Synthesis of fluorine-18 labeled GABA uptake inhibitors

Abstract

The first syntheses of fluorine-18 labeled inhibitors of GABA reuptake [(R,S)-1-{2-{4-[ 18F]fluorophenyl}phenyl}methoxyethyl]piperidine-3-carboxylic acid, (R,S)-1-{2-(4-[ 18F]fluorophenyl)(4-fluorophenyl)methoxyethyl}piperidine-3-carboxylic acid, and (R,S)-1-[2-{(4-[ 18F]trifluoromethyl)phenyl} {(4-trifluoromethyl)phenyl}-methoxyethyl]piperidine-3-carboxylic acid] are described. These N-substituted nipecotic acid derivatives were prepared in no-carrier-added form by the condensation of the appropriately substituted [ 18F]benzhydryl chlorides (prepared in three steps from [ 18F]fluoride ion) with N-(2-hydroxyethyl)nipecotic acid ethyl ester, followed by ester hydrolysis. Overall radiochemical yields were 17–28% (corrected, 150 min synthesis time). A simple new method for synthesis of a [ 18F]trifluoromethyl group by the nucleophilic substitution of a bromodifluoromethyl substituent has also been developed.