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A kind of α7 nicotinic acetylcholine receptor ligand and its preparation method

An acetylcholine receptor and ligand technology, which is applied in the field of acetylcholine receptor ligands, can solve the problems of low receptor affinity, low specificity connection and the like, and achieves the effects of mild conditions and simple synthesis method.

Inactive Publication Date: 2017-12-15
BEIJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

, although most of the ligands can enter the brain, they all show low receptor affinity, such as drugs[ 11 C] CHIBA-1001 is the only α7nAChR PET imaging agent that has been studied in humans, but it still shows low specific linkage (K i =46)

Method used

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  • A kind of α7 nicotinic acetylcholine receptor ligand and its preparation method
  • A kind of α7 nicotinic acetylcholine receptor ligand and its preparation method
  • A kind of α7 nicotinic acetylcholine receptor ligand and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: the preparation of compound Va1 and Va3

[0029] 1. 4-bromo-2-fluoroaniline (1.9g, 10mmol), potassium ethyl xanthate (3.53g, 22mmol) were dissolved in 20ml anhydrous DMF, in N 2 Under protection, it was heated to 95° C. and reacted for 4 h (TLC confirmed no reactants). The reaction mixture was cooled to room temperature, diluted with 20ml of water, then 27ml of 1M HCl solution was added to make a precipitate, and stirring was continued for 30min, the solid mixture collected by filtration was rinsed with distilled water, and the solid filter cake was dissolved in 34ml of ethyl acetate, and used without Dry over sodium sulfate, remove ethyl acetate by rotary evaporation, and vacuum-dry the residue to generate 2.24 g of 2-mercapto-5-bromobenzothiazole with a yield of 91%.

[0030]

[0031] ②In an ice-water bath and nitrogen protection, add 20ml of sulfonyl chloride to 2-mercapto-5-bromobenzothiazole (2.46g, 10mmol), react at room temperature for 2h, and p...

Embodiment 2

[0041] Embodiment 2: the preparation of compound Va2 and Va4

[0042] ①Dissolve 2-chlorobenzimidazole (1.52g, 10mmol) in 50ml DMF, then add NBS (N-bromosuccinimide) (1.78g, 10mmol) in 5 times, and react at room temperature for 20h, Add 50ml of water, stir for 18h, filter the precipitate, and wash with ice water repeatedly until it is neutral. Then recrystallized from a solution of methanol:water=1:1 to obtain 0.9 g of 2-chloro-5-bromobenzimidazole with a yield of 40%.

[0043]

[0044] ② Dissolve N,N-diisopropylethylamine (0.7mL, 2.213mmol) and 1,4-diazabicyclo[3.2.2]nonane (0.252g, 2mmol) in 5ml DMF at room temperature, A DMF solution (1 ml) of 2-chloro-5-bromobenzothiazole (0.494 g, 2.012 mmol) was added dropwise to the mixed solution under a steady nitrogen flow, and then the temperature was raised to 110° C. for 12 h. After the reaction was completed, the reaction was cooled to room temperature, extracted with ethyl acetate and water to obtain an organic phase, dried ...

Embodiment 3

[0052] Embodiment 3: the preparation of compound Vb1 and Vb3

[0053] 1. reaction process is with step 1. in embodiment 1, gets as the 2-mercapto-5-bromobenzothiazole in embodiment 1;

[0054] 2. reaction process is with step 2. in embodiment 1, obtains as 2-chloro-5-bromobenzothiazole among the embodiment 1;

[0055] 3. reaction process is with step 3. in embodiment 1, obtains as compound I among the embodiment 1;

[0056] 4. reaction process is with step 4. in embodiment 1, obtains as compound II among the embodiment 1;

[0057] 5. reaction process is with step 5. in embodiment 1, obtains as compound Va3 among the embodiment 1;

[0058] 6. At room temperature, add CuI (0.2285g, 1.2mmol, M=190.45), KF (0.0871g, 1.5mmol, M=58.1), and compound Va3 (385.27mg, 1.0mmol) in Example 1, DMF ( 2ml) was added trimethyl(trifluoromethylsilane) (0.1706g, 1.2mmol, M=142.19), the reaction mixture was stirred under nitrogen protection at 60°C for 24h, the reaction mixture was poured into ...

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Abstract

The present invention relates to an alpha7 nicotinic acetylcholine receptor ligand and a preparation method thereof. The ligand includes an agonist and an imaging agent, the agonist is a 1,4-diazabicyclo [3.2.2] nonane-benzo heterocyclic derivative, and the imaging agent is 125I and 18F-trifluoromethyl marker. The derivatives both have good brain uptake, the absorption values in different regions of the brain are basally consistent with the distribution of alpha7nAChR receptors, the uptake of the derives is highest in hippocampus, thalamus, cortex and other regions where the alpha7nAChR receptors targetedly distribute, and the derives can be blocked by known alpha7nAChR ligands but can not be blocked by alpha4beta2 medicine. Therefore, the 1,4-diazabicyclo [3.2.2] nonane-benzo heterocyclic derivative and the 125I and 18F-trifluoromethyl marker are potential agonist and imaging agent for alpha7 nicotinic acetylcholine receptors.

Description

technical field [0001] The present invention relates to a ligand of acetylcholine receptor in the technical field of radiopharmaceutical chemistry and clinical nuclear medicine, in particular to an α7 nicotinic acetylcholine receptor agonist and 125 I. 18 F-trifluoromethyl-labeled imaging agent and its preparation method. Background technique [0002] In China, Alzheimer's disease (senile dementia) is the fourth leading cause of death in humans after heart disease, tumor and stroke. Therefore, the early diagnosis and treatment of senile dementia has become a top priority. Radiopharmaceuticals based on Positron emission tomography (PET) and Single photon emission computed tomography (Single photon emission computed tomography, SPECT) are considered to be the best way to achieve early diagnosis and treatment. [0003] Nicotinic acetylcholine receptor (nAChR) is a kind of gate-transmitter ion channel, which is composed of α subunit (such as α2-α10) and β subunit (β2-β4). Th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/08A61K31/551A61P25/28A61P25/16A61K51/04A61K101/02
CPCC07D487/08
Inventor 张华北吴爱琴刘永娟
Owner BEIJING NORMAL UNIVERSITY
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