Synthesis and evaluation of racemic [C-11]NS2456 and its enantiomers as selective serotonin reuptake radiotracers for PET

Positron emission tomography (PET) radiotracers are needed for quantifying serotonin uptake sites in the living brain. Therefore, we evaluated a new s elective serotonin reuptake inhibitor, NS2456, to determine whether it is s uited for use in PET. Racemic NS2456 [(1RS,5SR)-8-methyl-3-[4-trifluorometh oxyphenyl]-8-azabicyclo [3.2.1]oct-2-ene] and its N-demethylated analog, ra cemic NS2463, selectively inhibited serotonin uptake in rat brain synaptoso mes; their IC50 values were 3000-fold lower for [H-3]serotonin than for eit her [H-3]dopamine or [H-3]noradrenaline. The enantiomers of NS2463 were als o potent inhibitors of serotonin uptake in vitro, but they failed to show s tereoselectivity. Racemic NS2463 as well as its enantiomers were radiolabel led by N-methylation with C-11, yielding [C-11]NS2456 for use in PET of the living porcine brain. The compounds crossed the blood-brain barrier rapidl y and accumulated preferentially in regions rich in serotonin uptake sites (e.g., brainstem, subthalamus and thalamus). However, their binding potenti als were relatively low and no stereoselectivity was found. Thus, neither r acemic [C-11]NS2456 nor its [C-11]-labelled enantiomers are ideal for PET n euroimaging of neuronal serotonin uptake sites. (C) 2001 Elsevier Science I nc. All rights reserved.