N-methylpiperidinemethyl, N-methylpyrrolidyl and N-methylpyrrolidinemethyl esters as PET radiotracers for acetylcholinesterase activity.
The N-[(11)C]methylpiperidinyl esters are used as radiopharmaceuticals for measuring brain cholinesterase activity. We have synthesized a series of N-methylpiperidinemethyl (1), N-methylpyrrolidinyl (2) and N-methylpyrrolidinemethyl (3) esters and examined the effects of sterric constraint and stereochemistry on cholinesterase-mediated cleavage. Acetylcholinesterase exhibited a preference for primary esters 1 and for the R-isomers of both 1 and 2. Biological data for (S)-N-[(11)C]methyl-2-piperidinemethyl acetate (1a) were similar to [(11)C]AMP. These data better define the structure-activity relationships for cholinesterase radiotracers and provide lead compounds for (18)F- labeling.
Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Xia
X
Shao
Jacinda M
JM
Lisi
Elizabeth R
ER
Butch
Michael R
MR
Kilbourn
Scott E
SE
Snyder
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004952:Esters; D005260:Female; D006868:Hydrolysis; D051379:Mice; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014055:Tomography, Emission-Computed
D004952:Esters; D010880:Piperidines; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D000110:Acetylcholinesterase