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18F-labeled polypeptide tumor apoptosis detection reagent, and preparation method and application thereof

A 18F and labeling technology, which is applied in the fields of radiopharmaceuticals and nuclear medicine, can solve the problems of long labeling time, harsh reaction conditions, cumbersome steps, etc., and achieve the effect of easy separation, mild reaction conditions and high purity

Active Publication Date: 2017-08-18
JIANGSU INST OF NUCLEAR MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, these labeled probes have some defects in radioactive labeling. First of all, in terms of preparation methods, the existing labeled probes are completed by a two-step method: first, the nucleophilic substitution reaction is used to synthesize 18 F ions are introduced, and then the labeling group is connected to the polypeptide sequence through a "click chemistry" reaction to obtain the target probe
Among them, the fluorination process needs to be carried out under anhydrous conditions, and semi-preparative HPLC method is required for purification. The reaction conditions are harsh and the steps are cumbersome, which leads to too long labeling time

Method used

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  • 18F-labeled polypeptide tumor apoptosis detection reagent, and preparation method and application thereof
  • 18F-labeled polypeptide tumor apoptosis detection reagent, and preparation method and application thereof
  • 18F-labeled polypeptide tumor apoptosis detection reagent, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Synthesis of Example 1 Labeled Precursor

[0052] The synthetic route of labeled precursor 1 described in this example is as follows:

[0053]

[0054] The synthesis of the labeled precursor 1 described in this example comprises the following steps:

[0055] (1) Connecting amino acids: Weigh 2-chlorotrityl chloride resin (544mg, Loading value: 1.106mmol / g) into a three-way sand core funnel, then add 10mL of dichloromethane (DCM) solvent, shake for 10min , drain the solvent;

[0056] Fmoc-L-aspartic acid beta-tert-butyl ester (272mg, 0.662mmol) was weighed and dissolved in 3mL DMF solvent, then DIPEA (200μL, 1.212mmol) was added, ultrasonically dissolved and added to a sand core funnel to react with the resin, and Shake at room temperature for 2 h; then drain the solvent, and add 7 mL of solution R (chromatographically pure DMF: CH 3 OH:DIPEA=17:2:1) Wash and shake in the three-way sand core funnel for 10min, drain the solvent, then wash with 7mL DMF solvent, then ...

Embodiment 2

[0077] Embodiment 2 polypeptide compound 18 F-AmBF 3 - Synthesis of GDEVD

[0078] Electron bombardment of oxygen-enriched water H 2 18 O, get 18 F ion, adsorbed by anion exchange column (QMA) 18 For F ions, use 300 μL of pyridazine (pH=2.5) buffer to 18 F ions were eluted from the QMA column, transferred to a 1 mL labeled reaction tube, added 10-20 μL (25 mmol / L, dissolved in DMF) of the labeled precursor compound 1 prepared in Example 1, and heated at 80 °C 30min reaction to get the peptide compound 18 F-AmBF 3 -GDEVD, denoted as probe 18 F-1.

[0079] Dilute a small amount of radioactive solution, and detect the labeling of the precursor by radioactive high-performance liquid phase. Add 20 mL of deionized water to the reaction solution for dilution, pass through a C18 column (SepPak plus C-18), wash with deionized water (10 mL) three times, and finally use 0.5 mL of ethanol to rinse the labeled product into a vial, add 4.5 Dilute with mL deionized water (ethanol ...

experiment example

[0083] 1. Determination of stability in PBS and serum

[0084] In order to simulate the in vivo environment, the 18 Stability of F-1 in PBS (pH=7.4) and serum. Take 4 parts of 400 μL PBS (pH=7.4) buffer and 100 μL labeled product 18 The F-1 solutions were mixed separately and heated at 37°C for 0.5, 1, 2, 3 and 4 h, respectively. A small amount of solution was taken for dilution, and the stability of the labeled product was detected by radioactive high-performance liquid phase.

[0085] Take 4 aliquots of 400 μL FBS and 100 μL labeled product 18 The F-1 solutions were mixed separately and incubated at 37°C for 0.5, 1, 2, 3 and 4 hours respectively. After the time point, 500 μL of acetonitrile was added, centrifuged at 12,000 g / min for 5 min with a high-speed centrifuge, and the supernatant was taken, and the stability of the labeled product was detected by radioactive high-performance liquid chromatography.

[0086] Detection of different incubation time points by radioac...

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Abstract

The invention belongs to the technical field of radiopharmaceuticals and nuclear medicine, in particular relates to an 18F-labeled polypeptide compound, and further discloses application thereof in preparation of a tumor apoptosis detection reagent. According to the 18F-labeled polypeptide compound 18F-AmBF3-GDEVD (probe 18F-1), high-yield and high-purity polypeptide is synthesized by using a solid-phase polypeptide synthesis method, an 18F-labeling group is introduced by 'click chemistry' to obtain a high-yield labeling precursor 1; a high-yield and high-purity PET probe 18F-1 is further successfully prepared by one-step 18F-labeling method. The whole reaction simplifies the step of 18F-labeling, the semi-preparation HPLC purification in a labeling process is avoided, and the labeling time is shortened. Meanwhile, the probe 18F-1 is displayed to be a potential targeted Caspase-3 apoptosis development probe, and has a good application prospect.

Description

technical field [0001] The invention belongs to the technical field of radiopharmaceuticals and nuclear medicine, and specifically relates to a 18 An F-labeled polypeptide tumor apoptosis detection reagent, and further discloses its preparation method and application. Background technique [0002] Inducing tumor cell apoptosis is one of the main mechanisms of various tumor treatments, so determining whether tumor cells undergo apoptosis has become an important indicator for evaluating the efficacy of tumor treatment. The current methods for detecting tumor cell apoptosis mainly include in vitro and in vivo methods: the traditional in vitro detection method is relatively mature, but it can only detect the apoptosis state at a certain time point, and cannot detect tumor cell apoptosis in real time and dynamically Therefore, the extensive clinical application of in vitro detection methods is limited. The in vivo detection method has received extensive attention because it can...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/13C07K1/06C07K1/04C12Q1/02
CPCC07K7/06G01N33/5044
Inventor 邱玲林建国李珂吕高超彭莹刘清竹
Owner JIANGSU INST OF NUCLEAR MEDICINE
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