Radionuclide-labeled glucose derivative molecular probe and application thereof

Abstract

The invention relates to a radionuclide-labeled glucose derivative molecular probe and application thereof, and belongs to the technical field of nuclear medicine. According to the present invention, propargyl glycine is used to synthesize an amino acid skeleton, and the amino acid skeleton reacts with glucose azide to prepare a series of radionuclide-labeled glucose derivative molecular probes, such as [68Ga] Ga-NOTA-SDG, [68Ga] Ga-NOTA-DDG, [68Ga] Ga-NOTA-TDG, [68Ga] Ga-DOTA-SDG, [68Ga] Ga-DOTA-DDG and the like; the glucose derivative molecular probe labeled by the series of radionuclides has the advantages of being simple and rapid in labeling, high in radiolabeling yield and good in stability, can accurately position tumors, has good tumor uptake and lower non-target tissue uptake, and has great application prospects in preparation of broad-spectrum tumor imaging agents.

Description

Technical Field

[0001] The present invention relates to a radioactive nuclide-labeled glucose derivative molecular probe and its application, belonging to the technical field of nuclear medicine. Background Art

[0002] In recent years, with the rapid development of molecular imaging in the field of tumor diagnosis, it focuses on achieving specific visualization of lesions by applying imaging agents (IAs) in various imaging modalities. Positron emission tomography (PET) is a diagnostic tool that uses positron-emitting radionuclides to visualize lesions at multiple levels, providing high resolution and significantly improving the accuracy of tumor diagnosis. Currently, PET imaging has become a major test method for tumor diagnosis. The overexpression of glucose transporters (GLUTs) and the Warburg effect in most cancer cells have catalyzed extensive research on glucose imaging agents. Among them, 2- 18 F]fluoro-2-deoxy-D-glucose( 18 F-FDG) has become the most successful broad-spectrum tumor PET imaging agent and is widely used in clinical diagnosis.

[0003] However, at the present stage, 18 the use of F-FDG in clinical practice is still restricted by many factors. For example, 18 the synthesis of F-FDG requires the use of a cyclotron to produce fluorine-18. And, 18 the production of F-FDG involves multiple steps, including azeotropic distillation, nucleophilic substitution, deprotection and purification, which makes the process relatively complex and time-consuming, thus restricting its widespread use in most hospitals. In addition, 18 F-FDG will be absorbed by tissues and organs with high glucose metabolism such as the brain and heart, making it difficult to distinguish tumors from normal tissues and organs. In this case, selecting a favorable radionuclide is crucial for the development of broad-spectrum tumor PET imaging agents targeting glucose transporters.

[0004] Gallium-68( 68 Ga) is a promising radioisotope with a good half-life (68 minutes), which is produced by 68 Ge / 68 Ga generator and does not require an accelerator, and can be obtained simply by eluting with hydrochloric acid. At the same time, the process of labeling compounds with 68 Ga is very simple. Currently, there have been research reports on 68 Ga-labeled glucose derivative PET molecular probes targeting glucose transporters, including 68 Ga-DOTA-DG and 68 Ga-ECG. Compared with 18Compared with F-FDG probe, the problem of nonspecific uptake of these two probes still exists, e.g. 68 The uptake of Ga-DOTA-DG in the lungs was higher than that in the tumors. 68 The uptake of Ga-ECG in the liver and lungs is higher than that in tumors. Therefore, it is urgent to develop targeted glucose transporters with lower nonspecific uptake. 68 Ga-labeled molecular probes can overcome the defects of existing broad-spectrum tumor PET imaging agents, thereby providing a basis for the development of more effective tumor diagnosis and efficacy evaluation tools. Summary of the Invention

[0005] To solve the above problems, the present invention provides a radionuclide-labeled glucose derivative molecular probe, which has the following structure:

[0006]

[0007] in:

[0008] The value of n is an integer from 1 to 3;

[0009] R1 is azido-glucose; the azido-glucose has the structure shown below:

[0010]

[0011] R2 is a signal group; the signal group consists of a chelating group and a radioactive nuclide.

[0012] In one embodiment of the present invention, the chelating group is NOTA (1,4,7-triazacyclononane-N,N',N"-triacetic acid), a NOTA derivative, DOTA (1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetyl dimethyl ester) or a DOTA derivative.

[0013] In one embodiment of the present invention, when the chelating group is NOTA, the radionuclide labeling group is 64 Cu, 111 In, 68 Ga or [ 18 F]AlF3; when the chelating group is DOTA, the radionuclide labeling group is 90 Y. 225 Ac, 68 Ga, 177 Lu or 64 Cu.

[0014] In one embodiment of the present invention, when n is 1, the chelating group is NOTA and the radionuclide labeling group is 68When n is 2, the chelating group is NOTA, and the radionuclide labeling group is

[0015]

[0016] Ga, the molecular probe has the structure shown below: 68 Ga, the molecular probe has the structure shown below:

[0017]

[0018] When n is 3, the chelating group is NOTA, and the radionuclide labeling group is 68 Ga, the molecular probe has the structure shown below:

[0019]

[0020] When n is 1, the chelating group is DOTA, and the radionuclide labeling group is 68 Ga, the molecular probe has the structure shown below:

[0021]

[0022] When n is 2, the chelating group is DOTA, and the radionuclide labeling group is 68 Ga, the molecular probe has the structure shown below:

[0023]

[0024] In one embodiment of the present invention, when n is 1 and the chelating group is NOTA, the labeling precursor of the molecular probe has the structure shown below:

[0025]

[0026] When n is 2 and the chelating group is NOTA, the labeling precursor of the molecular probe has the structure shown below:

[0027]

[0028] When n is 3 and the chelating group is NOTA, the labeling precursor of the molecular probe has the structure shown below:

[0029]

[0030] When n is 1 and the chelating group is DOTA, the labeling precursor of the molecular probe has the structure shown below:

[0031]

[0032] When n is 2 and the chelating group is DOTA, the labeling precursor of the molecular probe has the structure shown below:

[0033]

[0034] In one embodiment of the present invention, the molecular probe targets glucose transporters (GLUTs).

[0035] The present invention also provides a method for preparing the above-mentioned molecular probe. When n is 1, the method includes: chelating compound SDG with NOTA-NHS or DOTA-NHS to obtain the labeling precursor of the molecular probe; performing radionuclide labeling on the labeling precursor of the molecular probe to obtain the molecular probe;

[0036] When n is 2, the method includes: chelating compound DDG with NOTA-NHS or DOTA-NHS to obtain the labeling precursor of the molecular probe; performing radionuclide labeling on the labeling precursor of the molecular probe to obtain the molecular probe;

[0037] When n is 3, the method includes: chelating compound TDG with NOTA-NHS or DOTA-NHS to obtain the labeling precursor of the molecular probe; performing radionuclide labeling on the labeling precursor of the molecular probe to obtain the molecular probe;

[0038] Compound SDG has the structure shown below:

[0039]

[0040] Compound DDG has the structure shown below:

[0041]

[0042] Compound TDG has the structure shown below:

[0043]

[0044] In one embodiment of the present invention, the preparation method of compound SDG includes: mixing compound S1 and azidoglucose and performing a click reaction to obtain compound SDG;

[0045] The preparation method of compound DDG includes: mixing compound D1 and azidoglucose and performing a click reaction to obtain compound SDG;

[0046] The preparation method of compound TDG includes: mixing compound T1 and azidoglucose and performing a click reaction to obtain compound TDG;

[0047] The compound S1 has the structure shown below:

[0048]

[0049] The compound D1 has the structure shown below:

[0050]

[0051] The compound T1 has the structure shown below:

[0052]

[0053] In one embodiment of the present invention, the preparation method of the compound S1 includes: reacting benzylamine with Boc-protected propargylglycine to obtain the compound S1;

[0054] The preparation method of the compound D1 includes: deprotecting the compound S1 to obtain the compound D0; reacting the compound D0 with Boc-protected propargylglycine to obtain the compound D1;

[0055] The preparation method of the compound T1 includes: deprotecting the compound D1 to obtain the compound T0; reacting the compound T0 with Boc-protected propargylglycine to obtain the compound T1.

[0056] The present invention also provides the application of the above molecular probe in the preparation of an imaging agent targeting glucose transporter.

[0057] The present invention also provides an imaging agent targeting glucose transporter, and the composition of the imaging agent contains the above molecular probe.

[0058] The present invention also provides the application of the above molecular probe in the preparation of a tumor imaging agent.

[0059] In one embodiment of the present invention, the tumor imaging agent is a broad-spectrum tumor imaging agent.

[0060] In one embodiment of the present invention, the tumors include glucose transporter-positive tumors; the glucose transporter-positive tumors include breast cancer, esophageal cancer, liver cancer, colorectal cancer, glioblastoma, and / or non-small cell lung cancer.

[0061] The present invention also provides a tumor imaging agent, and the composition of the imaging agent contains the above molecular probe.

[0062] In one embodiment of the present invention, the tumor imaging agent is a broad-spectrum tumor imaging agent.

[0063] In one embodiment of the present invention, the tumor includes glucose transporter-positive tumors; the glucose transporter-positive tumors include breast cancer, esophageal cancer, liver cancer, colorectal cancer, glioblastoma, and / or non-small cell lung cancer.

[0064] The technical solution of the present invention has the following advantages:

[0065] The present invention provides a radionuclide-labeled glucose derivative molecular probe (including 68 Ga]Ga-NOTA-SDG, 68 Ga]Ga-NOTA-DDG, 68 Ga]Ga-NOTA-TDG, 68 Ga]Ga-DOTA-SDG, and 68 Ga]Ga-DOTA-DDG, etc.). This molecular probe has the following advantages:

[0066] First, the labeling method of this molecular probe has the advantages of short labeling time and simple labeling steps. Moreover, the radiochemical yield of the obtained molecular probe is higher than 95%. Compared with 18 F-FDG, its complex labeling process and high requirements for equipment are more suitable for clinical use ( 18 F-FDG refers to the literature "Rahmani, S.; Shahhoseinia, S.; Mohamadi, R.; Vojdani, M., Synthesis, Quality Control and Stability Studies of 2- 18 F]-Fluoro-2-Deoxy-D-Glucose ( 18 F-FDG) at Different Conditions of Temperature by Physicochemical and Microbiological Assays. Iranian Journal of Pharmaceutical Research 2017, 16(2), 602-610.").

[0067] Second, this molecular probe has the advantage of good water solubility. Good water solubility is more conducive to drug formation, can be directly injected intravenously, and has high bioavailability.

[0068] Third, this molecular probe has the advantage of good stability. After incubation in PBS and serum for 2 h, 68 the radiochemical purity of Ga]Ga-NOTA-SDG ≥ 99%, 68 the radiochemical purity of Ga]Ga-NOTA-DDG ≥ 98%.68 The radiochemical purity of Ga]Ga-NOTA-TDG ≥ 96%, all suitable for long-term storage and clinical applications;

[0069] Fourth, this molecular probe has lower non-target tissue uptake. Among them, the existing molecular probes 68 Although the non-target tissue uptake of Ga-DOTA-DG is lower than that of tumor tissue, the background signal in the lungs is still relatively high ( 68 The lung tissue uptake of Ga-DOTA-DG is 3.96 ± 0.51% ID / g, and the tumor uptake is 2.38 ± 0.30% ID / g. For details, see the literature "Yang, Z.; Xiong, C.; Zhang, R.; Zhu, H.; Li, C., Synthesis and evaluation of 68 Ga-labeled DOTA-2-deoxy-D-glucosamine as a potential radiotracer in μPET imaging. American journal of nuclear medicine and molecular imaging 2012, (2), 499 - 507."); The existing molecular probe 68 The uptake of Ga-ECG in liver and lung tissues is higher than that in tumors ( 68 The liver tissue uptake of Ga-ECG is 0.77 ± 0.05% ID / g, the lung tissue uptake is 1.07 ± 0.02% ID / g, and the tumor uptake is 0.70 ± 0.06% ID / g. For details, see the literature "Zhang, Y.H.; Bryant, J.; Kong, F.L.; Yu, D.F.; Mendez, R.; Edmund Kim, E.; Yang, D.J., Molecular imaging of mesothelioma with 99m Tc-ECG and 68 Ga-ECG. J Biomed Biotechnol 2012, 2012, 232863."); While the molecular probe of the present invention 68 The uptake of Ga-NOTA-SDG in tumors (9.48 ± 0.38% ID / g) is greater than that in non-target tissues (lung tissue uptake 2.69 ± 0.59% ID / g, liver tissue uptake 1.75 ± 0.20% ID / g, brain tissue uptake 0.22 ± 0.05% ID / g), with higher tumor imaging contrast and can significantly improve the imaging clarity of tumors.

[0070] In summary, the present invention uses propargylglycine to synthesize an amino acid skeleton, reacts with azidoglucose, and prepares a series of radiopharmaceutical-labeled glucose derivative molecular probes. This series of radiopharmaceutical-labeled glucose derivative molecular probes has the advantages of simple and rapid labeling, high radiochemical yield, and good stability. Moreover, they can accurately locate tumors, have good tumor uptake values, and lower non-target tissue uptake, showing great application prospects in the preparation of broad-spectrum tumor imaging agents, and can provide a basis for the development of more effective tumor diagnosis and therapeutic evaluation tools. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1 : Synthetic routes of compounds S1, D1, and T1.

[0072] Figure 2 : Synthetic routes of compounds NOTA-SDG, NOTA-DDG, and NOTA-TDG.

[0073] Figure 3 : Synthetic routes of compounds DOTA-SDG and DOTA-DDG.

[0074] Figure 4 : Electrospray mass spectrometry analysis chart of compound NOTA-SDG.

[0075] Figure 5 : Electrospray mass spectrometry analysis chart of compound NOTA-DDG.

[0076] Figure 6 : Electrospray mass spectrometry analysis chart of compound NOTA-TDG.

[0077] Figure 7 : Electrospray mass spectrometry analysis chart of compound DOTA-SDG.

[0078] Figure 8 : Electrospray mass spectrometry analysis chart of compound DOTA-DDG.

[0079] Figure 9 : Radioactive HPLC charts of different molecular probes (cold compounds and hot probes). Figure 9 In, (a): 68 Ga] / 69 Ga]Ga-NOTA-SDG; (b) 68 Ga] / 69 Ga]Ga-NOTA-DDG; (c) 68 Ga] / 69 Ga]Ga-NOTA-TDG.

[0080] Figure 10: HPLC analysis of the stability of different molecular probes incubated in PBS or mouse serum for different times. Figure 10 (a) 68 HPLC analysis of the stability of [ 68 Ga]Ga-NOTA-SDG incubated in PBS for 0.5, 1, and 2 hours; (b) 68 HPLC analysis of the stability of [ 68 Ga]Ga-NOTA-SDG incubated in mouse serum for 0.5, 1, and 2 hours; (c) 68 HPLC analysis of the stability of [ 68 Ga]Ga-NOTA-TDG incubated in PBS for 0.5, 1, and 2 hours; (d)

[0081] Figure 11 : 68 Results of the cellular uptake experiment of [ Figure 11 (a) Uptake of [ 68 Ga]Ga-NOTA-SDG by U87 cells under the action of 2 mg, 4 mg, and 8 mg D-glucose; (b) Uptake of [ 68 Ga]Ga-NOTA-SDG by U87 cells under the action of 2 U, 4 U, and 8 U insulin; (c) Uptake of [ 68 Ga]Ga-NOTA-SDG by A549 cells under the action of 2 mg, 4 mg, and 8 mg D-glucose; (d) Uptake of [ 68 Ga]Ga-NOTA-SDG by A549 under the action of 2 U, 4 U, and 8 U insulin. "ns" indicates that there is no statistically significant difference between groups. ns: no significant difference, *P < 0.05, **P < 0.01, ***P < 0.001.

[0082] Figure 12 : PET imaging results of [ 68 Ga]Ga-NOTA-SDG in U87 and A549 tumor-bearing mice. Figure 12 (a) Representative PET images of U87 and A549 tumor-bearing mice within 1 hour after injection of [ 68 Ga]Ga-NOTA-SDG; (b) Quantitative analysis based on the PET images obtained 68Tissue uptake values of Ga]Ga-NOTA-SDG; (c) T / M ratio calculated from the quantitative analysis results of the PET images.

[0083] Figure 13 : In U87 and A549 tumor-bearing mice 68 PET imaging results of Ga]Ga-NOTA-DDG. Figure 13 Among them, (a) Representative PET images of U87 and A549 tumor-bearing mice within 1 hour after injection of 68 Ga]Ga-NOTA-DDG; (b) Tissue uptake values of Ga]Ga-NOTA-DDG obtained from the quantitative analysis of the PET images; (c) T / M ratio calculated from the quantitative analysis results of the PET images. 68 Tissue uptake values of Ga]Ga-NOTA-DDG; (c) T / M ratio calculated from the quantitative analysis results of the PET images.

[0084] Figure 14 : In U87 and A549 tumor-bearing mice 68 PET imaging results of Ga]Ga-NOTA-TDG. Figure 14 Among them, (a) Injection of 68 Representative PET images of U87 and A549 tumor-bearing mice within 1 hour after injection of Ga]Ga-NOTA-TDG; (b) Tissue uptake values of Ga]Ga-NOTA-TDG obtained from the quantitative analysis of the PET images; (c) T / M ratio calculated from the quantitative analysis results of the PET images. 68 Tissue uptake values of Ga]Ga-NOTA-TDG; (c) T / M ratio calculated from the quantitative analysis results of the PET images.

[0085] Figure 15 : In U87 and A549 tumor-bearing mice 68 PET imaging results of Ga]Ga-DOTA-SDG. Figure 15 Among them, (a) Injection of 68 Representative PET images of U87 and A549 tumor-bearing mice within 1 hour after injection of Ga]Ga-DOTA-SDG; (b) Tumor and muscle uptake values of Ga]Ga-DOTA-SDG in U87 obtained from the quantitative analysis of the PET images; (c) Tumor and muscle uptake values of Ga]Ga-DOTA-SDG in A549 obtained from the quantitative analysis of the PET images; (d) T / M ratio calculated from the quantitative analysis results of the PET images. 68 Tumor and muscle uptake values of Ga]Ga-DOTA-SDG in U87; (c) Tumor and muscle uptake values of Ga]Ga-DOTA-SDG in A549 obtained from the quantitative analysis of the PET images; (d) T / M ratio calculated from the quantitative analysis results of the PET images. 68 Tumor and muscle uptake values of Ga]Ga-DOTA-SDG in A549; (d) T / M ratio calculated from the quantitative analysis results of the PET images.

[0086] Figure 16 : In U87 tumor-bearing mice 68 PET imaging results of Ga]Ga-DOTA-DDG. Figure 16 Among them, (a) Injection of 68Representative PET images of U87 tumor-bearing mice within 1 hour after [[Ga]]Ga-DOTA-DDG; (b) Obtained from quantitative analysis of PET images 68 Uptake values of [[Ga]]Ga-DOTA-SDG in tumors and muscles of U87; (c) T / M ratio calculated based on the quantitative analysis results of PET images.

[0087] Figure 17 : In ROI quantitative PET imaging analysis 68 Time-activity curves (TACs) of [[Ga]]Ga-NOTA-SDG in the heart, tumor, intestine, and brain of different tumor-bearing mice. Figure 17 Among them, (a) 68 Time-activity curves of [[Ga]]Ga-NOTA-SDG in the heart, tumor, intestine, and brain of U87 tumor-bearing mice; (b) 68 Time-activity curves of [[Ga]]Ga-NOTA-SDG in the heart, tumor, intestine, and brain of A549 tumor-bearing mice; (c) Calculated based on the time-activity curves in 68 Tumor / normal tissue (T / NT) ratios of [[Ga]]Ga-NOTA-SDG in U87 and A549 tumor-bearing mice. Detailed implementation manners

[0088] The following examples are provided to better understand the present invention further, and are not limited to the described optimal implementation manner. They do not limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with those of other existing technologies falls within the protection scope of the present invention.

[0089] For those not specifying specific experimental steps or conditions in the following examples, the operations or conditions of the conventional experimental steps described in the literature in this field can be followed. For reagents or instruments not specifying the manufacturer, they are all conventional reagent products that can be obtained commercially.

[0090] Example 1: A molecular probe targeting glucose transporter 68 [[Ga]]Ga-NOTA-SDG

[0091] This example provides a molecular probe targeting glucose transporter 68 [[Ga]]Ga-NOTA-SDG, and the molecular probe 68 [[Ga]]Ga-NOTA-SDG has the following structure:

[0092]

[0093] Example 2: A method for preparing a molecular probe68 Method of [¹⁷⁷Lu]Lu-NOTA-SDG

[0094] This example provides the preparation of the molecular probe described in Example 1 68 Method of [¹⁷⁷Lu]Lu-NOTA-SDG, and the specific steps are as follows (see the synthetic route in Figures 1 - 2 ):

[0095] Step 1: Dissolve (S)-N-BOC-propargylglycine (CAS: 63039-48-5, 597 mg, 2.8 mmol) and benzylamine (300 mg, 2.8 mmol) in 5 mL of dichloromethane (CH₂Cl₂, DCM) to obtain a solution; add O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (1222 mg, 3.2 mmol) and N,N-diisopropylethylamine (DIPEA, 1.8 g, 14 mmol) to the solution, and then continue to react at room temperature (25 °C) for 6 hours to obtain a reaction solution; after analyzing and confirming the target compound by high performance liquid chromatography (HPLC) and ESI-MS, perform silica gel column chromatography on the reaction solution using n-hexane / ethyl acetate (n-hexane: ethyl acetate = 2:1, v / v) as the eluent to obtain compound S1 (harvest 810 mg of white solid product, yield 90%).

[0096] Step 2: Dissolve sodium L - ascorbate (7.48 mg, 0.04 mmol), tris(3 - hydroxypropyltriazylmethyl)amine (THPTA, 8.20 mg, 0.02 mmol) and copper(II) sulfate pentahydrate (CuSO₄·5H₂O, 4.70 mg, 0.02 mmol) separately in ultrapure water (100 μL) to obtain a sodium L - ascorbate solution, a THPTA solution and a CuSO₄·5H₂O solution; Dissolve compound S1 (31.20 mg, 0.10 mmol) and 2 - deoxy - 2 - D - azidoglucose (CAS: 56883 - 39 - 7, 21.18 mg, 0.10 mmol) in N,N - dimethylformamide (DMF, 1200 μL) in a 25 - mL reaction flask to obtain a solution; Add the sodium L - ascorbate solution and the THPTA solution to the solution and mix well, then evacuate and fill with nitrogen 3 times to obtain a mixed solution; To avoid mixing in too much air, add the CuSO₄·5H₂O solution to the mixed solution with a syringe, and react at 45 °C for 1 hour to obtain a reaction solution; After vacuum rotary evaporation of the reaction solution, first add 2 mL of dichloromethane (CH₂Cl₂) and 1 mL of trifluoroacetic acid (TFA), and then react at room temperature (25 °C) for 30 min to remove the Boc protecting group to obtain a reaction product; After analyzing and confirming the target compound by high - performance liquid chromatography (HPLC) and electrospray mass spectrometry (ESI - MS), the reaction product is first purified by semi - preparative HPLC (the purification conditions of semi - preparative HPLC are shown in Table 1), and then freeze - dried to obtain compound SDG.

[0097] Step 3: Dissolve compound SDG (3 mg, 0.0073 mmol) and NOTA - NHS (CAS: 1338231 - 09 - 6, 4 mg, 0.01 mmol) in 1 mL of DMF to obtain a solution; Add DIPEA (6.40 μL, 0.037 mmol) to the solution to adjust the pH to 8, and then stir (500 rpm) at room temperature (25 °C) for 4 hours to obtain a reaction solution; After analyzing and confirming the target compound by HPLC and ESI - MS, the reaction solution is first purified by semi - preparative HPLC (the purification conditions of semi - preparative HPLC are shown in Table 1), and then freeze - dried to obtain the labeling precursor NOTA - SDG of the molecular probe (harvest 3.02 mg of white solid powder product, yield: 59%). Perform ESI - MS analysis on the labeling precursor NOTA - SDG of the molecular probe, and the ESI - MS analysis results are shown in Figure 4 。

[0098] Step 4: Use 1.0 mL of 0.05 M HCl to elute from 68 Ge / 68 Ga generator (ITG) 68Ga ions were used to obtain an eluate; the eluate was mixed with a 0.25 M NaOAc buffer solution to adjust the pH value to 4.0, obtaining a mixture; the mixture was directly transferred to a 5 mL centrifuge tube containing 20 μg of the labeled precursor NOTA-SDG. After mixing, the mixture was incubated in an oil bath at 37 °C for 15 min to obtain a molecular probe 68 Ga]Ga-NOTA-SDG (thermal probe). The reaction solution labeled with 68 Ga]Ga-NOTA-SDG was detected by radioactive HPLC using a POMO Nova radioactive detector. The results of the radioactive HPLC detection are shown in Figure 9 . The radiochemical purity (RCP) of 68 Ga]Ga-NOTA-SDG was calculated by the peak area of the radioactive product / total peak area, and the calculated result was: 99%. At the same time, the labeled precursor NOTA-SDG was reacted with 69 GaCl3 to obtain a cold compound 69 Ga]Ga-NOTA-SDG, and 69 Ga]Ga-NOTA-SDG was detected by HPLC. The results of the HPLC detection are shown in Figure 9 .

[0099] In the above radioactive high-performance liquid chromatography, the retention time of 68 Ga]Ga-NOTA-SDG was 11.03 min, which was close to the peak emergence time of the cold compound 69 Ga]Ga-NOTA-SDG (11.01 min). After attenuation correction, the final radiochemical yield (RCY) of 68 Ga]Ga-NOTA-SDG was calculated by radioactive HPLC detection, and the calculated result was: 98%. The molar activity (Am) of 68 Ga]Ga-NOTA-SDG was calculated by Am = radioactivity of the product / M (molar mass of the precursor), and the calculated result was: 6.4 GBq / μmol.

[0100] Table 1 Purification conditions of semi-preparative HPLC

[0101]

[0102] Example 3: A molecular probe targeting glucose transporters 68 Ga]Ga-NOTA-DDG

[0103] This example provides a molecular probe 68 Ga]Ga-NOTA-DDG targeting glucose transporters. The molecular probe 68Ga]Ga-NOTA-DDG has the structure shown below:

[0104]

[0105] Example 4: A method for preparing a molecular probe 68 Ga]Ga-NOTA-DDG

[0106] This example provides a method for preparing the molecular probe 68 Ga]Ga-NOTA-DDG described in Example 3. The specific steps are as follows (the synthetic route is shown in Figures 1 - 2 ):

[0107] Step 1: Dissolve compound S1 (200.00 mg, 0.66 mmol) in 4 mL of dichloromethane to obtain a solution. After adding trifluoroacetic acid (TFA, 2 mL) to the solution, stir (500 rpm) at room temperature (25 °C) for 40 minutes to obtain a reaction solution. After analyzing and confirming the target compound by HPLC and ESI-MS, evaporate the reaction solution by vacuum rotary evaporation to obtain compound D0 (yield: 90%).

[0108] Step 2: Dissolve compound D0 (135 mg, 0.44 mmol) and DIPEA (144 mg, 1.12 mmol) in 2 mL of DMF, and then stir (500 rpm) at room temperature (25 °C) for 5 minutes to obtain mixture A. Dissolve (S)-N-BOC-propargylglycine (95 mg, 2.8 mmol), HBTU (195 mg, 0.51 mmol) and DIPEA (144 mg, 1.12 mmol) in 2 mL of DMF, and then stir (500 rpm) at room temperature (25 °C) for 15 minutes to obtain mixture B. After mixing mixture A and mixture B, continue to react at room temperature (25 °C) for 6 hours to obtain a reaction solution. After analyzing and confirming the target compound by HPLC and ESI-MS, perform silica gel column chromatography on the reaction solution using n-hexane / ethyl acetate (n-hexane / ethyl acetate = 2 / 1, v / v) as the eluent to obtain compound D1 (106 mg of white solid product was obtained, yield: 60%).

[0109] Step 3: Add compound D1 (45.01 mg, 0.11 mmol), 2-deoxy-2-D-azidoglucose (46.48 mg, 0.22 mmol), sodium L-ascorbate (22.45 mg, 0.11 mmol), THPTA (24.60 mg, 0.05 mmol) and N,N-dimethylformamide / pure water (3 mL, N,N-dimethylformamide:pure water = 4:1, v / v) into a 25 mL reaction flask. First, evacuate and fill with nitrogen 3 times, then inject a CuSO4·5H2O solution (14.17 mg, 0.05 mmol, prepared as in Example 2) using a syringe. Then react at 45 °C for 1 hour to obtain a reaction solution. After vacuum rotary evaporation of the reaction solution, first add 2 mL of CH2Cl2 and 1 mL of TFA, and then react at room temperature (25 °C) for 30 min to obtain a reaction product. After analyzing and confirming the target compound by HPLC and ESI-MS, the reaction product is first purified by semi-preparative HPLC (the purification conditions of semi-preparative HPLC are shown in Table 1), and then freeze-dried to obtain compound DDG (harvest 34.6 mg of white solid powder product, with a yield of 46.8%).

[0110] Step 4: Dissolve compound DDG (3 mg, 0.0073 mmol) and NOTA-NHS (2.5 mg, 0.00625 mmol) in 1 mL of DMF to obtain a solution. Add DIPEA (6.4 μL, 0.039 mmol) to the solution to adjust the pH to 8, and then stir (500 rpm) at room temperature (25 °C) for 4 hours to obtain a reaction solution. After analyzing and confirming the target compound by HPLC and ESI-MS, the reaction solution is first purified by semi-preparative HPLC (the purification conditions of semi-preparative HPLC are shown in Table 1), and then freeze-dried to obtain the labeling precursor NOTA-DDG of the molecular probe (harvest 2.1 mg of white solid powder product, yield: 60%). Perform ESI-MS analysis on the labeling precursor NOTA-DDG of the molecular probe, and the ESI-MS analysis results are shown in Figure 5 .

[0111] Step 5: Elute 68 Ge / 68 Ga ions from a 68 Ge / 68Ga]Ga-NOTA-DDG. Using a POMO Nova radioactive detector, 68 the reaction solution labeled with Ga]Ga-NOTA-DDG was detected by radioactive HPLC. The results of the radioactive HPLC detection are shown in Figure 9 . By calculating the peak area of the radioactive product / total peak area 68 the radiochemical purity (RCP) of Ga]Ga-NOTA-DDG was calculated, and the calculation result was: 99%. At the same time, the labeling precursor NOTA-DDG was reacted with 69 GaCl3 to obtain the cold compound 69 Ga]Ga-NOTA-DDG, and HPLC was used to detect 69 Ga]Ga-NOTA-DDG. The results of the HPLC detection are shown in Figure 9 .

[0112] In the above radioactive high performance liquid chromatography, 68 the retention time of Ga]Ga-NOTA-DDG was 10.80 min, which was close to the peak emergence time of the cold compound 69 Ga]Ga-NOTA-DDG (10.60 min). After decay correction, the final radiochemical yield (RCY) of Ga]Ga-NOTA-DDG was calculated by radioactive HPLC detection. The calculation result was: 97%. The molar activity (Am) = product radioactivity / M (molar mass of the precursor) was used to calculate 68 the molar activity of Ga]Ga-NOTA-DDG, and the calculation result was: 3.4 GBq / μmol. 68

[0113] Example 5: A molecular probe targeting glucose transporter 68 Ga]Ga-NOTA-TDG

[0114] This example provides a molecular probe targeting glucose transporter 68 Ga]Ga-NOTA-TDG. The molecular probe 68 Ga]Ga-NOTA-TDG has the following structure:

[0115]

[0116] Example 6: A method for preparing the molecular probe 68 Ga]Ga-NOTA-TDG

[0117] This example provides a method for preparing the molecular probe described in Example 5 68 Ga]Ga-NOTA-TDG. The specific steps are as follows (the synthesis route is shown inFigures 1 - 2 ):

[0118] Step 1: Dissolve compound D1 (200.00 mg, 0.66 mmol) in 4 mL of dichloromethane to obtain a solution. After adding TFA (2 mL) to the solution, stir the reaction mixture at room temperature (25 °C) at 500 rpm for 40 minutes to obtain a reaction solution. After analyzing and confirming the target compound by HPLC and ESI-MS, evaporate the reaction solution by rotary evaporation under vacuum to obtain compound T0 (yield: 90%).

[0119] Step 2: Dissolve compound T0 (135 mg, 0.44 mmol) and DIPEA (144 mg, 1.12 mmol) in 2 mL of DMF, and then stir the reaction mixture at room temperature (25 °C) at 500 rpm for 5 minutes to obtain mixture A. Dissolve (S)-N-BOC-propargylglycine (95 mg, 2.8 mmol), HBTU (195 mg, 0.51 mmol) and DIPEA (144 mg, 1.12 mmol) in 2 mL of DMF, and then stir the reaction mixture at room temperature (25 °C) at 500 rpm for 15 minutes to obtain mixture B. After mixing mixture A and mixture B, continue to react at room temperature (25 °C) for 6 hours to obtain a reaction solution. After analyzing and confirming the target compound by HPLC and ESI-MS, perform silica gel column chromatography on the reaction solution using n-hexane / ethyl acetate (n-hexane: ethyl acetate = 2:1, v / v) as the eluent to obtain compound T1 (106 mg of white solid product was obtained, yield: 60%).

[0120] Step 3: Add compound T1 (20 mg, 0.04 mmol), 2-deoxy-2-D-azidoglucose (46.48 mg, 0.22 mmol), sodium L-ascorbate (4.20 mg, 0.04 mmol), THPTA (8.80 mg, 0.02 mmol) and N,N-dimethylformamide / water (3 mL, N,N-dimethylformamide: water = 4:1, v / v) into a 25 mL reaction flask. First, evacuate and refill with nitrogen 3 times, then inject a CuSO4·5H2O solution (14.17 mg, 0.05 mmol, prepared in the same way as in Example 2) with a syringe, and then react at 45 °C for 1 hour to obtain a reaction solution. After evaporating the reaction solution by rotary evaporation under vacuum, first add 2 mL of CH2Cl2 and 1 mL of TFA, and then react at room temperature (25 °C) for 30 min to obtain a reaction product. After analyzing and confirming the target compound by HPLC and ESI-MS, purify the reaction product by semi-preparative HPLC first (the purification conditions of semi-preparative HPLC are shown in Table 1), and then freeze-dry to obtain compound TDG (10 mg of white solid powder product was obtained, yield: 49%).

[0121] Step 4: Dissolve compound TDG (3 mg, 0.0073 mmol) and NOTA-NHS (2 mg, 0.005 mmol) in 1 mL of DMF to obtain a solution. Add DIPEA (6.4 μL, 0.0368 mmol) to the solution to adjust the pH to 8, and then stir (500 rpm) at room temperature (25 °C) for 4 hours to obtain a reaction solution. After analyzing and confirming the target compound by HPLC and ESI-MS, first purify the reaction solution by semi-preparative HPLC (the purification conditions of semi-preparative HPLC are shown in Table 1), and then freeze-dry to obtain the labeling precursor NOTA-TDG of the molecular probe (harvest 1.84 mg of white solid powder product, yield: 48%). Perform ESI-MS analysis on the labeling precursor NOTA-TDG of the molecular probe, and the ESI-MS analysis results are shown in Figure 6 .

[0122] Step 5: Elute 68 Ge / 68 Ga ions from a 68 Ga generator (ITG) using 1.0 mL of 0.05 M HCl to obtain an eluate; mix the eluate with 0.25 M NaOAc buffer solution to adjust the pH value to 4.0 to obtain a mixture; directly transfer the mixture to a 5 mL centrifuge tube containing 20 μg of the labeling precursor NOTA-TDG, mix well, and then incubate the mixture in an oil bath at 37 °C for 15 min to obtain the molecular probe 68 Ga]Ga-NOTA-TDG. Use a POMO Nova radioactive detector to perform radioactive HPLC detection on the reaction solution after labeling with 68 Ga]Ga-NOTA-TDG, and the radioactive HPLC detection results are shown in Figure 9 . Calculate the radiochemical purity (RCP) of 68 Ga]Ga-NOTA-TDG by the ratio of the peak area of the radioactive product to the total peak area, and the calculated result is: 95%. At the same time, react the labeling precursor NOTA-TDG with 69 GaCl3 to obtain the cold compound 69 Ga]Ga-NOTA-TDG, and use HPLC to detect 69 Ga]Ga-NOTA-TDG, and the HPLC detection results are shown in Figure 9 .

[0123] In the above radio high performance liquid chromatography, 68 Ga]Ga-NOTA-TDG has a retention time of 10.50 min, which is the same as that of the cold compound 69The retention time of 68 Ga]Ga-NOTA-TDG is similar to that of 68 Ga]Ga-NOTA-TDG(10.30 min). After decay correction, the final radiochemical yield (RCY) of

[0124] Example 7: A molecular probe targeting glucose transporter 68 Ga]Ga-DOTA-SDG

[0125] This example provides a molecular probe targeting glucose transporter 68 Ga]Ga-DOTA-SDG, and the molecular probe 68 Ga]Ga-DOTA-SDG has the following structure:

[0126]

[0127] Example 8: A method for preparing a molecular probe 68 Ga]Ga-DOTA-SDG

[0128] This example provides a method for preparing the molecular probe 68 Ga]Ga-DOTA-SDG described in Example 7, and the specific steps are as follows (the synthesis route is shown in Figures 1 - 3 ):

[0129] Step 1: Dissolve compound SDG (3 mg, 0.0073 mmol) and DOTA-NHS (CAS: 170908-81-3, 9 mg, 0.01 mmol) in 1 mL of DMF to obtain a solution. After adding DIPEA (6.40 μL, 0.012 mmol) to adjust the pH to 8 in the solution, stir (500 rpm) at room temperature (25 °C) for 4 hours to obtain a reaction solution. After analyzing and confirming the target compound by HPLC and ESI-MS, first purify the reaction solution by semi-preparative HPLC (the purification conditions of semi-preparative HPLC are shown in Table 1), and then freeze-dry to obtain the labeled precursor DOTA-SDG of the molecular probe (harvest 3.09 mg of white solid powder product, yield: 53%). Perform ESI-MS analysis on the labeled precursor DOTA-SDG of the molecular probe, and the ESI-MS analysis results are shown in Figure 7 .

[0130] Step 2: Use 1.0 mL of 0.05 M HCl to...68 Ge / 68 elute 68 Ga ions in the Ga generator (ITG) to obtain an eluate; mix the eluate with a 0.25 M NaOAc buffer solution to adjust the pH value to 4.0 to obtain a mixture; directly transfer the mixture to a 5 mL centrifuge tube containing 20 μg of the labeling precursor DOTA-SDG, and after mixing, incubate the mixture in an oil bath at 95 °C for 15 min to obtain a molecular probe 68 Ga]Ga-DOTA-SDG.

[0131] Example 9: A molecular probe targeting glucose transporter 68 Ga]Ga-DOTA-DDG

[0132] This example provides a molecular probe targeting glucose transporter 68 Ga]Ga-DOTA-DDG, and the molecular probe 68 Ga]Ga-DOTA-DDG has the following structure:

[0133]

[0134] Example 10: A method for preparing a molecular probe 68 Ga]Ga-DOTA-DDG

[0135] This example provides a method for preparing the molecular probe described in Example 9 68 Ga]Ga-DOTA-DDG, and the specific steps are as follows (the synthesis route is shown in Figures 1 - 3 ):

[0136] Step 1: Dissolve the compound DDG (3 mg, 0.0042 mmol) and DOTA-NHS (CAS: 170908-81-3, 5 mg, 0.01 mmol) in 1 mL of DMF to obtain a solution; add DIPEA (6.40 μL, 0.0064 mmol) to the solution to adjust the pH to 8, and then stir (500 rpm) at room temperature (25 °C) for 4 hours to obtain a reaction solution; after analyzing and confirming the target compound by HPLC and ESI-MS, first purify the reaction solution by semi-preparative HPLC (the purification conditions of semi-preparative HPLC are shown in Table 1), and then freeze-dry to obtain the labeling precursor DOTA-SDG of the molecular probe (harvest 2.14 mg of white solid powder product, yield: 46%). Perform ESI-MS analysis on the labeling precursor DOTA-DDG of the molecular probe, and the ESI-MS analysis results are shown in Figure 8 .

[0137] Step 2: Elute 68 Ge / 68 Ga ions from the 68 Ga generator (ITG) using 1.0 mL of 0.05 M HCl to obtain an eluate; mix the eluate with 0.25 M NaOAc buffer to adjust the pH to 4.0 to obtain a mixture; directly transfer the mixture to a 5 mL centrifuge tube containing 20 μg of the labeling precursor DOTA-DDG, mix well, and incubate the mixture in an oil bath at 95 °C for 15 min to obtain the molecular probe 68 Ga]Ga-DOTA-DDG.

[0138] Experimental Example 1: In vitro stability experiment of the molecular probe

[0139] This experimental example provides an in vitro stability experiment of the molecular probe, and the specific process is as follows:

[0140] Experiment 1: Mix the molecular probes 68 Ga]Ga-NOTA-SDG, 68 Ga]Ga-NOTA-DDG, and 68 Ga]Ga-NOTA-TDG with PBS buffer (pH 7.4, 0.01 M) respectively to obtain a mixed solution; incubate the mixed solution at 37 °C for 0.5, 1, 2 h; after the incubation, take the incubation solution and perform radio-HPLC analysis using a POMO Nova radioactive detector, and the analysis results are shown in Figure 10 .

[0141] Experiment 2: Mix the molecular probes 68 Ga]Ga-NOTA-SDG, 68 Ga]Ga-NOTA-DDG, and 68 Ga]Ga-NOTA-TDG with mouse serum (purchased from Nanjing Senbeijia Biotechnology Co., Ltd.) respectively to obtain a mixed solution; incubate the mixed solution at 37 °C for 0.5, 1, 2 h; after the incubation, add acetonitrile for precipitation, centrifuge at 12000 g for 5 min to separate the serum from the protein, aspirate the supernatant and perform radio-HPLC analysis using a POMO Nova radioactive detector, and the analysis results are shown in Figure 10 .

[0142] It can be seen from Figure 10 that the molecular probes 68 Ga]Ga-NOTA-SDG, 68 Ga]Ga-NOTA-DDG, and 68The radiochemical purity of [Ga]Ga-NOTA-TDG was greater than 95% after incubation in mouse serum and PBS at 37 °C for 2 h, indicating good stability.

[0143] Experimental Example 2: Experiment on the lipophilic-hydrophilic partition coefficient of the molecular probe

[0144] This experimental example provides an experiment on the lipophilic-hydrophilic partition coefficient of the molecular probe, and the specific process is as follows:

[0145] Take three centrifuge tubes, add 1 mL of deionized water and 1 mL of n-octanol to each centrifuge tube, and then add the molecular probe 68 [Ga]Ga-NOTA-SDG (25 μCi) to obtain a mixed solution; after shaking the mixed solution for 1 min, centrifuge it at 4000 g for 5 min at high speed to break the emulsion and separate the two phases; take 500 μL each of the n-octanol phase and the water phase into a radioimmunoassay tube, and then use a γ counter to detect the radioactivity of the n-octanol phase and the water phase respectively and calculate LogP (Log P = LogC o / C w ), where C o represents the radioactive dose of [Ga]Ga-NOTA-SDG in the n-octanol phase, and C 68 represents the radioactive dose of [Ga]Ga-NOTA-SDG in the water phase. Take the average value of three groups of data as the lipophilic-hydrophilic partition coefficient value, and the result is expressed as the average value ± standard deviation. Use the same method to detect the lipophilic-hydrophilic partition coefficients of the molecular probes w [Ga]Ga-NOTA-DDG and 68 [Ga]Ga-NOTA-TDG. 68 68 68 68

[0146] The experimentally measured lipophilic-hydrophilic partition coefficients of the molecular probes 68 [Ga]Ga-NOTA-SDG, 68 [Ga]Ga-NOTA-DDG and 68 [Ga]Ga-NOTA-TDG were -3.40 ± 0.04, -3.50 ± 0.08 and -3.61 ± 0.01 respectively, which indicates that the molecular probes 68 [Ga]Ga-NOTA-SDG, 68 [Ga]Ga-NOTA-DDG and 68 [Ga]Ga-NOTA-TDG are all water-soluble. Good water-solubility is more conducive to drug formation, can be directly injected intravenously, has a high bioavailability, and has the advantage of excretion from the kidneys and reduced liver metabolism in terms of metabolism.

[0147] Experimental Example 3: Experiment on the cellular uptake of the molecular probe

[0148] This experimental example provides a cell uptake experiment of molecular probes, and the specific process is as follows:

[0149] U87 cells (glioblastoma, purchased from the Cell Bank of the Chinese Academy of Sciences) and A549 cells (non-small cell lung cancer cells, purchased from the Cell Bank of the Chinese Academy of Sciences) were cultured in DMEM medium (purchased from Biological Industries, Israel) containing 1% (v / v) penicillin-streptomycin double antibody (purchased from Shanghai Beyotime Biotechnology Co., Ltd.) and 10% (v / v) fetal bovine serum (purchased from Biological Industries, Israel) in a 37°C, 5% (v / v) CO2 incubator until the logarithmic growth phase; U87 and A549 cells in the logarithmic growth phase were added to 24-well plates at a density of 3×10 5 cells / well and incubated in a 37°C, 5% CO2 incubator for 12 h; after incubation, the wells in the 24-well plates were grouped (n = 3), namely the control group and the 2, 4, and 8 mg D-glucose groups, as well as the control group and the 2, 4, and 8 unit insulin groups. After grouping, the experiment began.

[0150] One hour before the experiment, the DMEM medium in the 24-well plates was replaced with sugar-free DMEM medium (purchased from Thermo Fisher Scientific) and incubated in a 37°C, 5% CO2 incubator for 1 h to starve the cells; after incubation, the experiment was officially started. During the experiment, 2, 4, and 8 mg of D-glucose were added to the wells in the three D-glucose groups respectively, and 2, 4, and 8 units of insulin were added to the wells in the three insulin groups respectively, and incubated in a 37°C, 5% CO2 incubator for 30 min, then 68 Ga]Ga-NOTA-SDG (3.7×10 -1 MBq, 100 μL, with the solvent being sugar-free DMEM medium) was added to the wells in all groups and incubated in a 37°C, 5% CO2 incubator for 1 h; after incubation, the U87 or A549 cells in the wells were rinsed twice with 500 μL PBS buffer, and then lysed with 500 μL 1 M NaOH solution for 3 min to collect the lysate; the CPM value of the lysate was detected using a γ counter (1470Wizard, Perkins Elmer), and the cell uptake %AD result was expressed as the ratio of the CPM in the cells to the CPM of the total dose. The detection results are shown in Figure 11 .

[0151] It can be seen from Figure 11 that D-glucose cannot block the uptake of 68 Ga]Ga-NOTA-SDG by the two types of cells, while insulin significantly promotes the uptake of 68Uptake of 68 Ga]Ga-NOTA-SDG, in which, in the U87 cell line, compared with the control group (uptake value 0.22 ± 0.02% AD), the uptake values of U87 cells intervened with 2, 4, and 8 units of insulin for 68 Ga]Ga-NOTA-SDG increased by 11.40%, 29.67%, and 55.57% respectively. While in the A549 cell line, compared with the control group (uptake value 0.15 ± 0.02% AD), the uptake values of A549 cells intervened with 2, 4, and 8 units of insulin for 68 Ga]Ga-NOTA-SDG increased by 23.44%, 44.13%, and 67.90% respectively. And as is well known, insulin can up-regulate glucose transporters to promote cell uptake of glucose. It can be seen that

[0152] Experimental Example 4: PET Imaging Experiment of Molecular Probe

[0153] This experimental example provides a PET imaging experiment of a molecular probe, and the specific process is as follows:

[0154] U87 and A549 cells were respectively implanted subcutaneously into the upper right axilla of female BALB / C mice (5 weeks old, purchased from Changzhou Cavens Experimental Animal Co., Ltd.) at a dose of 5×10 6 individuals. The tumor diameter was monitored every other day. When the tumor diameter reached more than 3 cm, U87 and A549 tumor-bearing mice were anesthetized with oxygen containing 2% (v / v) isoflurane at a flow rate of 2 L / min; after fixing the limbs and tails of the tumor-bearing mice, the molecular probes 68 Ga]Ga-NOTA-SDG, 68 Ga]Ga-NOTA-DDG, 68 Ga]Ga-NOTA-TDG, 68 Ga]Ga-DOTA-SDG, and 68 Ga]Ga-DOTA-DDG (~180 μCi, 200 μL) dissolved in physiological saline were respectively injected into the mice through the tail vein; after the probe injection was completed, a 60-min dynamic PET scan was immediately performed, and the PET imaging results are shown in Figures 12 - 16 ; after the scan was completed, the 60-min PET imaging results were segmented into 12 frame images using the OSEM3D / MAP algorithm, with one frame every 5 min, to achieve real-time analysis of the imaging in the mice; the region of interest (ROI) technique in the ASIPRO software was used to outline and analyze the distribution of the probe in the tumor site and other organ tissues, and the analysis results are shown in Figures 12 - 17and Tables 2 - 3, wherein the uptake values of the molecular probes in various tissues in vivo are expressed as %ID / mL (percentage of the injection dose per milliliter).

[0155] As Figures 12 - 16 shown in and Tables 2 - 3, 68 Ga]Ga-NOTA-SDG showed the best effect among the three. The highest tumor uptake value reached 10.75 ± 0.37 %ID / mL in U87 tumor-bearing mice, and the tumor-to-muscle ratio was 4.40 ± 0.08. The highest tumor uptake value reached 4.08 ± 0.46 %ID / mL in A549 tumor-bearing mice, and the tumor-to-muscle ratio was 4.19 ± 0.99. 68 Ga]Ga-NOTA-DDG and 68 Ga]Ga-NOTA-TDG had a similar trend to 68 Ga]Ga-NOTA-SDG. Representative 68 Ga]Ga-NOTA-SDG was selected to analyze the uptake of non-target tissues by ROI. Figure 17 The results showed that 68 Ga]Ga-NOTA-SDG had relatively low uptake in tissues with high physiological glucose uptake (such as the brain, intestine, and heart), resulting in a relatively high overall signal-to-noise ratio. In the U87 tumor-bearing mouse model, 68 the maximum ratios of tumor / brain, tumor / heart, and tumor / intestine of Ga]Ga-NOTA-SDG were 6.45 ± 0.26, 1.17 ± 0.01, and 3.47 ± 0.07, respectively. Similarly, in the A549 model, these ratios were 6.19 ± 2.00, 1.20 ± 0.03, and 4.07 ± 0.09 within 1 hour ( Figure 17 c) in). These data indicate that 68 Ga]Ga-NOTA-SDG showed good tumor specificity in both tumor models, demonstrating its excellent molecular targeting performance.

[0156] Table 2 Tumor uptake values and tumor-to-muscle ratios of different molecular probes

[0157]

[0158] Table 3 Tumor uptake values and tumor-to-muscle ratios of different molecular probes

[0159]

[0160] Experimental Example 5: Biodistribution experiment of molecular probes

[0161] This experimental example provides a biodistribution experiment of molecular probes, and the specific process is as follows:

[0162] U87 and A549 cells were respectively implanted subcutaneously into the right upper axilla of female BALB / C mice (5 weeks old, purchased from Changzhou Cavens Laboratory Animal Co., Ltd.) at a dose of 5×10 6 cells. The tumor diameter was monitored every other day. When the tumor diameter reached more than 3 cm, U87 and A549 tumor-bearing mice were anesthetized with oxygen containing 2% (v / v) isoflurane at a flow rate of 2 L / min; after fixing the limbs and tails of the tumor-bearing mice (n = 3, a total of 6), the molecular probe 68

[0163] As shown in Table 4, 68 68

[0164] Table 4 Uptake values of the molecular probe in different organ tissues

[0165] Tissue [[ID=5 ​ ​ ​ ​ ​ 5.62±1.63 2.82±1.33 ​ 2.06±1.04 1.06±0.15 ​ 2.69±0.59 1.58±0.17 ​ 1.75±0.20 1.13±0.16 ​ 2.60±0.19 0.37±0.04 ​ 7.88±2.97 3.34±0.65 ​ 2.62±1.07 0.64±0.13 ​ 2.69±1.51 0.98±0.32 ​ 3.39±0.56 1.35±0.25 ​ 1.35±0.20 0.94±0.25 ​ 1.79±0.67 0.95±0.46 ​ 0.22±0.05 0.11±0.02 ​ 9.48±0.38 4.99±0.27 ​ 1.68±0.47 1.77±0.30 ​ 4.61±0.93 4.70±1.08 ​ 3.52±0.34 3.15±0.82 ​ 5.42±0.81 4.41±1.10 ​ 5.30±2.39 5.25±0.54 ​ 43.98±10.41 45.36±9.02

[0166] Obviously, the above embodiments are only examples for clear illustration and not limitations on the implementation manners. For those of ordinary skill in the art, other different forms of changes or variations can be made based on the above description. It is not necessary and impossible to enumerate all the implementation manners here. And the obvious changes or variations derived therefrom are still within the protection scope of the present invention.​​​

Claims

1. A radioactive nuclide-labeled glucose derivative molecular probe, characterized in that, The molecular probe has the structure shown below: Wherein: n is an integer with a value ranging from 1 to 3; R1 is azidoglucose; the azidoglucose has the structure shown below: R2 is a signal group; the signal group consists of a chelating group and a radionuclide.

2. The molecular probe according to claim 1, wherein The chelating group is NOTA, a NOTA derivative, DOTA or a DOTA derivative; When the chelating group is NOTA, the radionuclide labeling group is 64 Cu, 111 In, 68 Ga or 18 F]AlF3; When the chelating group is DOTA, the radionuclide labeling group is 90 Y, 225 Ac, 68 Ga, 177 Lu or 64 Cu.

3. The molecular probe according to claim 1 or 2, characterized in that, When n is 1, the chelating group is NOTA, and the radionuclide labeling group is 68 Ga, the molecular probe has the structure shown below: When n is 2, the chelating group is NOTA, and the radionuclide labeling group is 68 Ga, the molecular probe has the structure shown below: When n is 3, the chelating group is NOTA, and the radionuclide labeling group is 68 Ga, the molecular probe has the structure shown below: When n is 1, the chelating group is DOTA and the radionuclide labeling group is 68 Ga, the molecular probe has the structure shown below: When n is 2, the chelating group is DOTA, and the radionuclide labeling group is 68 Ga, the molecular probe has the structure shown below:

4. The molecular probe according to any one of claims 1 to 3, characterized in that, When n is 1 and the chelating group is NOTA, the labeling precursor of the molecular probe has the structure shown below: When n is 2 and the chelating group is NOTA, the labeling precursor of the molecular probe has the structure shown below: When n is 3 and the chelating group is NOTA, the labeling precursor of the molecular probe has the structure shown below: When n is 1 and the chelating group is DOTA, the labeling precursor of the molecular probe has the structure shown below: When n is 2 and the chelating group is DOTA, the labeling precursor of the molecular probe has the structure shown below:

5. The molecular probe according to any one of claims 1 to 4, characterized in that, The molecular probe targets glucose transporters.

6. A method for preparing the molecular probe according to any one of claims 1 to 5, characterized in that, When n is 1, the method includes: chelating the compound SDG with NOTA-NHS or DOTA-NHS to obtain the labeling precursor of the molecular probe; performing radionuclide labeling on the labeling precursor of the molecular probe to obtain the molecular probe; When n is 2, the method includes: chelating the compound DDG with NOTA-NHS or DOTA-NHS to obtain the labeling precursor of the molecular probe; performing radionuclide labeling on the labeling precursor of the molecular probe to obtain the molecular probe; When n is 3, the method includes: chelating the compound TDG with NOTA-NHS or DOTA-NHS to obtain the labeling precursor of the molecular probe; performing radionuclide labeling on the labeling precursor of the molecular probe to obtain the molecular probe; The compound SDG has the structure shown below: The compound DDG has the structure shown below: The compound TDG has the structure shown below:

7. Use of the molecular probe according to any one of claims 1 to 5 in the preparation of an imaging agent targeting glucose transporters.

8. A imaging agent targeting glucose transporters, characterized in that, The composition of the imaging agent contains the molecular probe according to any one of claims 1 to 5.

9. Use of the molecular probe according to any one of claims 1 to 5 in the preparation of a tumor imaging agent.

10. A tumor imaging agent, characterized in that, The composition of the imaging agent contains the molecular probe according to any one of claims 1 to 5.

Images