title: Synthesis, (18)F-labeling, and biological evaluation of piperidyl and pyrrolidyl benzilates as in vivo ligands for muscarinic acetylcholine receptors.
abstract: A series of 31 compounds based on the piperidyl or pyrrolidyl benzilate scaffold were prepared from methyl benzilate and 4-piperidinol, (R)-(+)-3-piperidinol, or (R)-(+)-3-pyrrolidinol. Amine substituents included alkyl and aralkyl groups. In vitro K(i) values ranged from 0.05 nM to >100 nM. (R)-N-(2-Fluoroethyl)-3-piperidyl benzilate (3-FEPB, 22, K(i) = 12.1 nM) and N-(2-fluoroethyl)-4-piperidyl benzilate (4-FEPB, 8, K(i) = 1. 83 nM) were selected for radiolabeling with fluorine-18. Using alkylation with 2-[(18)F]fluoroethyl triflate, 3-[(18)F]FEPB (42) and 4-[(18)F]FEPB (43) were produced in 7-9% radiochemical yield and >97% radiochemical purity. For in vivo studies, retention was moderate in mouse brain for 42; however, blocking with scopolamine showed that uptake was not muscarinic cholinergic receptor-mediated. Conversely, 43 exhibited high, receptor-mediated retention in mouse brain, with significant clearance after 1 h. These results suggest that 43 could have applications as an in vivo probe for measuring endogenous acetylcholine levels.
authors.affiliation: Departments of Radiology and Neurology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0028, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Skaddan
authors.forename: M R
authors.initials: MR
authors.lastname: Kilbourn
authors.forename: S E
authors.initials: SE
authors.lastname: Snyder
authors.forename: P S
authors.initials: PS
authors.lastname: Sherman
authors.forename: T J
authors.initials: TJ
authors.lastname: Desmond
authors.forename: K A
authors.initials: KA
authors.lastname: Frey
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001561:Benzilates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D005260:Female; D005462:Fluorine Radioisotopes; D007553:Isotope Labeling; D008024:Ligands; D051379:Mice; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012995:Solubility; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D001561:Benzilates; D001593:Benzyl Compounds; D005462:Fluorine Radioisotopes; D008024:Ligands; C416656:N-(2-fluoroethyl)-3-piperidyl benzilate; C416657:N-(2-fluoroethyl)-4-piperidyl benzilate; D010880:Piperidines; D011759:Pyrrolidines; D011976:Receptors, Muscarinic; D000109:Acetylcholine