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Synthesis of piperidinyl and pyrrolidinyl butyrates for potential In Vivo measurement of cerebral butyrylcholinesterase activity
Author(s) -
Kikuchi Tatsuya,
Fukushi Kiyoshi,
Ikota Nobuo,
Ueda Takao,
Nagatsuka Shinichiro,
Arano Yasushi,
Irie Toshiaki
Publication year - 2001
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.429
Subject(s) - butyrylcholinesterase , acetylcholinesterase , chemistry , in vivo , cholinesterase , cholinergic , biochemistry , hydrolysis , aché , enzyme , pharmacology , medicine , microbiology and biotechnology , biology
Biochemical changes in postmortem brains of Alzheimer's disease patients include decreased acetylcholinesterase and choline acetyl transferase activity, indicating reduced activity of the central cholinergic system, while butyrylcholinesterase (BChE) activity increases. A method that can measure regional BChE activity in the brain in vivo may be useful for investigating the relationship between BChE and Alzheimer's disease. Seven compounds, either piperidinyl or pyrrolidinyl butyrates, were synthesized as BChE substrate radiotracers to map central BChE activity in vivo by positron emission tomography (PET). 14 C‐labeled compounds were assayed to determine their hydrolysis rates by BChE and the partition coefficient. The five esters of secondary alcohols had lipophilic properties sufficient to pass readily through the blood‐brain barrier while the metabolites were sufficiently hydrophilic to be retained in the brain. The esters showed moderate hydrolysis rates by BChE and high specificity for BChE relative to acetylcholinesterase, while two esters of primary alcohols were hydrolyzed too rapidly to estimate reliably the local cerebral BChE activity. From these results, we conclude that one or more of these five esters, when labeled with 11 C, would be a useful tracer for quantification of BChE activity by PET. Copyright © 2001 John Wiley & Sons, Ltd.