Nuclear medicine program. Progress report for quarter ending June 30, 1995

In this report we describe the first synthesis of the (-)(-) and (-)(+) isomers of 1-azabicyclo oct-3-yl {alpha}-(1-fluoropent-5-yl)-{alpha}-hydroxy-{alpha}-phenylacetate ({open_quotes}FQNPe{close_quotes}). Earlier studies with the racemic FQNPe mixture had demonstrated high in vitro binding affinity for the muscarinic-cholinergic receptor and showed that pre-treatment of rats with this new agent significantly blocked receptor localization of subsequently injected -Z-(-,-)-IQNP. Because of the potential important use of fluorine-18-labeled analogues for clinical evaluation of changes in muscarinic-cholinergic receptors by positron emission tomography (PET), we have now synthesized the diastereomeric isomers of FQNPe. Multi-gram quantities of ethyl-{alpha}- (1-chloropent-5-yl)-{alpha}-hydroxy-{alpha}-phenylacetate were prepared and then saponified into the racemic {alpha}-(1-chloropent-5-yl)-{alpha}-hydroxy-{alpha}-phenylacetic acid mixture. The racemic acid was resolved into (-)- and (+)-{alpha}-(1-chloropent-5-yl)-{alpha}-hydroxy-{alpha}-phenylacetic acid enantiomers by isolation of the (-) salt of (S-)-(-)-{alpha}-methylbenzylamine and the (+) salt of (R)-(+)-{alpha}-methylbenzylamine. The resolved (-)- ([{alpha}]{sub D} = -12.1{degrees}, c = 5.8, chloroform) and (+)-acetic acids ([{alpha}]{sub D} = + 11.6{degrees}, c = 6.0, chloroform) were fully characterized and then converted to the enantiomeric ethyl-{alpha}-(1-fluoropent-5-yl)-{alpha}-hydroxy-{alpha}-phenylacetates by a four-step reaction sequence. The (-)- and (+)-ethyl-{alpha}-(1-fluoropent-5-yl)-{alpha}-hydroxy-{alpha}-phenylacetates were then each transesterified with (-)-quinuclidinol to form the (-)(-) FQNPe and (-)(+) FQNPe diastereomers. These diastereomeric esters will now be evaluated in in vitro studies. The availability of the substrates for preparation of the fluorine-18-labeled enantiomers will now allow evaluation of the radiolabeled compounds in animals.