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Programmed cell death protein receptor-1 targeted molecular probe and preparation

A technology of cell death and molecular probes, applied in preparations for in vivo experiments, radioactive carriers, in vivo radioactive preparations, etc., can solve the problem of difficult to predict the targeting effect of PD-L1, few researches and reports on small molecule probes, Problems such as compound structure changes, to achieve good radioactivity specific activity, low cost, and easy synthesis

Active Publication Date: 2020-12-04
JIANGSU INST OF NUCLEAR MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

WL12 is a successful precedent for the design of PD-L1 tracers, but there are few research reports on PD-L1 imaging using small molecule probes. The main reason is that for small molecule compounds, small differences may lead to Its role is completely different. For example, after choosing to modify a radioactive group on a compound targeting PD-L1, the structure of the compound has changed, and it is difficult to predict whether it still has a PD-L1 targeting effect
Therefore, there are very few related studies and reports on small molecule probes for PD-L1 imaging

Method used

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  • Programmed cell death protein receptor-1 targeted molecular probe and preparation
  • Programmed cell death protein receptor-1 targeted molecular probe and preparation
  • Programmed cell death protein receptor-1 targeted molecular probe and preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1 Synthesis of the PET probe precursor LN targeted by programmed cell death protein receptor-1

[0067] The PET probe precursor LN has a structure shown in the following formula:

[0068]

[0069] The synthetic route map of described PET probe precursor LN is as follows:

[0070]

[0071] The preparation method is as follows:

[0072] (1) Synthesis of Compound L1

[0073] First, a total of 200 ml of solvent (1,4-dioxane: pure water = 4:1, v / v) was blown through nitrogen to remove oxygen in the mixed solvent. Take benzo-1,4-dioxane-6-boronic acid (1.8g, 0.01mol), 3-bromo-2-methylbenzyl alcohol (2.0g, 0.01mol), anhydrous potassium carbonate (13.0g, 0.09mol) into a reaction flask, put a magnetic stirrer, and then add tetrakis(triphenylphosphine)palladium (1.0g, 0.80mmol). Insert a drying condenser into the reaction bottle, inject the solvent, heat at 100°C under the protection of nitrogen, reflux the condensed water, and react for 24 hours. After the rea...

Embodiment 2

[0094] Example 2 Programmed cell death protein receptor-1 targeted PET probe [ 18 F] Synthesis of LN

[0095] The PET probe [ 18 F]LN has the structure shown in the following formula:

[0096]

[0097] The PET probe [ 18 F]LN's marked route is as follows:

[0098]

[0099] The specific marking method is as follows:

[0100] (1) Before marking:

[0101] a. Sep-Pak light QMA column activation: draw 10mL of 0.5M sodium bicarbonate (NaHCO 3 ) solution, slowly pour it into the column for cleaning, then draw 10mL of sterile water for injection for cleaning, and finally suck air into the syringe to dry the QMA column. After activation, the QMA column is hung up and ready to be passed to the target.

[0102] b. Sep-Pak light C18 column activation: first take 10mL of ethanol and slowly inject the C18 column, and then wash it with 10mL sterile water for injection.

[0103] c. Preparation of labeling precursor: 10 mg of compound LN was dissolved in 465 μL of DMF to prepare ...

experiment example 1

[0107] Experimental example 1 in vitro stability study

[0108] After purification the probe [ 18 F] LN was incubated with PBS buffer (pH=7.4) or mouse serum for different times to evaluate, specifically: 50 μL probe [ 18 F] LN (37MBq) were mixed with 450 μL PBS or mouse serum solution, and then placed at 37°C for different time (1, 2, 4 hours). Among them, serum stability is at each detection time point, take about 20 μ L of the mixed solution and add an equal volume of acetonitrile to precipitate and centrifuge to remove protein impurities, and take the supernatant for radioactive HPLC analysis.

[0109] The result is as Figure 13 As shown, [ 18 F] LN was incubated with mouse serum or PBS at 37°C for 1 to 4 hours, showing a single peak in the HPLC spectrum, and also obtained good stability.

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Abstract

The invention relates to the technical field of radiopharmaceutical chemistry, and particularly relates to a programmed cell death protein receptor-1 targeted molecular probe and a preparation methodand application thereof. According to the programmed cell death protein receptor-1 targeted molecular probe, the small-molecule probe has medium affinity to target PD-L1, can be selectively taken in aPD-L1 positive tumor site, can well distinguish negative and positive tumors, has response to a PD-L1 high-expression tumor site, and can be used for developing a PD-L1 small-molecule PET developer.

Description

technical field [0001] The invention relates to the technical field of radiopharmaceutical chemistry, in particular to a programmed cell death protein receptor-1 targeting molecular probe, its preparation and application. Background technique [0002] Cancer, also known as malignant tumor, is the transformation of normal human cells into abnormal cells, namely cancer cells, under the action of exogenous or endogenous carcinogenic factors. Common clinical cancer treatment methods include surgery, chemotherapy, radiotherapy and biological therapy. Immunotherapy, which mobilizes the immune system to kill tumor cells, is considered to be one of the most promising methods for treating cancer, among which immune checkpoint blockade therapy is particularly effective. Programmed cell death protein 1 (PD-1) is an important immunosuppressive checkpoint with two ligands, PD-L1 or PD-L2. The ligand PD-L1 is a 40kDa type 1 transmembrane protein, which mainly exists on the surface of mo...

Claims

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Application Information

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IPC IPC(8): C07F5/02A61K51/04A61L101/02
CPCC07F5/02A61K51/0453C07B2200/05
Inventor 吕高超林建国邱玲谢敏浩缪银杏陈银飞
Owner JIANGSU INST OF NUCLEAR MEDICINE
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