title: Synthesis and evaluation of racemic [(11)C]NS2456 and enantiomers as selective serotonin reuptake radiotracers for PET.
abstract: Positron emission tomography (PET) radiotracers are needed for quantifying serotonin uptake sites in the living brain. Therefore, we evaluated a new selective serotonin reuptake inhibitor, NS2456, to determine whether it is suited for use in PET. Racemic NS2456 [(1RS,5SR)-8-methyl-3-[4-trifluoromethoxyphenyl]-8-azabicyclo [3.2.1]oct-2-ene] and its N-demethylated analog, racemic NS2463, selectively inhibited serotonin uptake in rat brain synaptosomes; their IC(50) values were 3000-fold lower for [(3)H]serotonin than for either [(3)H]dopamine or [(3)H]noradrenaline. The enantiomers of NS2463 were also potent inhibitors of serotonin uptake in vitro, but they failed to show stereoselectivity. Racemic NS2463 as well as its enantiomers were radiolabelled by N-methylation with C-11, yielding [(11)C]NS2456 for use in PET of the living porcine brain. The compounds crossed the blood-brain barrier rapidly and accumulated preferentially in regions rich in serotonin uptake sites (e.g., brainstem, subthalamus and thalamus). However, their binding potentials were relatively low and no stereoselectivity was found. Thus, neither racemic [(11)C]NS2456 nor its [(11)C]-labelled enantiomers are ideal for PET neuroimaging of neuronal serotonin uptake sites.
authors.affiliation: PET Center, Aarhus University Hospitals, Aarhus, Denmark. dfsmith@inet.uni2.dk
authors.forename: D F
authors.initials: DF
authors.lastname: Smith
authors.forename: D
authors.initials: D
authors.lastname: Bender
authors.forename: K
authors.initials: K
authors.lastname: Marthi
authors.forename: P
authors.initials: P
authors.lastname: Cumming
authors.forename: S B
authors.initials: SB
authors.lastname: Hansen
authors.forename: D
authors.initials: D
authors.lastname: Peters
authors.forename: E O
authors.initials: EO
authors.lastname: Nielsen
authors.forename: J
authors.initials: J
authors.lastname: Scheel-Krüger
authors.forename: A
authors.initials: A
authors.lastname: Gjedde
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000493:pharmacokinetics; D005260:Female; D008297:Male; D009638:Norepinephrine / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013552:Swine; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014326:Tropanes / Q000138:chemical synthesis / Q000493:pharmacokinetics
chemical_list: D004298:Dopamine; D009638:Norepinephrine; D017367:Selective Serotonin Reuptake Inhibitors; D014326:Tropanes; C433515:NS 2456