 mL of 0.1 M sodium citrate solution were added to the compound I-3 solution, and then a 0.01 mCi solution was added. 225 Add 1 mL of Ac salt solution, mix evenly, adjust the pH of the mixture to 5, and react at 95°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 5.5. 225 Ac-labeled compound formula II-3 was obtained.

[0070] 6. Radionuclides 64 Cu 40 μg of compound I-3 was dissolved in sterile water to obtain a compound I-3 solution with a concentration of 1 mg / mL. 1.0 mL of sodium acetate solution with a concentration of 0.25 M was added to the compound I-3 solution, and then a solution with an activity of 5 mCi was added. 64 Add 1 mL of Cu salt solution, mix evenly, adjust the pH of the mixture to 5, and react at 95°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 4.5. 64 Cu-labeled compound formula II-3 was obtained.

[0071] 7. Radionuclides211 At 40 μg of compound I-3 was dissolved in sterile water to obtain a compound I-3 solution with a concentration of 1 mg / mL. 1.0 mL of sodium borate solution with a concentration of 0.25 M was added to the compound I-3 solution, and then a 1 mCi solution was added. 211 Add 1 mL of At salt solution, mix evenly, adjust the pH of the mixture to 5, and react at 95°C for 15 minutes. After the reaction, adjust the pH of the reaction product to 6.5. 211 The At-labeled compound of formula II-3 was obtained.

[0072] The radiochemical purity of the compound of formula II-3 in this example was 95% or more.

[0073] Test Example 1 This test example is 68 PET / CT imaging experiments of Ga-labeled compound Formula II-1 in tumor-bearing mice were disclosed.

[0074] (1) Construction of tumor-bearing mouse model: Twelve SPF-grade female nude mice were prepared and anesthetized with isoflurane. The skin around the left knee joint was disinfected, the left hind leg was bent, and an insulin needle (29G gauge) was inserted vertically into the femur through the femoral head glenoid cavity and slowly rotated to penetrate into the bone marrow cavity. 25 μL (approximately 2 × 10 6 The wells were then infused with MDA-MB-231 (human breast cancer cells, from ATCC) cell culture medium containing 1000 cells / well. The wells were then disinfected and sealed with sterile bone wax. The animals were then placed on a 37°C hot plate to rewarm, and after resuscitation, they were returned to their cages for continued care.

[0075] (2) Testing of tumor-bearing mouse model: After 4 weeks of inoculation, 12 nude mice were scanned using Micro-CT. The results showed that each of the 12 nude mice had different degrees of bone destruction and soft tissue swelling, suggesting that the bone metastasis model was successfully constructed.

[0076] (3) Imaging of tumor-bearing mice: One tumor-bearing mouse from which the model was successfully constructed was taken and newly prepared 68 Approximately 0.1 mL of Ga-labeled compound Formula II-1 (concentration 1 mCi / mL) was injected via the tail vein, and whole-body imaging was performed by PET / CT 2 h after injection. The results are shown in Figure 10. 2 h after injection, bones throughout the body were imaged relatively clearly, and the joints of the limbs were clearly imaged. Uptake of the imaging agent was evident in the bone metastasis in the left knee joint.

[0077] Test Example 2 This test example is 68 Ga-labeled compound formula II-1 68 A comparative experiment of PET / CT imaging in tumor-bearing mice with Ga-DOTA-ibandronate was disclosed. 68 Ga-DOTA-ibandronic acid was prepared by method number 5 in Table 1 of the specification of the published document of the Chinese patent application with application number 202111419244.X.

[0078] Four tumor-bearing mice were selected from which the model was successfully constructed, two of which were newly generated. 68 Approximately 0.1 mL of Ga-labeled compound Formula II-1 (concentration 1 mCi / mL) was injected into the tail vein of the other two mice. 68 Approximately 0.1 mL of Ga-DOTA-ibandronic acid (concentration 1 mCi / mL) was injected into the tail vein, and PET / CT whole-body imaging was performed 2 hours after injection. The results are shown in Table 1 and Figures 11 and 12. Figure 11 shows the results. 68 Imaging of tumor-bearing mice injected with Ga-labeled compound Formula II-1. 68 Imaging of tumor-bearing mice injected with Ga-DOTA-ibandronate.

[0079] The T / N value is calculated according to the following formula: T / N value = SUVmax of lesion / SUVmax of background tissue

[0080] [Table 1]

[0081] As a result, the present invention 68 Ga-labeled compound Formula II-1 showed high uptake both in the head and in the lesion area. 68 The uptake of Ga-DOTA-ibandronate was significantly higher than that of Ga-DOTA-ibandronate, and the uptake in the lesion area was 68 The results were twice as high as those of Ga-DOTA-ibandronic acid. 68 The Ga-labeled compound of formula II-1 has unexpectedly better imaging effect. 68 The Ga-labeled compound of formula II-1 has a very high target / non-target ratio (T / N value), which can reach a maximum of 10 times or more. According to literature reports, if the T / N ratio is greater than 4-5, it has a very high potential therapeutic value. 68 The Ga-labeled compound of formula II-1 has great potential therapeutic value.

[0082] Finally, it should be noted that the above embodiments are merely preferred embodiments of the present invention for explaining the technical solution of the present invention, and are not intended to limit the same, and certainly not to limit the scope of the claims of the present invention. Even if changes or modifications that have no substantial meaning are made to the main design idea and spirit of the present invention, the technical problems they solve are all still consistent with the present invention, and all direct or indirect applications of the technical solution of the present invention to other related technical fields are also included in the scope of the claims of the present invention.

Claims

1. A precursor compound of a radiolabeled risedronate derivative having a structure represented by formula I or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Among them, R １ teeth 【Chemistry 2】 or 【Transformation 3】 or 【Chemistry 4】 That is, A precursor compound of a radiolabeled substance or a pharmaceutically acceptable salt thereof.

2. A radiolabeled risedronate derivative represented by formula II or a pharmaceutically acceptable salt thereof, 【Transformation 5】 Among them, R ２ teeth 【Transformation 6】 or 【Transformation 7】 or 【Transformation 8】 and A is a radionuclide, preferably ６８ Ga, １１１ In, ８９ Zr, １７７ Lu, ２２５ Ac, ６４ Cu or ２２１ At, A radiolabeled substance or a pharmaceutically acceptable salt thereof.

3. 3. The radiolabeled compound or pharmaceutically acceptable salt thereof according to claim 2, characterized in that its radiochemical purity is 95% or more.

4. A method for producing the radiolabeled compound or a pharmaceutically acceptable salt thereof according to claim 1, comprising the steps of: Step 1. Reacting compound 1 with N-Boc glycine to form compound 2; Step 2. Producing compound 3 from compound 2 under the action of LiOH; Step 3. Compound 3 is treated with chlorobenzene and H ３ P.O. ３ and POCl ３ and heating to react to form compound 4; 【Chemistry 9】 、 Step 4. R １ but 【Chemistry 10】 Then, compound 4 is reacted with NOTA-NHS-ester to produce compound I-1, the reaction scheme being: 【Chemistry 11】 and R １ but 【Chemistry 12】 Then, compound 4 is reacted with DOTA-NHS-ester to produce compound I-2, the reaction scheme being: 【Chemistry 13】 and Preferably, 【Chemistry 14】 and R １ but 【Chemistry 15】 Then, compound 4 is reacted with DOTA-p-Bn-NCS to form compound I-3, the reaction scheme being: 【Chemistry 16】 and Manufacturing method.

5. A method for producing a radiolabel according to claim 2 or 3, comprising reacting a compound of formula I according to claim 1 with a radionuclide salt solution to obtain a radiolabel of formula II: Manufacturing method.

6. The method comprises mixing a solution of the compound of formula I in claim 1, a sodium salt solution and a radionuclide salt solution, adjusting the pH value, reacting, adjusting the pH value and filtering to obtain a radiolabeled compound of formula II. The method of claim 5.

7. Radionuclides ６８ Ga, １１１ In, ８９ Zr, １７７ Lu or ６４ When the radiolabel is Cu, the radiolabel is obtained by mixing a solution of the compound of formula I in claim 1, a sodium acetate solution and a radionuclide salt solution, adjusting the pH value of the mixed solution, reacting, adjusting the pH value again, sterilizing, and filtering; Radionuclides ２２５ Ac, by mixing a solution of the compound of formula I in claim 1, a sodium citrate solution, a sodium ascorbate solution and a radionuclide salt solution, adjusting the pH of the mixed solution, reacting, adjusting the pH again, sterilizing and filtering, to obtain a radiolabeled product; radionuclides ２１１ When the radiolabel is At, the method is characterized in that a solution of the compound of formula I in claim 1, a sodium borate solution and a radionuclide salt solution are mixed, the pH value of the mixed solution is adjusted, the mixture is reacted, the pH value is adjusted again, sterilized, and filtered to obtain a radiolabel. The method for producing a radiolabeled compound according to claim 5 or 6.

8. The reaction of compound Formula I-1 with a radionuclide salt solution specifically comprises the following steps: 【Chemistry 17】 Radionuclides ６８ In the case of Ga, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of the compound of formula I-1 containing 30 to 40 μg of solute, and then a 10 mCi ６８ Add Ga salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 5 after the reaction, wherein the concentration of the compound of formula I-1 solution is 1 mg / mL; ６８ The concentration of the Ga salt solution is 5 to 10 mCi / mL; Radionuclides １１１ In the case of In, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of the compound of formula I-1 containing 30 to 40 μg of solute, and then a 10 mCi １１１ Add In salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5.5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 5 after the reaction, wherein the concentration of the compound of formula I-1 solution is 1 mg / mL; １１１ The concentration of the In salt solution is 10-20 mCi / mL; Radionuclides ８９ In the case of Zr, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of the compound of formula I-1 containing 30 to 40 μg of solute, and then the activity of the compound of formula I-1 is 2 mCi. ８９ Add Zr salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 80°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 4.5 after the reaction, wherein the concentration of the compound of formula I-1 solution is 1 mg / mL; ８９ The concentration of the Zr salt solution is 10 to 20 mCi / mL; Radionuclides １７７ In the case of Lu, 0.8-1.5 mL of a 0.25 M sodium acetate solution is added to a solution of compound formula I-1 containing 30-40 μg of solute, and then the activity of １７７ Add Lu salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 4.5 after the reaction, wherein the concentration of compound formula I-1 solution is 1 mg / mL; １７７ the concentration of the Lu salt solution is 20-30 mCi / mL; Radionuclides ２２５ In the case of Ac, 0.8-1.5 mL of a 0.1 M sodium ascorbate solution and 0.8-1.5 mL of a 0.1 M sodium citrate solution are added to a solution of compound formula I-1 containing 20-30 μg of solute, and then a solution of 0.01 mCi sodium citrate is added. ２２５ Add Ac salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 5.5 after the reaction, wherein the concentration of the compound of formula I-1 solution is 1 mg / mL; ２２５ The concentration of the Ac salt solution is 0.01 to 0.02 mCi / mL; Radionuclides ６４ In the case of Cu, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of the compound of formula I-1 containing 30 to 40 μg of solute, and then the activity of the solution is 5 mCi. ６４ Add Cu salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 4.5 after the reaction, wherein the concentration of the compound of formula I-1 solution is 1 mg / mL; ６４ The concentration of the Cu salt solution is 5 to 10 mCi / mL; Radionuclides ２１１ In the case of At, 0.8-1.5 mL of a sodium borate solution having a concentration of 0.25 M is added to a solution of the compound of formula I-1 having a solute content of 30-40 μg, and then an activity of 1 mCi is added. ２１１ Add At salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 6.5 after the reaction, wherein the concentration of the compound of formula I-1 solution is 1 mg / mL; ２１１ The concentration of the At salt solution is 1.0-2.0 mCi / mL; The method for producing a radiolabeled compound according to any one of claims 5 to 7, comprising:

9. The reaction of compound Formula I-2 with a radionuclide salt solution specifically comprises the following steps: [Chemistry 18] Radionuclides ６８ In the case of Ga, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of the compound of formula I-2 containing 30 to 40 μg of solute, and then the activity of ６８ Add Ga salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 4.5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 5 after the reaction, wherein the concentration of compound formula I-2 solution is 1 mg / mL; ６８ The concentration of the Ga salt solution is 5 to 10 mCi / mL; Radionuclides １１１ In the case of In, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of the compound of formula I-2 containing 30 to 40 μg of solute, and then the activity of the compound of formula I-2 is 10 mCi. １１１ Add In salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5.5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 4.5 after the reaction, wherein the concentration of compound formula I-2 solution is 1 mg / mL; １１１ The concentration of the In salt solution is 10-20 mCi / mL; Radionuclides ８９ In the case of Zr, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of the compound of formula I-2 containing 30 to 40 μg of solute, and then the activity of the compound of formula I-2 is 2 mCi. ８９ Add Zr salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 80°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 4.5 after the reaction, wherein the concentration of the compound formula I-2 solution is 1 mg / mL; ８９ The concentration of the Zr salt solution is 10 to 20 mCi / mL; Radionuclides １７７ In the case of Lu, 0.8-1.5 mL of a 0.25 M sodium acetate solution is added to a solution of compound formula I-2 containing 30-40 μg of solute, and then the activity of １７７ Add Lu salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 85°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 5 after the reaction, wherein the concentration of compound formula I-2 solution is 1 mg / mL; １７７ the concentration of the Lu salt solution is 20-30 mCi / mL; Radionuclides ２２５ In the case of Ac, 0.8-1.5 mL of a 0.1 M sodium ascorbate solution and 0.8-1.5 mL of a 0.1 M sodium citrate solution are added to a solution of compound formula I-2 containing 20-30 μg of solute, and then a solution of 0.01 mCi sodium citrate is added. ２２５ Add Ac salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 90°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 5.5 after the reaction, wherein the concentration of compound formula I-2 solution is 1 mg / mL; ２２５ The concentration of the Ac salt solution is 0.01 to 0.02 mCi / mL; Radionuclides ６４ In the case of Cu, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of the compound of formula I-2 containing 30 to 40 μg of solute, and then the activity of the compound of formula I-2 is 5 mCi. ６４ Add Cu salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5.5, react at 80-100°C, preferably 90°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 4.5 after the reaction, wherein the concentration of compound formula I-2 solution is 1 mg / mL; ６４ The concentration of the Cu salt solution is 5 to 10 mCi / mL; Radionuclides ２１１ In the case of At, 0.8-1.5 mL of a sodium borate solution having a concentration of 0.25 M is added to a solution of the compound of formula I-2 having a solute content of 30-40 μg, and then an activity of 1 mCi is added. ２１１ Add At salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 6.5 after the reaction, wherein the concentration of compound formula I-2 solution is 1 mg / mL; ２１１ The concentration of the At salt solution is 1.0-2.0 mCi / mL; The method for producing a radiolabeled compound according to any one of claims 5 to 7, comprising:

10. The reaction of compound formula I-3 with a radionuclide salt solution specifically comprises the following steps: 【Chemistry 19】 Radionuclides ６８ In the case of Ga, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of compound I-3 containing 20 to 40 μg of solute, and then the activity of ６８ Add Ga salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 85°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 5 after the reaction, wherein the concentration of the compound formula I-3 solution is 1 mg / mL; ６８ The concentration of the Ga salt solution is 5 to 10 mCi / mL; Radionuclides １１１ In the case of In, 0.7 to 1.4 mL of a 0.25 M sodium acetate solution is added to a solution of the compound of formula I-3 containing 30 to 40 μg of solute, and then the activity of the １１１ Add In salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5.5, react at 80-100°C, preferably 90°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 5 after the reaction, wherein the concentration of the compound formula I-3 solution is 1 mg / mL; １１１ The concentration of the In salt solution is 10-20 mCi / mL; Radionuclides ８９ In the case of Zr, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of the compound of formula I-3 containing 30 to 40 μg of solute, and then the activity of the compound of formula I-3 is 2 mCi. ８９ Add Zr salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 80°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 4.5 after the reaction, wherein the concentration of the compound formula I-3 solution is 1 mg / mL; ８９ The concentration of the Zr salt solution is 10 to 20 mCi / mL; Radionuclides １７７ In the case of Lu, 0.8-1.5 mL of a 0.25 M sodium acetate solution is added to a solution of compound formula I-3 containing 30-40 μg of solute, and then the activity of １７７ Add Lu salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 4.5 after the reaction, wherein the concentration of compound formula I-3 solution is 1 mg / mL; １７７ the concentration of the Lu salt solution is 20-30 mCi / mL; Radionuclides ２２５ In the case of Ac, 0.8-1.5 mL of a 0.1 M sodium ascorbate solution and 0.8-1.5 mL of a 0.1 M sodium citrate solution are added to a solution of compound formula I-3 containing 20-30 μg of solute, and then a solution of 0.01 mCi sodium citrate is added. ２２５ Add Ac salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 5.5 after the reaction, wherein the concentration of compound formula I-3 solution is 1 mg / mL; ２２５ The concentration of the Ac salt solution is 0.01 to 0.02 mCi / mL; Radionuclides ６４ In the case of Cu, 0.8 to 1.5 mL of a 0.25 M sodium acetate solution is added to a solution of the compound of formula I-3 containing 30 to 40 μg of solute, and then the activity of the solution is 5 mCi. ６４ Add Cu salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 4.5 after the reaction, wherein the concentration of compound formula I-3 solution is 1 mg / mL; ６４ The concentration of the Cu salt solution is 5 to 10 mCi / mL; Radionuclides ２１１ In the case of At, 0.8-1.5 mL of a sodium borate solution having a concentration of 0.25 M is added to a solution of the compound of formula I-3 having a solute content of 30-40 μg, and then an activity of 1 mCi is added. ２１１ Add At salt solution, mix, adjust the pH value of the mixed solution to 4-7, preferably 5, react at 80-100°C, preferably 95°C, the reaction time is 10-30 min, preferably 15 min, and adjust the pH value to 6.5 after the reaction, wherein the concentration of the compound formula I-3 solution is 1 mg / mL; ２１１ The concentration of the At salt solution is 1.0-2.0 mCi / mL; The method for producing a radiolabeled compound according to any one of claims 5 to 7, comprising:

11. A method for producing a drug for imaging and / or treating metastatic bone tumors, comprising administering to a subject a precursor compound or a pharmaceutically acceptable salt thereof according to claim 1 or a radiolabeled compound or a pharmaceutically acceptable salt thereof according to claim 2 or 3, use.

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