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

D. F. Smith, D. Bender, K. Marthi, P. Cumming, S. B. Hansen, D. Peters, E. Østergaard Nielsen, J. Scheel-Krüger, A. Gjedde

Research output: Contribution to journalArticle

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 IC50 values were 3000-fold lower for [3H]serotonin than for either [3H]dopamine or [3H]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 [11C]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 [11C]NS2456 nor its [11C]-labelled enantiomers are ideal for PET neuroimaging of neuronal serotonin uptake sites.

Original languageEnglish (US)
Pages (from-to)265-270
Number of pages6
JournalNuclear Medicine and Biology
Volume28
Issue number3
DOIs
StatePublished - 2001

Keywords

  • 8-azabicyclo[3.2.1]oct-2-ene
  • Chiral resolution
  • PET
  • Selective serotonin reuptake inhibitor
  • [C]NS2456

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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    Smith, D. F., Bender, D., Marthi, K., Cumming, P., Hansen, S. B., Peters, D., Østergaard Nielsen, E., Scheel-Krüger, J., & Gjedde, A. (2001). Synthesis and evaluation of racemic [11C]NS2456 and its enantiomers as selective serotonin reuptake radiotracers for PET. Nuclear Medicine and Biology, 28(3), 265-270. https://doi.org/10.1016/S0969-8051(00)00175-X