1. ¹Department of Medical Imaging, National Institute of Radiological Sciences, Graduate School of Medicine, Chiba University, Chiba, Japan
2. ²Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, Japan
3. ³Asahi Neurological Hospital, Chiba, Japan
4. ⁴ADME/TOX Research Institute, Daiichi Pure Chemicals, Ibaraki, Japan
5. ⁵Department of Neurosurgery, Tokyo Women's Medical College Daini Hospital, Tokyo, Japan
6. ⁶Department of Psychiatry, Juntendo University School of Medicine, Tokyo, Japan
7. ⁷Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan

Correspondence: Dr T Irie, Department of Medical Imaging, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan. Tel: +81 43 206 3191; Fax: +81 43 251 7147; E-mail: t_irie@nirs.go.jp

Received 7 December 2004; Revised 17 March 2005; Accepted 18 March 2005; Published online 25 May 2005.

Abstract

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 IC₅₀ of donepezil in living monkeys by measuring plasma donepezil concentration (LC/MS/MS) and brain AChE activity with positron emission tomography (PET) and N-[¹¹C]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 g/kg (donepezil-1; N=5) or 250 g/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, 17.22.9 ng/ml (donepezil-1) and 44.05.0 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 IC₅₀ estimation, measured plasma donepezil concentrations were corrected for the change during PET scan. The IC₅₀ values (estimateSE) were 429.0 (ng/ml; donepezil-1), 343.2 (donepezil-2), and 374.1 (combined data). The present method may be useful for in vivo evaluation of other AChE inhibitors and novel drugs.