Synthesis and biological evaluation of both enantiomers of [18F]flubatine, promising radiotracers with fast kinetics for the imaging of α4β2-nicotinic acetylcholine receptors

Both enantiomers of the epibatidine analogue flubatine display high affinity towards the alpha 4 beta 2 nicotinic acetylcholine receptor (nAChR) in vitro, accompanied by negligible interactions with diverse off-target proteins. Extended single dose toxicity studies in rodent indicated a NOEL (No Observed Effect Level) of 6.2 mu g/kg for (-)-flubatine and 1.55 mu g/kg for (+)-flubatine. We developed syntheses for both flubatine enantiomers and their corresponding precursors for radiolabeling. The newly synthesized trimethylammonium precursors allowed for highly efficient F-18-radiolabelling in radiochemical yields >60% and specific activities >750 GBq/mu mol, thus making the radioligands practical for clinical investigation. (C) 2013 Elsevier Ltd. All rights reserved.