Nir/pet bimodal probe precursor targeting cyp1b1 enzyme and its preparation and use

A dual-mode, probe technology, applied in the direction of in vivo radioactive preparations, in vivo test preparations, radioactive carriers, etc., can solve the problem of low diagnostic specificity, difficult diagnosis, and near-infrared single-mode molecular probe penetration Problems such as limited depth, to achieve the effect of deep non-destructive testing, large detection depth, good application prospects and clinical transformation value

Active Publication Date: 2022-06-28
SHANGHAI JIAO TONG UNIV
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Problems solved by technology

Through the NIR and PET imaging of the expression level of intracellular CYP1B1 enzyme, it provides a new method for the early diagnosis and treatment of tumors, and solves the current difficulties in diagnosis and low diagnostic specificity in tumor treatment and the penetration of near-infrared single-mode molecular probes. The problem of limited penetration depth

Method used

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  • Nir/pet bimodal probe precursor targeting cyp1b1 enzyme and its preparation and use
  • Nir/pet bimodal probe precursor targeting cyp1b1 enzyme and its preparation and use
  • Nir/pet bimodal probe precursor targeting cyp1b1 enzyme and its preparation and use

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Embodiment 1

[0049] This embodiment relates to a method for preparing a NIR / PET bimodal probe with structural formula 6. The synthetic route is as follows figure 1 shown, including the following steps:

[0050] Step 1: Boc-L-glutamic acid methyl ester (1 g, 3.8 mmol) and N-hydroxysuccinimide (NHS) (440 mg, 3.8 mmol) were dissolved in 7 mL of tetrahydrofuran (THF), and then added and dissolved in 5 mL of 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) (594 mg, 3.8 mmol) in dichloromethane (DCM). The reaction was mixed and stirred overnight and monitored by thin layer chromatography (TLC). After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was dissolved in 20 mL of DCM. After that, the solution was washed with water, saturated NaHCO 3 and brine wash. After drying the organic phase with magnesium sulfate, it was concentrated under reduced pressure to obtain compound 2 as a white solid product, yield: 95%. 1 H NMR (400MHz, CDCl 3 ): 5...

Embodiment 2

[0056] The inhibitory activity of compound 5 obtained in Example 1 on CYP1A1, CYP1A2, and CYP1B1 enzymes was determined.

[0057] In this experiment, 7-ethoxy-3H-phenoxazine 3-one deethoxylation (EROD) assay was used to determine its inhibitory activity and selectivity to CYP1A1, CYP1A2, and CYP1B1 enzymes (Yamaori et al, Biochem. Pharmacol. 2010 , 79:1691-1698.). The reaction system (200 μL) contained CYP1A1 (10 fmol), CYP1A2 (60 fmol) or CYP1B1 (20 fmol), different concentrations of the test compound, NADPH regeneration system (1.3 mM NADPNa2, 3.3 mM glucose-6-phosphate, 0.5 U / ml glucose- 6-phosphate-dehydrogenase), 3.3 mM magnesium chloride solution and 150 nM 7-ethoxy-3H-phenoxazin-3-one. Four replicate wells were set up in each experimental group or control group as a parallel experiment. The reaction buffer was 50 mM Tris-HCl (pH 7.4) buffer containing 1% BSA solution. After the reaction system was preheated at 37°C for 5 min, the NADPH regeneration system was added t...

Embodiment 3

[0062] In this example, the confocal microscopy imaging study of the NIR / PET dual-modality molecular probe precursor (compound 6) on the colon cancer cell HCT-15 with high expression of CYP1B1 enzyme was carried out.

[0063] HCT-15 colon cancer cells with high expression of CYP1B1 enzyme were seeded in 8-well Nunc at appropriate density TM Lab-Tek TM Chamber slide system, in a cell incubator at 37 °C, 5% CO 2 After culturing in medium for 24h, aspirate the excess medium, add 2*1μM and 2*0.5μM NIR / PET dual-modality molecular probe precursors respectively, and set up a blocking control group (the blocking group adds 2*1μM probe and 20 μM solution of α-naphthoflavone derivatives), 2 duplicate wells in each group. 37°C, 5% CO 2 After 1 hour incubation in medium, the probe-containing medium was aspirated and washed three times with PBS buffer. Afterwards, the chamber on the slide was removed according to the instructions, and the sealing oil containing the nuclear dye DAPI was...

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Abstract

The present invention provides a NIR / PET bimodal probe precursor targeting CYP1B1 enzymes and its preparation method and application. The bimodal probe precursor includes an affinity ligand, a signal group and a A connecting chain of an affinity ligand and a signal group; the affinity ligand is an α-naphthoflavone derivative, and the signal group is a near-infrared fluorescent molecule and can be 18 The F-labeled chelating group NODA; the connecting chain is a glutamic acid chain with multiple chemical reaction active sites. The present invention is a NIR / PET dual-modal probe precursor targeting CYP1B1 enzyme, a specific marker of tumors. By targeting CYP1B1 enzyme, the accuracy of tumor imaging is improved, and at the same time, the dual-modal signal group The introduction effectively overcomes the limitations of single modality probes, promotes the application of CYP1B1 enzyme in vivo imaging in tumor live imaging, and will have good application prospects and clinical transformation value in the early diagnosis of tumors.

Description

technical field [0001] The present invention relates to the technical field of molecular probes, in particular, to a NIR / PET dual-modality probe precursor targeting CYP1B1 enzyme and its preparation and use. Background technique [0002] Molecular imaging is one of the common methods for tumor diagnosis. It refers to the non-invasive display of a specific molecule at the cellular level and real-time monitoring of its changes through molecular imaging methods. Quantitative research can effectively improve the probability of successful early diagnosis. Molecular imaging utilizes molecular probes to specifically bind to biomarkers, obtains signals from the imaging of molecular probes, and monitors the targeted biomarkers by monitoring signal changes. Therefore, at the technical level, it is not only required that the molecular probe has a strong affinity with the target site, but also that it has cell membrane penetration and non-toxicity. [0003] Commonly used molecular ima...

Claims

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Application Information

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IPC IPC(8): A61K49/00A61K51/04C07D405/12
CPCA61K49/0002A61K49/0021A61K51/0482A61K51/0421A61K49/0052C07D405/12Y02P20/55
Inventor 孟青青王增涛陈冬梅徐婷李绍顺吴志豪范琪琪崔家华
Owner SHANGHAI JIAO TONG UNIV
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