Bisphosphonate radiomarker, precursor compound thereof, preparation method and application

Abstract

The invention discloses a bisphosphonate radiomarker, and a precursor compound, a preparation method and application thereof, and belongs to the technical field of nuclear medicine. The structure of the precursor compound of the radioactive marker or the salt of the precursor compound is shown as a formula I; the structure of the radioactive marker or the salt thereof is shown as a formula II. The invention also discloses a preparation method of the precursor compound and the radioactive marker. The invention also discloses application of the precursor compound and the radioactive marker in preparation of a bone metastatic tumor targeted tumor imaging agent or / and a tumor therapeutic agent. The radioactive marker disclosed by the invention is relatively high in water solubility, relatively good in-vitro stability at room temperature and high in plasma protein binding rate, relatively high and relatively long-lasting skeleton uptake is shown in imaging and in-vivo distribution in mice, the imaging effect is superior to that of 99mTc-MDP, 68Ga-DOTA-ibandronic acid and 68Ga-labeled dithiophosphoric acid derivatives, and the radioactive marker has a wide application prospect. The compound is an excellent bone developer and a medicine for treating tumor bone metastasis.

Description

Technical Field

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

[0002] Malignant tumors seriously endanger human health, and bone metastasis is common in advanced stages, particularly in prostate cancer, breast cancer, lung cancer, liver cancer, and thyroid cancer. With advancements in primary tumor diagnosis and treatment, patient survival has increased, leading to a corresponding rise in the incidence of bone metastasis. Bone metastasis typically indicates advanced disease progression, often accompanied by severe and uncontrollable bone pain, and is prone to triggering a series of bone-related events such as pathological fractures, spinal cord compression, and hypercalcemia, severely impacting the patient's quality of life.

[0003] In terms of treatment, radionuclide therapy has become a safe and effective treatment method due to its ability to effectively relieve bone pain, kill tumor cells, and has relatively few toxic side effects. Commonly used clinical drugs include 223 RaCl2, 89 SrCl2 and 153 Drugs such as Sm-EDTMP can significantly reduce bone pain and the incidence of bone-related events. However, they do not directly target cancer cells, but rather act on the tumor microenvironment in bone tissue. Due to differences in their physicochemical properties, there are problems such as uneven drug distribution, insufficient uptake by lesions, and off-target risks, which affect their precise guiding value for the treatment of bone metastases.

[0004] In the imaging diagnosis of bone metastases, the most commonly used imaging agent in clinical practice is currently... 99 mTc-methylene diphosphonate ( 99 mTc-MDP), but its imaging is limited by the spatial resolution and sensitivity of SPECT equipment, and the drug itself has limited bone affinity, resulting in low image contrast and affecting lesion identification. 18 While F-NaF offers superior image quality, its production relies on cyclotrons, limiting its availability and increasing its cost. In contrast, 68 Ga nuclides can be obtained through 68 Ge / 68 Ga generators are readily available and more suitable for widespread use; furthermore, due to 68 Ga and 177 Lu are all trivalent metal ions, which can achieve dual labeling of the same type of ligands, and are expected to build a diagnostic and therapeutic probe. 177 Lu has a suitable half-life (6.7 days) and can emit therapeutic beta-12. These particles can also emit gamma rays for imaging, possessing the potential for integrated diagnosis and treatment.

[0005] also, 225 Ac and 64Cu is also a current research hotspot. 225 Ac emits high-energy-density alpha rays, which have a strong killing effect on tumor cells. Its half-life is 9.9 days, and its daughter nuclei... 213 Bi has a half-life of 46 minutes, making it suitable for targeted alpha therapy. 64 Cu has a half-life of 12.7 hours and also possesses β-type properties. + With β - Its decay properties make it easy to combine with a variety of ligands, showing promising application prospects in nuclear medicine imaging and therapy.

[0006] Hydroxyethylidene bisphosphonate (HEDP), as a first-generation nitrogen-free bisphosphonate, has been used in imaging and treatment studies of bone metastases. However, its efficacy is significantly lower than that of second- and third-generation nitrogen-containing bisphosphonates, such as alendronate and risedronate. There is still considerable room for improvement in its targeting ability and efficacy.

[0007] Therefore, providing a novel radiopharmaceutical based on a highly efficient bone-targeting ligand, which has excellent bone affinity, high-contrast imaging capability, effective therapeutic effect, and is easy to produce and promote, in order to solve the problems of insufficient targeting, limited image quality, low treatment efficiency, and poor accessibility of existing bone metastasis diagnosis and treatment drugs, has become a technical problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0008] One of the objectives of this invention is to provide a precursor compound of the radiolabeled substance of Formula I or a pharmaceutically acceptable salt thereof, which, after being labeled with a radionuclide, exhibits good imaging effects and can treat bone tumors.

[0009] A second objective of this invention is to provide a radiolabeled substance of Formula II or a pharmaceutically acceptable salt thereof, which is prepared by radiolabeling of a compound of Formula I.

[0010] A third objective of this invention is to provide a method for preparing the compound of formula I.

[0011] A fourth objective of this invention is to provide a method for preparing compounds of formula II.

[0012] The seventh objective of this invention is to provide applications of compounds of formula I and formula II.

[0013] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The first aspect of this invention provides a precursor compound of a radiolabeled substance with the structure shown in Formula I, or a pharmaceutically acceptable salt thereof. , Wherein, R is H or OH; Linker is a flexible linking group that is attached to the 4, 5, or 6 position of the pyridine ring in the structure shown in Formula I.

[0014] In some embodiments of the present invention, the Linker is selected from at least one of the following groups: alkylene groups represented by Formula III, polyethylene glycol segments or peptide chains represented by Formula IV;

[0015] In Formula III, a is an integer from 1 to 9, more preferably an integer from 1 to 7; In Formula IV, b is an integer from 1 to 6, more preferably 2, 3 or 4.

[0016] In some embodiments of the present invention, the precursor compound of the radiolabeled substance or its pharmaceutically acceptable salt has the structure shown in Formula V or Formula VI; .

[0017] A second aspect of the present invention provides a radiolabeled substance as shown in Formula II or a pharmaceutically acceptable salt thereof. , Wherein, R is H or OH; Linker is a flexible linking group that is attached to the 4, 5, or 6 position of the pyridine ring in the structure shown in Formula II; Preferably, the Linker is selected from at least one of the following groups: alkylene groups represented by Formula III, polyethylene glycol segments or peptide chains represented by Formula IV;

[0018] In Formula III, a is an integer from 1 to 9, more preferably an integer from 1 to 7; In Formula IV, b is an integer from 1 to 6, more preferably 2, 3 or 4; A is a radioactive nuclide, preferably... 68 Ga、 177 Lu、 225 Ac or 64 Cu.

[0019] In some embodiments of the present invention, the structure is as shown in Formula VII or Formula VIII;

[0020] A is a radioactive nuclide, preferably... 68 Ga、 177 Lu、 225 Ac or 64 Cu.

[0021] In some embodiments of the present invention, the radiochemical purity is greater than or equal to 95%.

[0022] A third aspect of the present invention provides a method for preparing a precursor compound of a radiolabeled substance or a pharmaceutically acceptable salt thereof, wherein the precursor compound of the radiolabeled substance has the structure shown in Formula V, and the preparation method comprises the following steps: Step 1. Compound V-1 reacts with tetraethyl methylene diphosphate to form compound V-2; Step 2. Compound V-2 is reduced by PMHS under the catalysis of copper acetate to generate compound V-3; Step 3. Compound V-3 was hydrogenated under Raney Ni catalysis to give compound V-4; Step 4. Compound V-4 undergoes deethylation under the action of TMSBr to generate compound V-5; Step 5. Compound V-5 reacts with DOTA-tris(t-Bu)ester NHS ester to give compound V-6; Step 6. Compound V-6 undergoes detert-butylation under TFA to generate compound V; Its synthetic route is as follows:

[0023] When the structure of the precursor compound of the radiolabeled substance is as shown in Formula VI, its preparation method includes the following steps: S1. Compound VI-1 reacts with tetraethyl methylene diphosphate to form compound VI-2; S2. Compound VI-2 is reduced by PMHS under the catalysis of copper acetate to generate compound VI-3; S3. Compound VI-3 reacts with compound VI-3a under tetraphenylphosphine palladium / cuprous iodide catalysis to give compound VI-4; S4. Compound VI-4 was hydrogenated under Pd(OH)2 catalysis to give compound VI-5; S5. Compound VI-5 undergoes ethyl deacetylation under the action of TMSBr to generate compound VI-6; S6. Compound VI-6 reacts with DOTA-tris(t-Bu)ester NHS ester to give compound VI-7; S7. Compound VI-7 undergoes detert-butylation under TFA to generate compound VI; Its synthetic route is as follows:

[0025] The fourth aspect of the present invention provides a method for preparing a radiolabel or a pharmaceutically acceptable salt thereof, comprising the following steps: reacting the above-described compound of formula I with a solution of a radionuclide salt to obtain the radiolabel shown in formula II; Preferably, the radioactive nuclide is 68 Ga、 177 Lu or 64 In Cu, the solution of compound I in claim 1, sodium acetate solution and radioactive nuclide salt solution are mixed, the pH value of the mixed solution is adjusted, the reaction is carried out, the pH value is adjusted again, sterilized, filtered, and the radioactive label is obtained. Preferably, when the radionuclide is 225 During Ac, a solution of the compound of formula I in claim 1, a sodium citrate solution, a sodium ascorbate solution, and a radioactive nuclide salt solution are mixed, the pH value of the mixed solution is adjusted, the reaction is carried out, the pH value is adjusted again, sterilization is performed, and filtration is performed to obtain the radiolabeled substance.

[0026] In some embodiments of the present invention, when the radionuclide is 68 When Ga is added, 0.8-1.5 ml of 0.25 M sodium acetate solution is added to a solution of compound V or VI with a solute content of 25-50 μg, followed by the addition of a solution with an activity of 10 mCi. 68 Ga salt solution, mix; 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 reaction; the concentration of the compound formula V or VI 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 177 When adding Lu, add 0.08-0.15 ml of 0.5 M sodium acetate solution to a solution of compound V or VI with a solute content of 25-50 μg, followed by adding a solution with an activity of 20 mCi. 177 Lu salt solution, mixed; pH of the mixed solution adjusted to 4-7, preferably 5; reaction at 80-100℃, preferably 95℃; reaction time 10-30 min, preferably 15 min; pH adjusted to 5 after reaction; concentration of compound formula V or formula VI solution 1 mg / ml; 177 The concentration of Lu salt solution is 200 mCi / ml to 300 mCi / ml; When the radioactive nuclide is 225When adding Ac, add 0.3-0.5 ml of 0.1 M sodium ascorbate solution and 0.3-0.5 ml of 0.1 M sodium citrate solution to a solution of compound V or VI with a solute content of 25-50 μg, followed by the addition of 0.1 mCi. 225 Ac salt solution, mix; 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 reaction; the concentration of compound formula V or formula VI solution is 1 mg / ml; 225 The concentration of the Ac salt solution is 1 mCi / ml to 2 mCi / ml; When the radioactive nuclide is 64 When adding Cu, add 0.8-1.5 ml of 0.25 M sodium acetate solution to a solution of compound V or VI with a solute content of 25-50 μg, followed by the addition of a solution with an activity of 5 mCi. 64 Cu salt solution, mixed; pH of the mixed solution adjusted to 4-7, preferably 5; reaction at 80-100℃, preferably 95℃; reaction time 10-30 min, preferably 15 min; pH adjusted to 5 after reaction; concentration of compound formula V or formula VI solution 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml.

[0027] The fifth aspect of the present invention provides the use of the precursor compound of the above-mentioned radiolabeled substance or a pharmaceutically acceptable salt thereof in the preparation of a tumor imaging agent and / or tumor therapeutic agent targeting bone metastases; preferably, in the preparation of a medicament that targets bone metastases and has both imaging and therapeutic effects.

[0028] The sixth aspect of the present invention provides the use of the above-mentioned radiolabel or a pharmaceutically acceptable salt thereof in the preparation of tumor imaging agents and / or tumor therapeutic agents targeting bone metastases; preferably, in the preparation of medicaments targeting bone metastases that combine imaging and therapeutic effects.

[0029] Compared with the prior art, the present invention has the following beneficial effects: The method of this invention is simple and rationally designed. The radiolabel of this invention has good water solubility and excellent in vitro stability (at room temperature), and high plasma protein binding rate. Imaging and in vivo distribution experiments in mouse models show that the label has a significant and durable uptake effect on bone, demonstrating excellent targeting performance. It is a high-performance bone imaging agent and a radiopharmaceutical for the treatment of metastatic bone tumors.

[0030] The preparation method provided by the present invention 68 Ga、 177 Lu、225 Ac、 64 The Cu radiolabeling method has significant advantages such as simple operation, high labeling yield, short reaction time, and low precursor dosage (microgram level). Imaging results in tumor-bearing mice show that the present invention... 68 The uptake of Ga-labeled compounds VII and VIII at the lesion site was significantly higher than that of... 68 Ga-DOTA-ibandronic acid (patent publication number CN114230610 A) and 68 Ga-labeled ritidiadronate derivatives (patent publication number CN 116120367 A). Patient imaging further confirmed that, with 99m Tc-MDP and 68 Compared to Ga-DOTA-ibandronic acid, the compounds of this invention can detect more lesions and have a higher SUVmax value. These results demonstrate that this invention has unexpected technical effects and promising clinical application prospects.

[0031] The abbreviations corresponding to the names in this invention are: DPPBZ: 1,2-Bis(diphenylphosphine)benzene PMHS: Polymethylhydrosiloxane TMSBr: Trimethylbromosilane DIPEA: N,N-diisopropylethylamine DOTA-tris(t-Bu)ester NHS ester: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-tri-tert-butyl ester-succinimide ester DMF: N,N-dimethylformamide TFA: Trifluoroacetic acid. Attached Figure Description

[0032] Appendix Figure 1 For compound formula V 1 H-NMR spectrum; Appendix Figure 2 Here is the LC-MS chromatogram of compound V; Appendix Figure 3 For compound formula VI 1 H-NMR spectrum; Appendix Figure 4 Here is the LC-MS chromatogram of compound VI; Appendix Figure 5 for 68 TLC plot of Ga-labeled compound formula VII; Appendix Figure 6 for 177 TLC plot of Lu-labeled compound formula VII; Appendix Figure 7for 68 TLC image of Ga-labeled compound VIII; Appendix Figure 8 for 177 TLC diagram of Lu-labeled compound VIII; Appendix Figure 9 For example 4, tumor-bearing rats were injected via the tail vein. 68 PET / CT image of Ga-labeled compound formula VII Appendix Figure 10 The tumor-bearing rats in Experiment 4 were injected via the tail vein. 68 PET / CT images of Ga-labeled compound formula VIII. Appendix Figure 11 For example 4 177 Imaging of tumor-bearing mice with Lu-labeled compound formula VII Appendix Figure 12 For example 4 177 Imaging of tumor-bearing mice with Lu-labeled compound formula VIII. Appendix Figure 13 for 68 Comparison of Ga-labeled compound VIII and MDP imaging results (left image is MDP; the three small images in the right image are axial tomographic images of the patient's pelvis, from top to bottom: CT, PET, and PET / CT fusion images).

[0033] Appendix Figure 14 for 68 Comparison of imaging results of Ga-labeled compound VIII and DOTA-ibandronic acid (left image is DOTA-ibandronic acid). Detailed Implementation

[0034] 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.

[0035] Example 1 This embodiment discloses a method for preparing compound V, and its synthetic route is as follows:

[0036] Specifically: Step 1. At 0°C, TiCl4 (8.61 g, 45.4 mmol, 3 eq) and CCl4 (18.8 g, 122 mmol, 11.8 mL, 8.1 eq) were added sequentially to a dry 500 mL round-bottom flask. Tetrahydrofuran (90 mL) was added dropwise, followed by compound V-1 (2 g, 15.1 mmol, 1 eq) dissolved in tetrahydrofuran (10 mL) and tetraethyl methylene diphosphate (5.24 g, 18.1 mmol, 1.2 eq). While stirring, 4-methylmorpholine solution (6.43 g, 63.5 mmol, 4.2 eq) dissolved in tetrahydrofuran (11 mL) was added dropwise. After the addition was complete, the temperature was raised to 15°C and stirring was continued for 12 hours. Thin-layer chromatography (developing solvent: petroleum ether: ethyl acetate = 10:1) showed that compound V-1 was essentially reacted to completion. The reaction was quenched with ice water (500 mL) and extracted with ethyl acetate (250 mL × 3 times). The ethyl acetate phase was washed successively with saturated sodium bicarbonate solution (200 mL) and brine (100 mL), and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Purification by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate = 20:1 to 10:1) gave compound V-2 (1.05 g, 2.61 mmol, yield 17.2%) as a brown oil.

[0037] Step 2. Under nitrogen protection at 15°C, tert-butanol (539 mg, 7.27 mmol, 3 eq), Cu(OAc)2·H2O (48.1 mg, 241 μmol, 0.1 eq), and DPPBZ (86.6 mg, 194 μmol, 0.08 eq) were added to toluene (13 mL), and the mixture was stirred for 5 minutes. PMHS (2.42 mmol, 1.61 mL, 1 eq) was then added. The mixture was stirred for another 5 minutes, and compound V-2 (975 mg, 2.42 mmol, 1 eq) dissolved in toluene (4 mL) was added. The reaction mixture was stirred for another 18 hours. Thin-layer chromatography (developing solvent: ethyl acetate: methanol = 5:1) showed that the starting compound V-2 had been completely consumed. The reaction mixture was concentrated, and the residue was purified by preparative thin-layer chromatography (silica gel, developing solvent: ethyl acetate: methanol = 10:1) to obtain the crude product, a yellow oily compound V-3 (825 mg, 1.91 mmol, yield 78.9%).

[0038] Step 3. Under nitrogen protection, Raney Ni (1.45 g, 3.59 mmol, 1 eq) was added to an ethanol (30 mL) solution of compound V-3 (1.45 g, 3.59 mmol, 1 eq). A 25% ammonia solution (3.59 mmol, 3 mL, 1 eq) was added to the reaction solution at 20 °C. The suspension was degassed under vacuum and then repeatedly purged with hydrogen. The mixture was stirred at 50 °C for 3.5 hours under a hydrogen atmosphere (50 psi). Thin-layer chromatography (developing solvent: ethyl acetate: methanol = 5:1) showed that the starting compound V-3 had reacted completely. The mixture was filtered and concentrated to give a purple oily compound V-4 (1.47 g, 2.62 mmol, yield 72.9%).

[0039] Step 4. Compound V-4 (1.47 g, 2.62 mmol, 1 eq) was dissolved in dichloromethane (15 mL) at 20 °C. A solution of TMSBr (6.61 g, 43.2 mmol, 12 eq) in dichloromethane (7 mL) was added under nitrogen protection. The mixture was stirred at 20 °C for 18 hours under nitrogen protection. Thin-layer chromatography (developing solvent: ethyl acetate: methanol = 5:1) showed that compound V-4 had reacted completely. The solution was concentrated under reduced pressure to obtain a light green solid, which was then ground with pure water (1 mL) at 20 °C for 12 hours. The mixture was filtered, and the filtrate was dried at 45 °C to give a yellow solid compound V-5 (0.626 g, 2.11 mmol, yield 80.5%).

[0040] Step 5. Under nitrogen protection and at 20°C, compound V-5 (18.1 mg, 61.1 μmol, 1 eq) and DOTA-tris(t-Bu)ester NHS ester (40.9 mg, 61.1 μmol, 1 eq) were added to DMF (1 mL), and DIPEA (15.8 mg, 122 μmol, 2 eq) was added dropwise. The mixture was cooled to 0°C, and water (1 mL) was added to the reaction solution. The mixture was stirred under nitrogen protection and at 0-20°C for 12 hours. LC-MS analysis showed that compound V-5 had reacted completely. The reaction solution was concentrated by purging with nitrogen, and the residue was dissolved in water (7.50 mL) and acetonitrile (1.50 mL). After purification by preparative high performance liquid chromatography (neutral conditions), the residue was freeze-dried (column: Phenomenex luna C18 100×40 mm×3 μm; mobile phase: [water (containing 10 mM ammonium bicarbonate) - acetonitrile]; gradient: phase B (acetonitrile) increased from 20% to 50% within 12.0 min), yielding a yellow solid compound V-6 (11.4 mg, 13.2 μmol, yield 21.6%).

[0041] Step 6. Under nitrogen protection and at 25°C, compound V-6 (22.8 mg, 26.4 μmol, 1 eq) was dissolved in dichloromethane (4 mL) and cooled to 0°C. Trifluoroacetic acid (1.58 g, 13.9 mmol, 518 eq) was added dropwise to the reaction solution, and the mixture was stirred at 0–25°C for 16 hours. LC-MS analysis showed that compound V-6 had reacted completely. The solvent was removed by purging with nitrogen to obtain the crude product. The crude product was dissolved in pure water (10.0 mL) and freeze-dried to give a yellow oily compound V (12.8 mg, 18.4 μmol, yield 69.7%).

[0042] Compound VI 1 H-NMR and LC-MS images are attached. Figure 1 Appendix Figure 2 As shown.

[0043] Example 2 This embodiment discloses a method for synthesizing compound VI, and the synthetic route is as follows:

[0044] Specifically: Step 1. At 0°C, TiCl4 (6.12 g, 32.2 mmol, 3 eq) and CCl4 (13.3 g, 86.9 mmol, 11.8 mL, 8.1 eq) were added sequentially to a dry 500 mL round-bottom flask. Tetrahydrofuran (65 mL) was added dropwise, followed by compound VI-1 (2 g, 10.7 mmol, 1 eq) dissolved in tetrahydrofuran (8 mL) and tetraethyl methylene diphosphate (3.72 g, 12.9 mmol, 1.2 eq). While stirring, 4-methylmorpholine solution (4.57 g, 45.1 mmol, 4.2 eq) dissolved in tetrahydrofuran (11 mL) was added dropwise. After the addition was complete, the temperature was raised to 15°C and stirring was continued for 12 hours. Thin-layer chromatography (developing solvent: petroleum ether: ethyl acetate = 10:1) showed that compound VI-1 was essentially complete. The reaction was quenched with ice water (500 mL) and extracted with ethyl acetate (250 mL × 3 times). The ethyl acetate phase was washed successively with saturated sodium bicarbonate solution (200 mL) and brine (100 mL), and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Purification by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate = 50:1 to 30:1) gave a brown oily compound VI-2 (3.17 g, 6.95 mmol, yield 64.6%).

[0045] Step 2. Under nitrogen protection at 15°C, tert-butanol (1.55 g, 20.8 mmol, 3 eq), Cu(OAc)₂·H₂O (139 mg, 695 μmol, 0.1 eq), and DPPBZ (248 mg, 556 μmol, 0.08 eq) were added to toluene (42 mL), and the mixture was stirred for 5 minutes. Then, PMHS (6.95 mmol, 5.43 mL, 1 eq) was added. The mixture was stirred for another 5 minutes, and then compound V-2 (3.17 g, 6.95 mmol, 1 eq) dissolved in toluene (16 mL) was added. The reaction mixture was stirred for another 18 hours. Thin-layer chromatography (developing solvent: ethyl acetate: methanol = 5:1) showed that the starting compound V-2 had been completely consumed by the reaction. The reaction mixture was concentrated, and the residue was purified by preparative thin-layer chromatography (silica gel, developing solvent: ethyl acetate: methanol = 5:1) to obtain the crude product, which was then purified by acetonitrile to obtain compound VI-3 (1.49 g, 3.13 mmol, yield 45.0%).

[0046] Step 3. Under nitrogen protection, compound VI-3 (2.12 g, 4.63 mmol, 1 eq) was dissolved in 1,2-dimethoxyethane (22 mL) at 20 °C. Then, compound VI-3a (3.59 g, 23.1 mmol, 5 eq), CuI (159 mg, 833 μmol, 0.18 eq), sodium carbonate (1.47 g, 13.9 mmol, 3 eq) and Pd(PPh3)4 (267 mg, 231 μmol, 0.05 eq) were added sequentially, and the mixture was stirred at 85 °C for 6 hours. The filter cake was filtered, washed with ethyl acetate (EtOAc, 100 mL), concentrated, and the residue was purified by preparative high performance liquid chromatography (column: Welch Xtimate C18 250×70 mm×10 μm; mobile phase: [water (containing 10 mM ammonium bicarbonate)-acetonitrile]; gradient: phase B (acetonitrile) increased from 25% to 55% over 17.0 min) and then lyophilized to give a yellow oily compound VI-4 (1.63 g, 3.03 mmol, yield 65.4%).

[0047] Step 4. Under nitrogen protection, 10 wt% palladium hydroxide (4.24 g, 3.03 mmol, 1 eq) was added to an ethanol (41 mL) solution of compound VI-4 (1.63 g, 3.03 mmol, 1 eq). The mixture was degassed under vacuum, and then hydrogen was introduced and the reaction was repeated several times. The mixture was stirred at 50 °C for 2 hours under hydrogen (50 psi). LC-MS showed that compound VI-4 had reacted completely. The mixture was filtered, and the filtrate was concentrated at 40 °C to give a pale yellow oily compound VI-5 (1.50 g, 2.63 mmol, yield 85.8%).

[0048] Step 5. Under anhydrous conditions, compound VI-5 (500 mg, 932 μmol, 1 eq) in dichloromethane (5 mL) was added to a solution of TMSBr (1.71 g, 11.2 mmol, 12 eq) in dichloromethane (1 mL). The mixture was stirred at 20 °C for 12 hours under nitrogen protection. LC-MS showed that compound VI-5 had reacted completely. The mixture was concentrated under reduced pressure at 25 °C, and the residue was added to deionized water (50 mL) and filtered. The filtrate was freeze-dried to give compound VI-6 (590 mg, crude product, hydrobromide) as a brown oil.

[0049] Step 6. Under nitrogen protection and at 20°C, compound VI-6 (24.7 mg, 61.1 μmol, 1 eq) and DOTA-tris(t-Bu)ester NHS ester (40.9 mg, 61.1 μmol, 1 eq) were added to DMF (1 mL), and DIPEA (31.6 mg, 244 μmol, 4 eq) was added dropwise. The mixture was cooled to 0°C, and water (1 mL) was added to the reaction solution. The mixture was stirred under nitrogen protection and at 0-20°C for 16 hours. LC-MS analysis showed that compound VI-6 had reacted completely. The reaction solution was concentrated by purging with nitrogen, and the residue was dissolved in water (5 mL). After purification by preparative high performance liquid chromatography, the residue was freeze-dried (column: Waters XbridgePrep OBD C18 100*30*5; mobile phase: [water (containing 10 mM ammonium bicarbonate) - acetonitrile]; gradient: phase B (acetonitrile) increased from 20% to 50% within 12.0 minutes), yielding a yellow solid compound VI-7 (29.6 mg, 33.7 μmol, yield 55.1%).

[0050] Step 7. Under nitrogen protection and at 25°C, compound VI-7 (28.6 mg, 32.6 μmol, 1 eq) was dissolved in dichloromethane (4 mL) and cooled to 0°C. Trifluoroacetic acid (1.93 g, 16.9 mmol, 518 eq) was added dropwise to the reaction solution, and the mixture was stirred at 0–25°C for 16 hours. LC-MS analysis showed that compound VI-7 had reacted completely. The solvent was removed by purging with nitrogen to obtain the crude product. The crude product was dissolved in pure water (10.0 mL) and freeze-dried to give a yellow oily compound VI (10.11 mg, 13.4 μmol, yield 41.1%).

[0051] Compound VI 1 H-NMR and LC-MS images are attached. Figure 3 Appendix Figure 4 As shown.

[0052] Example 3 This embodiment discloses a method for preparing compound VII, which involves reacting compound V with a radioactive nuclide salt solution. The radioactive nuclides used in this embodiment are... 68 Ga、 177 Lu、 64 Cu and 64 Cu.

[0053] 1. Radioactive nuclides are 68 Ga Dissolve 30 μg of compound V in sterile water to prepare a solution with a concentration of 1 mg / mL. Add 1.0 mL of 0.25 M sodium acetate solution to this solution; then add 2 mL of a solution with an activity of 10 mCi. 68 GaCl3 hydrochloric acid solution was mixed thoroughly; the pH of the mixture was adjusted to 5, and the reaction was carried out at 95℃ for 15 min. After the reaction was completed, the pH of the product solution was adjusted to 5 to obtain the final product. 68 The TLC chromatogram of the Ga-labeled compound formula VII is attached. Figure 5 As shown.

[0054] 2. Radioactive nuclides are 177 Lu Dissolve 30 μg of compound V in sterile water to prepare a solution with a concentration of 1 mg / mL. Add 0.1 mL of 0.5 M sodium acetate solution to this solution; then add 0.1 mL of a solution with an activity of 20 mCi. 177 LuCl3 hydrochloride solution was mixed thoroughly; the pH of the mixture was adjusted to 5, and the reaction was carried out at 95℃ for 15 min. After the reaction was completed, the pH of the product solution was adjusted to 5 to obtain... 177 The TLC chromatogram of the Lu-labeled compound formula VII is attached. Figure 6 As shown.

[0055] 3. Radioactive nuclides are 225 Ac Dissolve 30 μg of compound V in sterile water to prepare a solution with a concentration of 1 mg / mL. Add 0.25 mL of 0.1 M sodium ascorbate solution and 0.25 mL of 0.1 M sodium citrate solution to this solution, followed by the addition of 0.1 mL of a solution with an activity of 0.1 mCi. 225 AcCl3 hydrochloric acid solution was mixed thoroughly; the pH of the mixture was adjusted to 5, and the reaction was carried out at 95℃ for 15 min; after the reaction was completed, the pH of the product solution was adjusted to 5 to obtain... 225 Compound VII marked with Ac.

[0056] 4. Radioactive nuclides are 64 Cu Dissolve 30 μg of compound V in sterile water to prepare a solution with a concentration of 1 mg / mL. Add 1.0 mL of 0.25 M sodium acetate solution to this solution, followed by 1 mL of a solution with an activity of 5 mCi. 64 A CuCl2 hydrochloric acid solution was mixed thoroughly; the pH of the mixture was adjusted to 5, and the reaction was carried out at 95°C for 15 minutes. After the reaction was completed, the pH of the product solution was adjusted to 5 to obtain... 64 The compound with Cu labelling is formula VII.

[0057] The radiochemical purity of compound formula VII in this embodiment is greater than or equal to 95%.

[0058] Example 4 This embodiment discloses a method for preparing compound VIII, which involves reacting compound VI with a radioactive nuclide salt solution. The radioactive nuclides used in this embodiment are... 68 Ga、 177 Lu、 64 Cu and 64 Cu.

[0059] 1. Radioactive nuclides are 68 Ga Dissolve 30 μg of compound VI in sterile water to prepare a solution with a concentration of 1 mg / mL. Add 1.0 mL of 0.25 M sodium acetate solution to this solution, followed by 2 mL of a solution with an activity of 10 mCi. 68 GaCl3 hydrochloric acid solution was mixed thoroughly; the pH of the mixture was adjusted to 5, and the reaction was carried out at 95℃ for 15 min. After the reaction was completed, the pH of the product solution was adjusted to 5 to obtain... 68 The TLC chromatogram of the Ga-labeled compound VIII is attached. Figure 7 As shown.

[0060] 2. Radioactive nuclides are 177 Lu Dissolve 30 μg of compound VI in sterile water to prepare a solution with a concentration of 1 mg / mL. Add 0.1 mL of 0.5 M sodium acetate solution to this solution, followed by 0.1 mL of a solution with an activity of 20 mCi. 177 LuCl3 hydrochloride solution was mixed thoroughly; the pH of the mixture was adjusted to 5, and the reaction was carried out at 95℃ for 15 min. After the reaction was completed, the pH of the product solution was adjusted to 5 to obtain... 177 The TLC chromatogram of the Lu-labeled compound VIII is attached. Figure 8 As shown.

[0061] 3. Radioactive nuclides are 225 Ac Dissolve 30 μg of compound VI in sterile water to prepare a solution with a concentration of 1 mg / mL. Add 0.25 mL of 0.1 M sodium ascorbate solution and 0.25 mL of 0.1 M sodium citrate solution to this solution, followed by the addition of 0.1 mL of a solution with an activity of 0.1 mCi. 225 Mix AcCl3 with hydrochloric acid solution until homogeneous; adjust the pH of the mixture to 5, and react at 95℃ for 15 min. After the reaction is complete, adjust the pH of the product solution to 5 to obtain... 225 The Ac-labeled compound is of formula VIII.

[0062] 4. Radioactive nuclides are 64 Cu Dissolve 30 μg of compound VI in sterile water to prepare a solution with a concentration of 1 mg / mL. Add 1.0 mL of 0.25 M sodium acetate solution to this solution, followed by 1 mL of a solution with an activity of 5 mCi. 64 A CuCl2 hydrochloric acid solution was mixed thoroughly; the pH of the mixture was adjusted to 5, and the reaction was carried out at 95°C for 15 minutes. After the reaction was completed, the pH of the product solution was adjusted to 5 to obtain... 64 The Cu-labeled compound is of formula VIII.

[0063] The radiochemical purity of compound VIII in this embodiment is greater than or equal to 95%.

[0064] The compounds VII or VIII used in Experimental Examples 1-4 were prepared according to the methods in Examples 3-4.

[0065] Experimental Example 1 This experimental example illustrates the invention. 68 Ga or 177 The in vitro stability test of Lu-labeled compound VII or compound VIII is performed as follows: Take two clean EP tubes and label them A and B respectively. Add 0.2 mL of physiological saline to tube A and 0.2 mL of fresh human serum (diluted 10 times) to tube B. Then add equal volumes of [unspecified substance] to tubes A and B respectively. 68 Ga or 177 Lu-labeled compounds (compound VII or compound VII). Tube A was placed at room temperature (26±2 °C); tube B was incubated in a metal bath at 37 °C.

[0066] for 68 The radiochemical purity of Ga-labeled compounds was determined by paper chromatography at time points of 30 min, 1 h, 2 h, and 4 h. 177The radiochemical purity of Lu-labeled compounds was determined by paper chromatography at time points of 1 h, 4 h, 24 h, 48 h, 72 h, 120 h, and 168 h. The results are shown in Tables 1 and 2.

[0067] Table 1. Different treatments and time periods 68 Radiochemical purity of Ga-labeled compound VII or compound VIII

[0068] Table 2. Different treatments and time periods 177 Radiochemical purity of Lu-labeled compound VII or compound VIII

[0069] As can be seen from Tables 1 and 2, 68 Ga or 177 Lu-labeled compounds VII or VIII exhibit good in vitro stability. 68 Ga marker placed for 4 hours and 177 The radiochemical purity of the Lu-labeled material remained >95% even after 168 hours of storage.

[0070] Experimental Example 2 This experimental example tested the invention. 68 Ga or 177 The lipid-water partition coefficient of compound VII or compound VIII is determined by labeling with Lu, and the specific steps are as follows: Take three clean centrifuge tubes and label them A, B, and C. Add the following to each centrifuge tube in sequence: 0.5 mL of n-octanol, 0.5 mL of sterile water for injection, and 0.5 mL of an appropriate dose of [unspecified ingredient]. 68 Ga / 177 Lu-labeled compounds (compound VII or compound VIII). An octanol-water two-phase system was formed in each tube for subsequent partition coefficient determination. The centrifuge tubes were shaken for 25 min, followed by centrifugation at 1800 r / min for 6 min. 0.1 mL of the upper organic phase was placed in corresponding numbered tubes a1, b1, and c1; 0.1 mL of the lower aqueous phase was placed in corresponding numbered tubes a2, b2, and c2. The experiment was repeated three times. A gamma counter was used to measure the radioactivity counts of the organic and aqueous phases in each tube, and the lipid-water distribution coefficients (logP) were calculated using the following formula.

[0071] LogP = log[(a1 radioactivity count - background radioactivity count) / (a2 radioactivity count - background radioactivity count)] Results are expressed as mean ± standard deviation. Experimental results show that the lipid-water partition coefficients of the markers are all less than -3.2, indicating good water solubility.

[0072] Table 3 68 Ga or 177 Lipid-water partition coefficient of Lu-labeled compound VII or compound VIII

[0073] Experimental Example 3 This experimental case was investigated using a tumor-bearing mouse model. 68 The in vivo distribution of Ga-labeled compounds VII or VIII was determined. The specific steps are as follows: 1. Establishment of a tumor-bearing mouse model SPF-grade female nude mice were anesthetized with isoflurane, and the skin around the right knee joint was disinfected. The right hind limb was flexed. A 1 mL sterile syringe was slowly inserted into the bone marrow cavity by rotation, and 20 μL (containing approximately 2 × 10⁻⁶ ppm) was injected. 6 4T1 (triple-negative breast cancer cells) cell culture medium was used. The cells were then carefully sterilized, placed on a 37°C hot plate for rewarming, and returned to their cages for continued rearing after recovery.

[0074] 2. Detection of tumor-bearing mouse model Seven to ten days after inoculation, each nude mouse was scanned using Micro-CT. Different degrees of bone destruction and soft tissue swelling were observed in each mouse, indicating successful establishment of the bone transfer model.

[0075] 3. In vivo distribution investigation Twelve mice with the 4T1 breast cancer tumor model were selected and injected with 3.7 MBq via the tail vein. 68 Ga-labeled mice were anesthetized and euthanized by decapitation at 30, 60, 120, and 240 minutes post-injection. n=3 mice were used at each time point. Heart, lung, liver, spleen, kidney, stomach, small intestine, muscle, contralateral tibia, brain, blood, salivary glands, and tumor (bone) samples were weighed and their radioactivity measured; the percentage of injection dose per gram of tissue (% ID / g) was calculated. The results are shown in Tables 4 and 5.

[0076] Table 4 68 Distribution of Ga-labeled compound VII in animals

[0077] Table 5 68 Distribution of Ga-labeled compound VIII in animals

[0078] As can be seen from Table 4, 68Ga-labeled compound VII showed high uptake in tumors, reaching 15.88% ID / g at 30 min, followed by a slow decline to 12.36% ID / g at 4 h. Uptake in the healthy tibia was stable (4.75-5.66% ID / g), consistently lower than in the tumor. Uptake in other major organs (such as the heart, liver, spleen, and lungs) was generally low (all below 1.5% ID / g), with moderate uptake in the kidneys (1.75-2.28% ID / g). Blood radioactivity was rapidly cleared (from 1.96% to 0.67% ID / g).

[0079] As can be seen from Table 5, 68 Ga-labeled compound VIII was uptaken more strongly in tumors, reaching 19.98% ID / g at 30 min and significantly increasing to 22.96% ID / g at 4 h; however, uptake in the healthy tibia fluctuated more significantly (9.45% ID / g at 30 min and 7.86% ID / g at 4 h); uptake in other organs was also lower, and blood clearance was faster (from 2.29% to 0.90% ID / g).

[0080] Test Example 4 This experimental example uses a parallel-controlled imaging method to compare the targeting performance of the markers of this invention with that of prior art compounds in a tumor-bearing mouse model. Specifically: I. Markings Used 1. Markings of this invention: 68 Ga-compound VII, 68 Ga - Compound VIII.

[0081] 2. Control markers: (1) 68 Ga-DOTA-ibandronic acid: prepared according to the method described in Example 2 of patent publication CN114230610 A, wherein the amount of DOTA-ibandronic acid used is 25 μg.

[0082] (2) 68 Ga-labeled ritidiodinic acid derivative: prepared according to the method described in Example 5 of patent publication CN 116120367 A. 68 Ga-labeled compound formula II 1.

[0083] II. Experimental Procedure The establishment and testing of the tumor-bearing mouse model were the same as in Experiment 3.

[0084] One successfully modeled tumor-bearing mouse was injected with a freshly prepared marker via the tail vein. Each 68 The Ga marker injection dose was approximately 0.2 mCi, and whole-body PET / CT imaging was performed at 30 min, 1 h, 2 h and 4 h after injection.

[0085] III. Imaging Results The results are attached. Figure 9 Appendix Figure 10 As shown in Table 6. The images show that the whole-body bone scintigraphy of each marker is relatively clear, the joints of the limbs are clearly visualized, and there is obvious uptake of the bone metastasis in the left knee joint.

[0086] Compared with control compound 68 Ga-DOTA-ibandronic acid and 68 Compared to Ga-labeled rithidrotic acid derivatives, the 68Ga-labeled compounds VII and VIII of this invention showed significantly higher uptake at the lesion site.

[0087] Table 6 Imaging results of tumor-bearing mice

[0088] Experimental Example 5 This experimental example discloses the present invention. 68 Ga-labeled compound VIII and existing technologies 99m Comparison of Tc-MDP imaging results in patients.

[0089] Patient Information: The patient, a 78-year-old male, was clinically diagnosed with prostate cancer with multiple bone metastases. He underwent treatment at the Affiliated Hospital of Southwest Medical University. 99m Tc-MDP whole-body bone scan and 68 PET / CT scan of Ga-labeled compound VIII.

[0090] Imaging procedure: The dosage of 68Ga-labeled compound VIII was determined based on the patient's weight (calculated at 0.05 mCi / kg). 68 Ga-labeled compound VIII was administered intravenously to the patient, who was instructed to drink plenty of water afterward. 100 minutes after administration, the patient emptied their bladder, and PET / CT images were acquired under the following conditions: tube voltage 120 kV, tube current 100 mA, and slice thickness 5.0 mm. The patient was in a supine position, and the acquisition range was from head to toe (whole-body scan), with the feet facing forward. A total of 10-11 images were acquired, with each image acquired for 120 seconds. After image acquisition, the images were processed using post-processing software.

[0091] The results are attached. Figure 13 As shown. The left image is... 99m Tc-MDP whole-body bone scan image, right image is... 68 PET / CT MIP images and pelvic tomographic images of Ga-labeled compound VIII. The images show that... 68 Ga-labeled compound VIII showed clear whole-body skeletal imaging, compared to... 99mCompared to Tc-MDP, it can detect more lesions.

[0092] Experimental Example 6 This experimental example discloses the present invention. 68 Ga-labeled compound VIII and 68 Comparison of imaging results of Ga-DOTA-ibandronic acid in patients.

[0093] 68Ga-DOTA-ibandronic acid was prepared according to the method described in Example 2 of patent publication CN114230610A, wherein the amount of DOTA-ibandronic acid used was 25 μg.

[0094] Patient Information: The patient is a 41-year-old female who underwent breast cancer surgery with bone metastasis. She received treatment at the Affiliated Hospital of Southwest Medical University. 68 Ga-DOTA-ibandronic acid and 68 PET / CT scan of Ga-labeled compound VIII.

[0095] Imaging process: Same as in Experiment 5.

[0096] The results are attached. Figure 14 As shown, the left figure is: 68 PET / CT MIP image of Ga-DOTA-ibandronic acid, SUVmax 13.3; Right image: 68 PET / CT MIP image of Ga-labeled compound VIII, SUVmax 16.8. The images show that the number of lesions detected in both methods is comparable, while... 68 The SUVmax value of Ga-labeled compound VIII is higher than that of... 68 Ga-DOTA-IBA. The results show that the present invention... 68 While maintaining lesion detection capabilities comparable to 68Ga-DOTA-ibandronic acid, Ga-labeled compound VIII's higher SUVmax value indicates stronger uptake signal in targeted imaging, resulting in superior affinity and imaging contrast.

[0097] 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 substance with the structure shown in Formula I, or a pharmaceutically acceptable salt thereof. ， in, R is H or OH; Linker is a flexible linking group that is attached to the 4, 5, or 6 position of the pyridine ring in the structure shown in Formula I.

2. The precursor compound of the radiolabeled substance according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Linker is selected from at least one of the following groups: alkylene groups represented by Formula III, polyethylene glycol segments or peptide chains represented by Formula IV; In Formula III, a is an integer from 1 to 9, more preferably an integer from 1 to 7; In Formula IV, b is an integer from 1 to 6, more preferably 2, 3 or 4.

3. The precursor compound of the radiolabeled substance according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, Its structure is shown in Equation V or Equation VI; 。 4. A radiolabeled substance as shown in Formula II or a pharmaceutically acceptable salt thereof, ， in, R is H or OH; Linker is a flexible linking group that is attached to the 4, 5, or 6 position of the pyridine ring in the structure shown in Formula II; Preferably, the Linker is selected from at least one of the following groups: alkylene groups represented by Formula III, polyethylene glycol segments or peptide chains represented by Formula IV; In Formula III, a is an integer from 1 to 9, more preferably an integer from 1 to 7; In Formula IV, b is an integer from 1 to 6, more preferably 2, 3 or 4; A is a radioactive nuclide, preferably... 68 Ga、 177 Lu、 225 Ac or 64 Cu.

5. The radiolabeled substance or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that, Its structure is shown in Equation VII or Equation VIII; The definition of A is the same as in claim 4.

6. The radiolabeled substance or a pharmaceutically acceptable salt thereof according to claim 4 or 5, characterized in that, Its radiochemical purity is greater than or equal to 95%.

7. A method for preparing a precursor compound of a radiolabeled substance or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, When the precursor compound of the radiolabeled substance has the structure shown in Formula V, its preparation method includes the following steps: Step 1. Compound V-1 reacts with tetraethyl methylene diphosphate to form compound V-2; Step 2. Compound V-2 is reduced by PMHS under the catalysis of copper acetate to generate compound V-3; Step 3. Compound V-3 was hydrogenated under Raney Ni catalysis to give compound V-4; Step 4. Compound V-4 undergoes ethyl deacetylation under the action of TMSBr to generate compound V-5; Step 5. Compound V-5 reacts with DOTA-tris(t-Bu)ester NHS ester to give compound V-6; Step 6. Compound V-6 undergoes detert-butylation under TFA to generate compound V; Its synthetic route is as follows: When the precursor compound of the radiolabeled substance has the structure shown in Formula VI, its preparation method includes the following steps: S1. Compound VI-1 reacts with tetraethyl methylene diphosphate to form compound VI-2; S2. Compound VI-2 is reduced by PMHS under the catalysis of copper acetate to generate compound VI-3; S3. Compound VI-3 reacts with compound VI-3a under tetraphenylphosphine palladium / cuprous iodide catalysis to give compound VI-4; S4. Compound VI-4 was hydrogenated under Pd(OH)2 catalysis to give compound VI-5; S5. Compound VI-5 undergoes ethyl desorption under the action of TMSBr to generate compound VI-6; S6. Compound VI-6 reacts with DOTA-tris(t-Bu)ester NHS ester to give compound VI-7; S7. Compound VI-7 undergoes detert-butylation under TFA to generate compound VI; Its synthetic route is as follows: 。 8. The method for preparing the radiolabeled substance or its pharmaceutically acceptable salt according to any one of claims 4-6, characterized in that, The process includes the following steps: reacting the compound of formula I according to claim 1 with a radioactive nuclide salt solution to obtain the radioactive labeling substance shown in formula II; Preferably, the radioactive nuclide is 68 Ga、 177 Lu or 64 In Cu, the solution of compound I in claim 1, sodium acetate solution and radioactive nuclide salt solution are mixed, the pH value of the mixed solution is adjusted, the reaction is carried out, the pH value is adjusted again, sterilized, filtered, and the radioactive label is obtained. Preferably, when the radionuclide is 225 During Ac, a solution of the compound of formula I in claim 1, a sodium citrate solution, a sodium ascorbate solution, and a radioactive nuclide salt solution are mixed, the pH value of the mixed solution is adjusted, the reaction is carried out, the pH value is adjusted again, sterilization is performed, and filtration is performed to obtain the radiolabeled substance.

9. The method for preparing radiolabeled substances according to claim 8, characterized in that, When the radioactive nuclide is 68 When Ga is added, 0.8-1.5 ml of 0.25 M sodium acetate solution is added to a solution of compound V or VI with a solute content of 25-50 μg, followed by the addition of a solution with an activity of 10 mCi. 68 Ga salt solution, mix; 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 reaction; the concentration of the compound formula V or VI 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 177 When adding Lu, add 0.08-0.15 ml of 0.5 M sodium acetate solution to a solution of compound V or VI with a solute content of 25-50 μg, followed by adding a solution with an activity of 20 mCi. 177 Lu salt solution, mixed; pH of the mixed solution adjusted to 4-7, preferably 5; reaction at 80-100℃, preferably 95℃; reaction time 10-30 min, preferably 15 min; pH adjusted to 5 after reaction; concentration of compound formula V or formula VI solution 1 mg / ml; 177 The concentration of Lu salt solution is 200 mCi / ml to 300 mCi / ml; When the radioactive nuclide is 225 When adding Ac, add 0.3-0.5 ml of 0.1 M sodium ascorbate solution and 0.3-0.5 ml of 0.1 M sodium citrate solution to a solution of compound V or VI with a solute content of 25-50 μg, followed by the addition of 0.1 mCi. 225 Ac salt solution, mix; 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 reaction; the concentration of compound formula V or formula VI solution is 1 mg / ml; 225 The concentration of the Ac salt solution is 1 mCi / ml to 2 mCi / ml; When the radioactive nuclide is 64 When adding Cu, add 0.8-1.5 ml of 0.25 M sodium acetate solution to a solution of compound V or VI with a solute content of 25-50 μg, followed by the addition of a solution with an activity of 5 mCi. 64 Cu salt solution, mixed; pH of the mixed solution adjusted to 4-7, preferably 5; reaction at 80-100℃, preferably 95℃; reaction time 10-30 min, preferably 15 min; pH adjusted to 5 after reaction; concentration of compound formula V or formula VI solution 1 mg / ml; 64 The concentration of the Cu salt solution is 5 mCi / ml to 10 mCi / ml.

10. The use of the precursor compound of the radiolabeled substance as claimed in claims 1-3 or a pharmaceutically acceptable salt thereof, or the use of the radiolabeled substance or a pharmaceutically acceptable salt thereof as claimed in any one of claims 4-6, characterized in that, Application in the preparation of tumor imaging agents and / or tumor therapeutic agents targeting bone metastases; Preferably, its application in the preparation of drugs that target bone metastases and combine imaging and therapeutic functions.

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