In vivo evaluation of N-[18F]fluoroethylpiperidin-4ylmethyl acetate in rats compared with MP4A as a probe for measuring cerebral acetylcholinesterase activity.

[(11)C]MP4A is an established radioprobe for quantification of cerebral acetylcholinesterase (AChE) activity by positron emission tomography (PET) based on the kinetics of AChE-mediated metabolism and metabolite trapping. It has been used to assess the deficiency in cholinergic innervation in the brain of patients with dementia. Because (18)F has a longer half-life than (11)C, (18)F-labeled derivatives of [(11)C]MP4A allow delivery of the probe to other PET centers, making AChE measurement more widely applicable. Previously, N-[(18)F]fluoroethylpiperidin-4ylmethyl acetate ([(18)F]FEP-4MA) showed that the (18)F-labeled analog of MP4A possessed desirable properties for the quantification of cerebral AChE activity by PET. Here, we evaluated the in vivo kinetics of [(18)F]FEP-4MA and validated the responsiveness of brain uptake to AChE activity based on a mathematical model derived from the AChE-mediated trapping rationale and compared it with MP4A in rats. Almost all radioactivity in the brain was composed of [(18)F]FEP-4MA and the hydrolyzed metabolite at 0-60-min postinjection. When the authentic radioprobe was not observed in the brain, the regional (18)F uptake in the brain correlated well with regional MP4A uptake, and the elimination rate of (18)F from the brain was higher than that of the metabolite of MP4A. The responsiveness of regional (18)F uptake in the brain was examined by simultaneous assay of (18)F concentration, relative blood flow, and AChE activity. Regional (18)F uptake correlated with regional AChE activity as well as that of MP4A. Therefore, we concluded that [(18)F]FEP-4MA would be applicable to clinical PET study for quantifying cerebral AChE activity. (c) 2009 Wiley-Liss, Inc.