In Vivo Evaluation of N-[F-18]Fluoroethylpiperidin-4ylmethyl Acetate in Rats Compared With MP4A as a Probe for Measuring Cerebral Acetylcholinesterase Activity

摘要

[C-11]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 F-18 has a longer half-life than C-11, F-18-labeled derivatives of [C-11]MP4A allow delivery of the probe to other PET centers, making AChE measurement more widely applicable. Previously, N-[F-18]fluoroethylpiperidin-4ylmethyl acetate ([F-18]FEP-4MA) showed that the F-18-labeled analog of MP4A possessed desirable properties for the quantification of cerebral AChE activity by PET. Here, we evaluated the in vivo kinetics of [F-18]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 [F-18]FEP-4MA and the hydrolyzed metabolite at 0-60-min post-injection. When the authentic radioprobe was not observed in the brain, the regional F-18 uptake in the brain correlated well with regional MP4A uptake, and the elimination rate of F-18 from the brain was higher than that of the metabolite of MP4A. The responsiveness of regional F-18 uptake in the brain was examined by simultaneous assay of F-18 concentration, relative blood flow, and AChE activity. Regional F-18 uptake correlated with regional AChE activity as well as that of MP4A. Therefore, we concluded that [(18)]FEP-4MA would be applicable to clinical PET study for quantifying cerebral AChE activity. Synapse 64:209-215, 2010.