Is subnanomolar binding affinity required for the in vivo imaging of acetylcholinesterase? Studies on 18F-labeled G379

Acetylcholinesterase (AChE) is an important cholinergic marker of Alzheimer's disease (AD) and shows reduced activity in postmortem AD brain tissues. 1-(4-Fluorobenzyl)-4-[(5,6-dimethoxy-1-oxoindan-2-fluoro-2-yl)methyl]piperidine (G379, 1), an AChE inhibitor with a subnanomolar IC50 (0.56 nM), was prepared as a 18F-labeled radioligand ([18F]1) and evaluated in mice. Metabolism studies of [18F]1 showed no metabolites in the mouse brain. Tissue distribution studies demonstrated its uniform regional distribution in the mouse brain, suggesting that this radioligand is not suitable for the in vivo imaging of AChE. This result along with reports on radiolabeled N-benzylpiperidine lactam benzisoxazole (IC50<1 nM) and other radiolabeled benzylpiperidine derivatives (IC50>1 nM) suggested that a subnanomolar IC50 may not be the only important factor in determining the suitability of a radioligand for in vivo studies of AChE.