Syntheses of carbon-11 labeled piperidine esters as potential in vivo substrates for acetylcholinesterase.
A series of carbon-11 labeled N-methylpiperidinyl esters were prepared as potential in vivo substrates for acetylcholinesterase (AChE). Target compounds were designed based on the structure of N-[11C]methylpiperidin-4-yl propionate, an ester currently used to measure AChE enzymatic activity in the human brain, to examine the structure-activity relationship for in vivo enzymatic hydrolysis. Changes in steric bulk and in the ester order ("reverse" esters) were made. Addition of methyl groups was made to both the acid side chain (synthesis of N-[11C]methylmethylpiperidin-4-yl isobutyrate) and to the piperidine ring (syntheses of N-[11C]methyl-4-methylpiperidin-4-yl propionate, N-[11C]methyl-4-methylpiperidin-4-yl acetate, and N-[11C]methyl-3-methylpiperidin-4-yl propionate). Alterations of the order of the ester heteroatoms was accomplished through syntheses of the N-[11C]methyl-2,3- and 4-piperidinecarboxylic acid ethyl esters. Finally, an additional piperidine-based ester (N-[11C]methylpiperidin-2-yl)methyl propionate was also prepared. All carbon-11-labeled esters were prepared by N-[11C]methylation reactions, using the desmethyl precursors and no-carrier-added [11C]methyltriflate, and were obtained in decay-corrected yields (not optimized) of 10-40% and high specific activities.
Nguyen
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TB
Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor 48109-0028, USA.
Snyder
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SE
Kilbourn
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MR
D000110:Acetylcholinesterase / Q000378:metabolism*; D001812:Blood-Brain Barrier; D001921:Brain / Q000201:enzymology*; D002250:Carbon Radioisotopes; D004952:Esters; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014055:Tomography, Emission-Computed
D002250:Carbon Radioisotopes; D004952:Esters; D010880:Piperidines; D019275:Radiopharmaceuticals; D000110:Acetylcholinesterase