Estimation of plasma IC50 of donepezil hydrochloride for brain acetylcholinesterase inhibition in monkey using N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) and PET.

Donepezil hydrochloride is a potent and selective inhibitor for brain acetylcholinesterase (AChE) and is currently used worldwide for the treatment of Alzheimer's disease. Until now, there is no in vivo study on the relation between the plasma concentration and the brain AChE inhibition. The purpose of this study was to estimate in vivo plasma IC(50) of donepezil in living monkeys by measuring plasma donepezil concentration (LC/MS/MS) and brain AChE activity with positron emission tomography (PET) and N-[(11)C]methylpiperidin-4-yl acetate, which is an acetylcholine analog recently developed by us for quantifying in vivo brain AChE activity. PET scans with donepezil at two doses, 100 microg/kg (donepezil-1; N=5) or 250 microg/kg (donepezil-2; N=5), were performed using the same monkeys at 4-week intervals. Before each PET scan, baseline PET scans (N=10 in total) were performed without donepezil. The plasma donepezil concentrations 14 min after intravenous injection were proportional to the doses, 17.2+/-2.9 ng/ml (donepezil-1) and 44.0+/-5.0 ng/ml (donepezil-2), and the mean AChE inhibitions in four neocortical regions as evaluated by PET were also dose-dependent, 27% (donepezil-1) and 53% (donepezil-2). In IC(50) estimation, measured plasma donepezil concentrations were corrected for the change during PET scan. The IC(50) values (estimate+/-SE) were 42+/-9.0 (ng/ml; donepezil-1), 34+/-3.2 (donepezil-2), and 37+/-4.1 (combined data). The present method may be useful for in vivo evaluation of other AChE inhibitors and novel drugs.