In vivo studies of acetylcholinesterase activity using a labeled substrate, N -[ 11 C]methylpiperdin-4-yl propionate ([ 11 C]PMP)

Abstract

Two esters, N -[ 11 C]methylpiperidyl acetate ([ 11 C]AMP) and N -[ 11 C]methylpiperidyl propionate ([ 11 C]PMP), were synthesized in no-carrier-added forms and evaluated as in vivo substrates for brain acetylcholinesterase (AChE). After peripheral injection in mice, each ester showed rapid penetration into the brain and a regional retention of radioactivity (striatum > cortex, hippocampus > cerebellum) reflecting known levels of AChE activity in the brain. Regional brain distributions after [ 11 C]PMP administration showed better discrimination between regions of high, intermediate, and low AChE activities. Chromatographic analysis of blood and brain tissue extracts showed rapid and nearly complete hydrolysis of [ 11 C]PMP within 10 min after injection. For both [ 11 C]AMP and [ 11 C]PMP, retention of radioactivity in all regions was reduced by pretreatment with diisopropylfluorophosphate (DFP), a specific irreversible AChE inhibitor. DFP treatment also significantly increased the proportions of unhydrolyzed ester in both blood and brain. Radioactivity localization in brain after peripheral injection was thus dependent on AChE-catalyzed hydrolysis to the hydrophilic product N -[ 11 C]methylpiperidinol. PET imaging of [ 11 C]AMP or [ 11 C]PMP distributions in monkey brain showed clear accumulation of radioactivity in areas of highest AChE activity (striatum, cortex). These esters are thus in vivo substrates for brain AChE, with potential applications as in vivo imaging agents of enzyme action in the human brain. [ 11 C]PMP, the ester with a slower rate of hydrolysis, appears to be the better candidate radiotracer for further development. © 1996 Wiley-Liss, Inc.