Nuclear medicine diagnosis and treatment medicine for targeted recognition of TSPO and application of nuclear medicine diagnosis and treatment medicine

Abstract

The invention belongs to the field of nuclear medicine diagnosis and treatment, and discloses a nuclear medicine diagnosis and treatment medicine for targeted recognition of TSPO and application of the nuclear medicine diagnosis and treatment medicine. The novel TSPO targeted recognition nuclear medicine diagnosis and treatment medicine can be chelated with nuclides with imaging and treatment functions, and diagnosis and treatment of TSPO high expression tumors (such as brain glioma), inflammation (such as osteoarthritis and myocardial infarction) and other diseases are achieved.

Description

Technical Field

[0001] This invention belongs to the field of nuclear medicine diagnosis and treatment, specifically relating to the preparation and application of a small molecule therapeutic drug targeting TSPO. Background Technology

[0002] TSPO (18kDa mitochondrial transporter) is a highly hydrophobic transmembrane protein, primarily located in the outer mitochondrial membrane and distributed in most peripheral organs, including the kidneys, nasal epithelium, adrenal glands, lungs, and heart. This protein participates in various cellular functions, including cholesterol transport, steroid hormone synthesis, mitochondrial respiration, permeability switching, pore opening, apoptosis, and cell proliferation. Depending on its specific function, changes in TSPO expression are associated with a variety of diseases, ranging from cancer to endocrine and neurological disorders. Therefore, TSPO has become a highly attractive subcellular target. In humans, TSPO expression levels are higher in various cancers, including breast cancer, prostate cancer, oral cancer, rectal cancer, liver cancer, and glioma, than in normal tissues. Previous studies have shown a positive correlation between TSPO protein expression and tumor malignancy, and a negative correlation with patient survival. TSPO expression is upregulated in various inflammation-related diseases and tumor tissues, making it a potential imaging and therapeutic target for inflammation-related diseases and tumors.

[0003] TSPO-targeting molecules can be used for imaging in tumors, inflammation, and cardiovascular diseases, with significant research focused on their detection in neuroinflammatory and tumor-related diseases. Early first-generation TSPO imaging agents... 11 C-(R)-PK11195 was initially used for the diagnosis of glioma patients, and later primarily for Alzheimer's disease imaging. However, its clinical application is limited due to low brain uptake, easy off-target effects, and short half-life (20 minutes). Currently, scientists have developed second- and third-generation targeted TSPO radiopharmaceuticals. One advantage of second-generation TSPO tracers is their affinity; Wilson et al. demonstrated this by using […] on rat mitochondrial membranes… 3 The affinity of FEPPA for TSPO was determined by competition with H]PK11195, and three other compounds with TSPO affinity were also tested. FEPPA was three times more potent than PBR28 and ten times more potent than DPA713 or the prototype PK 11195. However, the binding performance of second-generation TSPO tracers varied in different populations, possibly due to differences in TSPO expression levels among different disease groups. Third-generation TSPO tracers... 18 F-GE-180 (GE Healthcare) is a molecule containing a tricyclic indole nucleus of F-18. 18F-GE-180 showed high uptake in neuroinflammatory areas of preclinical models of middle cerebral artery occlusion and Alzheimer's disease, and low nonspecific binding in unaffected brain tissue. Besides tumor imaging, TSPO-targeted radiopharmaceuticals are also used for the diagnosis and treatment of cardiovascular diseases and osteoarthritis. Studies have shown that using radiotracers to target inflammatory lesions can maximize the efficiency of imaging detection of inflammatory sites. Endogenous synthetic TSPO ligands (PK11195 and 4-ClDzp) can affect normal cardiac energy supply and electrical activity stability. It has been reported that the development of various cardiovascular diseases can cause abnormal TSPO expression, such as myocardial infarction, myocarditis, arrhythmia, myocardial ischemia-reperfusion injury, atherosclerosis, and vasculitis. Therefore, TSPO can serve as a therapeutic and diagnostic target for cardiovascular diseases. Several TSPO tracers have been reported for imaging cardiac diseases, such as […]. 18 FDG, used for non-invasive observation of myocardial infarction in its early stages, has been approved by the FDA for myocardial viability imaging. However, its drawback is poor specificity, with high uptake observed in normal tissues (such as the brain). Reported PET imaging agents specifically targeting TSPO include […]. 11 C]PK11195,[ 11 C]PBR28,[ 18 F]PBR06,[ 18 F]GE180, where, [ 11 C]PK11195 has been used for human carotid artery atherosclerotic plaque imaging, while [ 18 [F]GE180 showed high uptake at the lesion site in a mouse model of myocardial infarction. For osteoarthritis, studies have confirmed the presence of inflammatory responses in the synovium of osteoarthritis patients, and the severity of synovitis is closely related to the severity and progression of osteoarthritis. Macrophages are the main inflammatory cells in diseased synovial tissue, and their secreted pro-inflammatory factors and cartilage matrix degrading enzymes are important factors aggravating osteoarthritis and accelerating joint degeneration. Due to increased expression of M1 macrophages in synovial tissue, tissue inflammation develops. Currently, several imaging agents for osteoarthritis have been reported, such as […]. 99m Tc]EC20,[ 11 C]PBR28. 11 C]PBR28 has been reported for use in the detection of early inflammatory arthritis using PET, and significant uptake has been observed at osteoarthritis sites. This demonstrates that TSPO is overexpressed in a variety of diseases and can serve as a target for the diagnosis of multiple diseases, enabling early diagnosis and timely treatment.

[0004] Currently, most molecular imaging probes targeting TSPO are... 18 F and 11 C-labeled small molecule PET imaging, such as: 18F-FEDAC, etc. But 18 F labeling is difficult, so it is of great significance to develop a nuclear medicine probe that is easy to label and applicable to multiple nuclide labeling capabilities for the diagnosis and treatment of tumors and inflammation.

[0005] To this end, we designed and synthesized a series of TSPO molecules with DOTA-modified side chains, and verified the uptake of TSPO-targeting molecules linked to chelating agents in osteoarthritis, myocardial infarction, and glioma. We analyzed labeling conditions, drug stability, cell binding assays, in vivo PET imaging, and in vitro distribution studies to evaluate the efficacy of these drugs. 68 Ga-DOTA-HK-002, 68 Ga / 177 Lu-DOTA-HK-011, 68 Ga / 177 Lu-DOTA-HK-013, 68 The efficacy of Ga-DOTA-HK-015 in TSPO imaging and treatment demonstrates the effectiveness of TSPO probes linked to chelating agents. 68 Ga-DOTA-HKs exhibit good imaging performance against tumor cells and osteoarthritis tissues, while showing low uptake in normal tissues. Furthermore, the novel [Gadot-HKs] have been demonstrated in a mouse model of myocardial infarction. 177 Lu-DOTA-HKs have significant therapeutic effects on cardiovascular diseases. Summary of the Invention

[0006] The purpose of this invention is to provide a nuclear medicine therapeutic agent that targets TSPO and its application. TSPO is expressed at low levels in normal tissues but at high levels in tumor and inflamed tissues. Developing nuclear medicine therapeutic agents that target TSPO is of great significance for the early detection and effective treatment of diseases. Based on the chemical structural characteristics of clinically used F-18-labeled small molecule drugs targeting TSPO, this invention constructs four drugs that specifically bind to TSPO through end-cap modifications. 68 Ga / 177 Novel Lu-labeled radiopharmaceuticals can be used for the diagnosis and treatment of diseases such as tumors and inflammation, achieving the goal of early diagnosis and treatment.

[0007] To achieve the above objectives, the present invention provides the following solution:

[0008] This invention provides a nuclear medicine therapeutic drug marker precursor that targets and identifies TSPO, characterized in that the precursor has a structure of GX-X'-R, wherein X and X' are connecting arms, and R is a chelating agent, and its molecular structure is as follows:

[0009]

[0010] The X-connector arm is selected from one of the following structures:

[0011]

[0012] Where n is an integer between 0 and 5;

[0013] Y can be carbon, nitrogen, oxygen, sulfur, phosphorus or their oxides and salts, Y is attached to phenyloxyethyl, and the preferred structure of Y is oxygen.

[0014] The X' connecting arm is selected from one of the following structures:

[0015]

[0016] Where n is an integer between 0 and 5;

[0017] Y' can be carbon, nitrogen, oxygen, sulfur, phosphorus or their oxides and salts, Y' is linked to chelating agent R, and the preferred structure of Y' is oxygen.

[0018] The present invention discloses a nuclear medicine diagnostic and therapeutic drug marker precursor for targeted recognition of TSPO, characterized in that the chelating agent is at least one selected from DOTA, NOTA, NODAGA, DOTAGA, DFO, DTPA, DOTAM, and DiAmSar, with DOTA being the preferred chelating agent.

[0019] The nuclear medicine therapeutic drug marker precursor for targeted recognition of TSPO described in this invention is characterized by the following structure:

[0020]

[0021] This invention also provides a nuclear medicine therapeutic agent targeting TSPO, wherein the radiopharmaceutical is obtained by chelating the above-mentioned labeled precursor with a radionuclide, the radionuclide being selected from... 64 Cu、 67 Cu、 68 Ga、 18 F, 177 Lu、 90 Y、 89 Zr、 99m Tc, 89 Sr、 212 Pb or 225 Ac, the preferred radionuclide is 68 Ga and 177 Lu.

[0022] This invention provides the application of nuclear medicine diagnostic and therapeutic agents that target TSPO in the preparation of reagents, drugs, and / or drug combinations for the diagnosis and / or treatment of tumors highly expressing TSPO. The tumors highly expressing TSPO include gliomas, pancreatic cancer, lung cancer, liver cancer, thyroid cancer, thymoma, cervical cancer, colonic adenocarcinoma, prostate cancer, rectal adenocarcinoma, sarcoma, melanoma, and lymphoma. Gliomas are preferred.

[0023] This invention provides the application of a nuclear medicine diagnostic and therapeutic drug that targets and identifies TSPO in the preparation of reagents, drugs, and / or drug combinations for the diagnosis and / or treatment of inflammatory diseases that highly express TSPO, wherein the inflammatory diseases that highly express TSPO include cerebral inflammation, osteoarthritis, myocardial infarction, and myocarditis, with osteoarthritis and myocardial infarction being preferred inflammatory diseases.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] This invention is scientifically designed and ingeniously conceived. It creatively links the bifunctional chelator DOTA with a small-molecule TSPO inhibitor, synthesizing a labeled precursor of a nuclear medicine probe targeting TSPO in brain tumors, as shown in Formula I. This precursor compound, after being labeled with a radionuclide, yields a compound of general formula II, exhibiting good stability, excellent pharmacokinetics, high specificity for binding to tumor TSPO, and is easily synthesized. This precursor can specifically bind to cells with high TSPO expression (such as tumor cells, inflammatory macrophages, etc.), and through chelation with radioactive diagnostic radionuclides, novel radiopharmaceuticals for disease diagnosis and treatment can be obtained. Most reported TSPO-targeting radioactive small molecules are... 11 C and 18 The innovation of this invention lies in the discovery of a novel TSPO-targeted radiopharmaceutical labeling precursor molecule, which can achieve F-labeling. 68 Ga, 177 Lu, 64 Using multiple radionuclides such as Cu to label TSPO will further enrich TSPO-targeted radiotherapies and help develop diagnostic and therapeutic drugs for diseases with high TSPO expression. Attached Figure Description

[0026] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0027] Figure 1 Synthetic routes for labeled precursor compounds;

[0028] Figure 2The 1H and 1C NMR spectra of the key intermediate 11;

[0029] Figure 3 The 1H and 1C NMR spectra of intermediate 13;

[0030] Figure 4 The 1H and 1C NMR spectra of intermediate 14;

[0031] Figure 5 HPLC and mass spectrometry for DOTA-HK-002;

[0032] Figure 6 HPLC and mass spectrometry for DOTA-HK-011;

[0033] Figure 7 HPLC and mass spectrometry of DOTA-HK-013;

[0034] Figure 8 HPLC and mass spectrometry for DOTA-HK-015;

[0035] Figure 9 for 68 Ga-DOTA-HK-002, 68 Ga-DOTA-HK-011, 68 Ga-DOTA-HK-013, 68 Radio-HPLC analysis of Ga-DOTA-HK-015;

[0036] Figure 10 for 68 Ga-DOTA-HK-002, 68 Ga-DOTA-HK-011, 68 Ga-DOTA-HK-013, 68 Radiolabeling data of Ga-DOTA-HK-015 and binding affinity data of TSPO-overexpressing cells;

[0037] Figure 11 for 68 Ga-DOTA-HK-002, 68 Ga-DOTA-HK-011, 68 Ga-DOTA-HK-013, 68 Stability of Ga-DOTA-HK-015 in blood and urine of mice;

[0038] Figure 12 for 177 Lu-DOTA-HK-011, 177 Radio-HPLC analysis of Lu-DOTA-HK-013;

[0039] Figure 13 for 177 Lu-DOTA-HK-011, 177 Radiolabeling data for Lu-DOTA-HK-013;

[0040] Figure 14 for 68 Ga-DOTA-HK-002, 68 Ga-DOTA-HK-011, 68 Ga-DOTA-HK-013, 68 PET / CT imaging results of Ga-DOTA-HK-015 in situ glioma;

[0041] Figure 15 for 68 Ga-DOTA-HK-002, 68 Ga-DOTA-HK-011, 68 Ga-DOTA-HK-013, 68 Imaging results in a mouse model of osteoarthritis using Ga-DOTA-HK-015;

[0042] Figure 16 for 68 Ga / 177 Imaging / treatment results of Lu-DOTA-HK-013 in a mouse model of myocardial infarction. Detailed Implementation

[0043] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0044] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0045] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0046] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0047] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0048] The test methods involved in the following embodiments and comparative examples are as follows:

[0049] In this invention 177 Lu was purchased through commercial channels; the radionuclide purity is 98%. 68 Ga by 68 Ge / 68 Ga was obtained by rinsing with hydrochloric acid. All radiometric high-performance liquid chromatography (Radio-HPLC) analyses were performed using an HPLC system.

[0050] The method for synthesizing the TSPO therapeutic drug according to the present invention includes the following steps:

[0051] The reaction route is attached. Figure 1 As shown, compound 10 was synthesized according to the literature method, and ethylene glycol linker arms of different lengths were introduced through azidation modification and click reaction, and then coupled with DOTA to generate novel therapeutic drugs DOTA-HK-002, DOTA-HK-011, DOTA-HK-013, and DOTA-HK-015.

[0052] Example 1

[0053] This embodiment discloses the synthesis of DOTA-HK-002, DOTA-HK-011, DOTA-HK-013, and DOTA-HK-015. The synthesis method of the intermediates is as follows:

[0054] Synthesis method of compound 3

[0055] Compound 1 (152 mg, 1 mmol) was dissolved in 4 mL of DMF, and compound 2 (229 mg, 1.1 mmol) and Cs2CO3 (423 mg, 1.3 mmol) were added. The mixture was reacted at 70 °C for 8 h. After the reaction was completed, the mixture was extracted with DCM and water, the organic phase was evaporated to dryness, and separated by silica gel column chromatography (PE:EA = 3:1) to obtain compound 3 in 65% yield.

[0056] Synthesis method of compound 6

[0057] Compound 4 (52.5 mg, 0.42 mmol) and compound 5 (79.6 mg, 0.5 mmol) were dissolved in 5 ml of DMF, and Na2CO3 (106 mg, 1 mmol) was added. The mixture was reacted at 100 °C for 14 h. After the reaction was completed, the reaction solution was poured into water to precipitate the product. The product was filtered and dried to obtain compound 6 with a yield of 98%.

[0058] Synthesis method of compound 7

[0059] Compound 6 (98.4 mg, 0.4 mmol) was dissolved in 2 mL of DCM, and 1.0 mL of glacial acetic acid and zinc powder (128 mg, 2.0 mmol) were added. The mixture was reacted at 20 °C for 10 h. After the reaction was complete, the mixture was extracted separately with DCM using a saturated NaHCO3 aqueous solution. The organic phase was evaporated to dryness and separated by silica gel column chromatography (PE; EA = 3:1) to give compound 7. The yield was 33%.

[0060] Synthesis method of compound 8

[0061] Compound 7 (28 mg, 0.13 mmol) was dissolved in 2 ml DCM, and 1.5 ml glacial acetic acid and compound 3 (36.4 mg, 0.13 mmol) were added. Finally, NaBH(OAc)3 (0.195 mmol) was added, and the mixture was reacted at 20 °C for 2 h. After the reaction was completed, water was added for extraction, the organic phase was collected, dried, filtered, and evaporated under reduced pressure. The mixture was then purified by silica gel column chromatography (PE:EA = 10:1) to give compound 8 in 85% yield.

[0062] Synthesis method of compound 9

[0063] Compound 8 (52.8 mg, 0.11 mmol) was dissolved in 5 mL of acetic acid, and acetic anhydride (17 mg, 0.165 mmol) was added. The mixture was stirred and refluxed at 75 °C for 20 min. After the reaction was complete, the mixture was extracted with saturated NaHCO3 aqueous solution, and the organic phase was evaporated to dryness to give crude compound 9. Compound 9 was then separated by silica gel column chromatography (PE:EA = 2:1) to obtain compound 9 in 40% yield.

[0064] Synthesis method of compound 10

[0065] Compound 9 (24 mg, 0.1 mmol) was dissolved in 3 ml of DCM, and TEA (10 mg, 0.1 mmol) and MsCl (11.4 mg, 0.1 mmol) were added. The mixture was reacted at 20 °C for 1 h. After the reaction was completed, the mixture was evaporated to dryness, and water and DCM were added for extraction. The mixture was separated by silica gel column chromatography (PE:EA = 1:1) to obtain compound 10, with a yield of 75%.

[0066] Synthesis method of compound 11

[0067] 2-Azidoethanol (13 mg, 0.15 mmol) was dissolved in 3 mL of anhydrous DMF, and NaH (18 mg, 0.75 mmol) was added and stirred for 5 min. Then, 2 mL of anhydrous DMF solution containing compound 10 (57 mg, 0.11 mmol) was added, and the reaction was carried out at 20 °C for 6 h. After the reaction was completed, water was added to quench the reaction, and DCM was added for liquid-liquid extraction. The organic phase was evaporated to dryness. Compound 11 was obtained by silica gel column chromatography (PE:EA = 1:1), with a yield of 17.4%.

[0068] Synthetic methods of compounds 12-15

[0069] Compound 11 (2.4 mg, 0.005 mmol) and different PEG chain alkynyl compounds (0.01 mmol) were dissolved in DMF and TBTA (0.27 mg, 0.0005 mmol) were added. CuSO4(5H2O) (1.25 mg, 0.005 mmol) and sodium ascorbate (1 mg, 0.001 mmol) aqueous solution were added sequentially. The reaction was carried out at room temperature for 20 min. After the reaction was completed, the supernatant was collected by centrifugation, filtered, and purified by HPLC to obtain compounds 12-15.

[0070] Synthesis method of compound DOTA-HK-002

[0071] DOTA (3.5 mg, 0.0086 mmol) and N-hydroxythiosuccinimide (2.2 mg, 0.0086 mmol) were dissolved in 2 mL of water, and the pH was adjusted to 6.5. EDCI (1.6 mg, 0.0086 mmol) was added, and the reaction was carried out at 4 °C for 30 min. Compound 12 (2.6 mg, 0.0043 mmol) was added, and the pH was adjusted to 7-8. The reaction was carried out at 20 °C for 16 h. After the reaction was completed, compound DOTA-HK-002 was obtained by separation and purification by HPLC, with a yield of 20%. The synthesis methods of DOTA-HK-011, DOTA-HK-013 and DOTA-HK-015 are the same as those of DOTA-HK-002.

[0072] Example 2

[0073] This embodiment discloses a compound of formula II. 68Ga-DOTA-HK-002, 68 Ga-DOTA-HK-011, 68 Ga-DOTA-HK-013, 68 The specific steps to synthesize Ga-DOTA-HK-015 are as follows:

[0074] Take 5 mL of 0.05 mol / L HCl solution and slowly inject it into the germanium-gallium generator for rinsing. When about 1.5 mL of rinsing solution has been discharged, start collecting the leaching liquid. Add an aliquot of 10 μg of DOTA-HK-002 dissolved in 500 μL sodium acetate buffer (0.25 mol / L) to 185 MBq (5 mCi). 68 GaCl3 was added to 2 mL of 0.05 mol / L HCl. The solution was vortexed for 10 seconds and then incubated in a preheated metal bath at 100 °C for 10 min. Finally, the mixture was cooled to room temperature, and the radiochemical purity of the product was determined by radio-HPLC to be greater than 99%. Flow time: 15 min, acetonitrile: 0% to 100%; flow rate: 1.0 mL / min.

[0075] 68 Ga-DOTA-HK-011, 68 Ga-DOTA-HK-013 and 68 The synthesis of Ga-DOTA-HK-015 is the same as the synthesis method described above, and its Radio-HPLC results are as follows: Figure 9 , tag data such as Figure 10 As shown.

[0076] Example 3

[0077] This embodiment discloses 68 Ga-DOTA-HK-002, 68 Ga-DOTA-HK-011, 68 Ga-DOTA-HK-013, 68 In vivo hematuria drug stability of Ga-DOTA-HK-015 in mice.

[0078] Mice were injected with 37 MBq (1 mCi) 68 Ga-DOTA-HK-002, 68 Ga-DOTA-HK-011, 68 Ga-DOTA-HK-013, 68 Two hours after ingestion of Ga-DOTA-HK-015 mice, urine was collected via bladder compression and blood was collected via orbital sampling. Mice were euthanized by cervical dislocation after blood and urine collection. Proteins in the blood and urine were precipitated using acetonitrile, and the supernatant was collected after centrifugation. The radiochemical stability of the products was then analyzed by Radio-HPLC. Figure 11 The results showed that the four drugs had good stability. Flow time: 15 min; acetonitrile: 0% to 100%; flow rate: 1.0 mL / min.

[0079] Example 4

[0080] This embodiment discloses 177 Lu-DOTA-HK-002, 177 Lu-DOTA-HK-011, 177 Lu-DOTA-HK-013, 177 The synthesis of Lu-DOTA-HK-015 is as follows:

[0081] Add an aliquot of 10 μg DOTA-HK-002 dissolved in 1 ml of sodium acetate buffer (0.25 mol / L) to 185 MBq (5 mCi). 177 LuCl3 was added to 4 mL of 0.05 mol / L HCl. The solution was vortexed for 10 s and then incubated in a preheated metal bath at 100 °C for 10 min. Finally, the mixture was cooled to room temperature, and the radiochemical purity of the product was determined by Radio-HPLC to be greater than 99%. Flow time: 15 min, acetonitrile from 0% to 100%; flow rate: 1.0 mL / min.

[0082] 177 Lu-DOTA-HK-011, 177 Lu-DOTA-HK-013 and 177 The synthesis of Lu-DOTA-HK-015 is the same as the method described above. Its Radio-HPLC results are as follows: Figure 12 , tag data such as Figure 13 As shown.

[0083] Example 5

[0084] This embodiment discloses the imaging effect of a novel TSPO probe in gliomas.

[0085] In mice with orthotopic brain tumors (U87MG), via tail vein injection 68 Ga-DOTA-HK-002, 68 Ga-DOTA-HK-011, 68 Ga-DOTA-HK-013, 68 Ga-DOTA-HK-015 was used to perform PET / CT imaging on mice. In this embodiment, it was found that... 68 Ga-DOTA-HK-002, 68 Ga-DOTA-HK-011, 68Ga-DOTA-HK-013 and 68 Ga-DOTA-HK-015 can selectively accumulate in areas of glioma and provide reliable imaging results 30 minutes after probe injection. Figure 14 A). At 30 minutes, the four probes showed high tumor / tissue ratios ( Figure 14 B) demonstrated its specificity in targeting tumor tissue in vivo. Imaging parameters were 80 kV, 100 mA S, and 0.32 s / revolution.

[0086] Example 6

[0087] This embodiment discloses probe-based in vivo animal imaging and its diagnostic efficacy in osteoarthritis.

[0088] Experimental data showed that pathological sections of patients with clinical osteoarthritis showed positive expression of TSPO. Figure 15 A) TSPO expression in an inflammation-induced model of chondrocytes was detected, and protein imprinting expression analysis confirmed the heterogeneity of TSPO expression between normal and inflamed chondrocytes. Figure 15 B). In rats with osteoarthritis, PET / CT imaging was performed using probes. In this embodiment, probes DOTA-HK-002, DOTA-HK-011, DOTA-HK-013, and DOTA-HK-015 were found to selectively accumulate in the inflammatory areas of osteoarthritis, demonstrating their potential as diagnostic probes for osteoarthritis. Figure 15 C). Imaging parameters were 80kV, 100mA S, and 0.32s / revolution.

[0089] Example 7

[0090] This embodiment discloses 177 In vivo animal imaging and therapeutic effects of Lu-DOTA-HK-013.

[0091] After myocardial infarction modeling in mice, Western blot analysis showed high expression of TSPO protein at 5 and 28 days after the infarction modeling. Figure 16 A). On day 28, the time of film formation in myocardial infarction, pathological section results revealed high expression of TSPO in the myocardial infarction. Figure 16 B). In this embodiment, DOTA-HK-013 plays a role in early diagnosis and disease treatment as a therapeutic agent. On day 5 of high TSPO expression, 68 Ga-DOTA-HK-013 exhibits specific uptake at the site of myocardial infarction lesions. Figure 16 C,16D), demonstrating its specific targeting in vivo. 177After 28 days of treatment with Lu-DOTA-HK-013, the area of ​​myocardial infarction in WT MI further decreased. Figure 16 E). The results of this embodiment indicate that, 177 The Lu-DOTA-HK-013 imaging system targets the preoperative window period, creating favorable conditions for targeted therapy and helping to address the challenges in treating myocardial infarction patients. Imaging parameters are 80kV, 100mA S, and 0.32s / revolution.

[0092] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A nuclear medicine therapeutic drug marker precursor that targets and identifies TSPO, characterized in that, The structure of the precursor is G-X-X'-R, wherein X, X' is a connecting arm, and R is a chelating agent, and the molecular structure is as follows: The X connecting arm is selected from one of the following structures: n is an integer of 0-5; Y can be carbon, nitrogen, oxygen, sulfur, phosphorus or its oxide and salt, and Y is connected with phenyloxyethyl; The X' connecting arm is selected from one of the following structures: n is an integer of 0-5; Y' can be carbon, nitrogen, oxygen, sulfur, phosphorus or its oxide and salt, and Y' is connected with the chelating agent R.

2. The nuclear medical diagnosis and therapy drug marker precursor for targeting recognition of TSPO according to claim 1, characterized in that, The chelating agent is at least one of DOTA, NOTA, NODAGA, DOTAGA, DFO, DTPA, DOTAM, DiAmSar.

3. The nuclear medical theranostic drug marker precursor targeting recognition TSPO according to claim 1, characterized in that, The structure is as follows:

4. A nuclear medicine therapeutic agent that targets and identifies TSPO, characterized in that, Said radiodiagnostic and radiotherapeutic agent is obtained by chelating the labeling precursor of claim 1 with a radionuclide selected from 64 Cu, 67 Cu, 68 Ga, 18 F, 177 Lu, 90 Y, 89 Zr, 99m Tc, 89 Sr, 212 Pb or 225 Ac.

5. The use of the nuclear medicine diagnosis and treatment drug for targeting and recognizing TSPO according to claim 4 in the preparation of reagents, drugs and / or drug combinations for diagnosing and / or treating tumors with high expression of TSPO.

6. Use according to claim 5, wherein, The tumors with high expression of TSPO include brain glioma, pancreatic cancer, lung cancer, liver cancer, thyroid cancer, thymoma, cervical cancer, colon adenocarcinoma, prostate cancer, rectal adenocarcinoma, sarcoma, melanoma, lymphoma.

7. The use of the nuclear medicine diagnosis and treatment drug for targeting and recognizing TSPO according to claim 4 in the preparation of reagents, drugs and / or drug combinations for diagnosing and / or treating inflammatory diseases with high expression of TSPO.

8. Use according to claim 7, characterized in that, The inflammatory diseases with high expression of TSPO include brain inflammation, osteoarthritis, myocardial infarction, myocarditis.

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