IN-VIVO STUDIES OF ACETYLCHOLINESTERASE ACTIVITY USING A LABELED SUBSTRATE, N-[C-11]METHYLPIPERDIN-4-YL PROPIONATE ([C-11]PMP)

Two esters, N-[C-11]methylpiperidyl acetate ([C-11]AMP) and N-[C-11]me thylpiperidyl propionate ([C-11]PMP), were synthesized in no-carrier-a dded forms and evaluated as in vivo substrates for brain acetylcholine sterase (AChE). After peripheral injection in mice, each ester showed rapid penetration into the brain and a regional retention of radioacti vity (striatum > cortex, hippocampus > cerebellum) reflecting known le vels of AChE activity in the brain. Regional brain distributions after [C-11]PMP administration showed better discrimination between regions of high, intermediate, and low AChE activities. Chromatographic analy sis of blood and brain tissue extracts showed rapid and nearly complet e hydrolysis of [C-11]PMP within 10 min after injection. For both [C-1 1]AMP and [C-11]PMP, retention of radioactivity in all regions was red uced by pretreatment with diisopropylfluorophosphate (DFP), a specific irreversible AChE inhibitor. DFP treatment also significantly increas ed the proportions of unhydrolyzed ester in both blood and brain. Radi oactivity localization in brain after peripheral injection was thus de pendent on AChE-catalyzed hydrolysis to the hydrophilic product N-[C-1 1]methylpiperidinol. PET imaging of [C-11]AMP or [C-11]PMP distributio ns 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 viv o imaging agents of enzyme action in the human brain. [C-11]PMP, the e ster with a slower rate of hydrolysis, appears to be the better candid ate radiotracer for further development. (C) 1996 Wiley-Liss, Inc.