Design, synthesis and biological evaluation of 1,4-Diazobicylco[3.2.2]nonane derivatives as α7-Nicotinic acetylcholine receptor PET/CT imaging agents and agonists for Alzheimer's disease.

Abstract

α7-Nicotinic acetylcholine receptor (α7-nAChR) agonists are promising therapeutic drug candidates for treating the cognitive impairment associated with Alzheimer's disease (AD). Thus, a novel class of derivatives of 1,4-diazobicylco[3.2.2]nonane has been synthesized and evaluated as α7-nAChR ligands. Five of them displayed high binding affinity (Ki = 0.001-25 nM). In particular, the Ki of 14 was 0.0069 nM, which is superior to that of the most potent ligand that was previously reported by an order of magnitude. Four of them had high selectivity for α7-nAChRs over α4β2-nAChRs and no significant hERG (human ether-a-go-go-related gene) inhibition. Their agonist activity was also discussed preliminarily. One of the compounds, 15 (Ki = 2.98 ± 1.41 nM), was further radiolabeled with 18F to afford [18F]15 for PET imaging, which exhibited high initial brain uptake (11.60 ± 0.14%ID/g at 15 min post injection), brain/blood value (9.57 at 30 min post injection), specific labeling of α7-nAChRs and fast clearance from the brain. Blocking studies demonstrated that [18F]15 was α7-nAChR selective. In addition, micro-PET/CT imaging in normal rats further indicated that [18F]15 had obvious accumulation in the brain. Therefore, [18F]15 was proved to be a potential PET radiotracer for α7-nAChR imaging.

• Authors: Shuxia Wang, Yu Fang, Huan Wang, Hang Gao, Guohua Jiang, Jianping Liu, Qianqian Xue, Yueheng Qi, Mengying Cao, Bingchao Qiang, Huabei Zhang
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 159 Pg. 255-266 (Nov 05 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 30296684 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Ether-A-Go-Go Potassium Channels
• alpha7 Nicotinic Acetylcholine Receptor

Topics

• Alzheimer Disease (diagnostic imaging, drug therapy, metabolism)
• Animals
• Bridged Bicyclo Compounds, Heterocyclic (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Design
• Ether-A-Go-Go Potassium Channels (antagonists & inhibitors, metabolism)
• Female
• Humans
• Male
• Mice
• Mice, Inbred Strains
• Molecular Structure
• Positron Emission Tomography Computed Tomography
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship
• Tissue Distribution
• alpha7 Nicotinic Acetylcholine Receptor (agonists, analysis)