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Molecular probe for cancer diagnosis, application and synthesis method

A technology of molecular probes and atoms, applied in organic chemical methods, preparations for in vivo experiments, pharmaceutical formulations, etc., can solve the problems of molecular probes that have not yet been reported, and achieve the effect of long imaging duration and high specificity

Inactive Publication Date: 2020-11-10
XIEHE HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI & TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] So far, no nuclide-labeled molecular probes have been reported to non-invasively trace MELK in the body

Method used

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  • Molecular probe for cancer diagnosis, application and synthesis method
  • Molecular probe for cancer diagnosis, application and synthesis method
  • Molecular probe for cancer diagnosis, application and synthesis method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment 1, the preparation of molecular probe and reference product

[0061] 11 C-methoxy-OTSSP167 was obtained by using 11 C-MeI radiolabeled OTSSP167 was prepared using an automated General Electric Tracerlab FXc synthesizer. Synthesis process: generated externally by the cyclotron 11 C-CO 2 . and transported into the reactor with H 2 mix, generate 11 C-CH 4 . Generated 11 C-CH 4 React with sublimated iodine at 720°C to form methyl iodide ( 11 C-CH 3 I). 11 CH 3 I went into a reaction vial (room temperature, 1 mg OTSSP167 in 5N NaOH / 400 μl DMSO). The mixture was reacted at 65°C for 5 minutes, and then cooled to 30°C. The crude radiolabeled mixture enters HPLC for separation and purification, the radioactive peak components are collected and filtered through a 0.22 μm sterile filter membrane to obtain the product 11 C-Methoxy-OTSSP167. Radiochemical purity was determined by radioactive high performance liquid chromatography (HPLC, 250 mm x 4.6 mm). ...

Embodiment 2

[0066] Embodiment 2, stability of molecular probe in vivo and in vitro

[0067] Will 11 C-methoxy-OTSSP167 (3.7MBq) was incubated in PBS and fetal bovine serum at 37°C for 90 minutes, and the 18 F-Ethyl-OTSSP167 was incubated in PBS and fetal bovine serum for 1, 2 and 4 hours at 37°C to investigate the stability in vitro and in vitro-mimicking in vivo. For the PBS group, samples (~10 kBq) were directly used for radio-HPLC analysis. For the FBS group, the same volume of acetonitrile was added, and then the mixture was centrifuged (4000 rpm, 5 min) to precipitate serum proteins. The supernatant (~10kBq) was taken for radioactive high-performance liquid chromatography analysis.

[0068] Normal mice were used for evaluation 11 C-methoxy-OTSSP167 and 18 In vivo stability of F-ethyl-OTSSP167. Mice were anesthetized intraperitoneally with 1% sodium pentobarbital in water (0.1 mL / 20 g mouse). Each mouse was injected via the tail vein 11 C-Methoxy-OTSSP167 (3.7-7.4 MBq, 150 mic...

Embodiment 3

[0071] Example 3, Affinity Determination of Molecular Probes and Breast Cancer Cells

[0072] 11 C-methoxy-OTSSP167 and 18 The binding affinity of F-ethyl-OTSSP167 to MDA-MB-231 and MCF-7 breast cancer cells was measured by cellular uptake assay. Briefly, experiments were performed in 24-well plates (2×10 5 / well, 0.5 ml culture medium), the plate was mixed with 11 C-Methoxy-OTSSP167 (2nM, 0.074MBq) in 0.5ml serum-free DMEM was incubated at 37°C for 10 minutes, 30 minutes, 60 minutes and 90 minutes, with 18 F-Ethyl-OTSSP167 (2 nM, 0.074 MBq) was incubated in 0.5 ml serum-free DMEM at 37°C for 30 min, 60 min, 120 min and 240 min. Cells were then washed twice with 1 mL of PBS and dissolved with 0.8 mL of 1M NaOH. Radioactivity in cell lysates was counted using an automated well gamma counter (PerkinElmer WIZARD2 2470, Shelton CT, USA). For blocking studies, in the presence of 100 nM unlabeled OTSSP167 at 37 °C with 11 C-methoxy-OTSSP167 (2nM) or 18 F-Ethyl-OTSSP167 (2nM)...

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Abstract

The invention relates to the field of molecular detection, in particular to a molecular probe of an MELK inhibitor, provides a molecular probe of which the structure is shown as a chemical formula (I), and further provides application and a preparation method of the molecular probe. The molecular probe disclosed by the invention can be used for well imaging tumors with high MELK expression, particularly triple negative breast cancer, and is high in specificity and long in imaging duration.

Description

technical field [0001] The present invention relates to the field of molecular detection, more specifically, to molecular probes of MELK inhibitors, which are used for early diagnosis of cancer, more particularly, for early diagnosis of triple-negative breast cancer. Background technique [0002] Maternal embryonic leucine zipper kinase (MELK) is a serine / threonine protein kinase that belongs to the AMP-activated protein kinase-related kinase family. It is highly expressed in breast cancer (especially triple negative breast cancer, TNBC), melanoma, colon cancer, glioma, astrocytoma and other tumor cells and tumor stem cells, and plays a role in tumor cell cycle regulation and play a key role in growth signaling pathways. DBNL and PSMA1 are novel substrates of MELK that are critical for stem cell identity and invasion. MELK can phosphorylate DBNL Ser269, activate the regulatory function of DBNL-14-3-3 signaling pathway, promote the growth and migration of cancer cells, and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K51/04A61K101/02A61K101/00
CPCA61K51/0455C07B2200/05C07D471/04
Inventor 兰晓莉胡佳盖永康唐荣梅李坤胡帆龚成鹏
Owner XIEHE HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI & TECH UNIV
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