Synthesis, in vitro characterization, and radiolabeling of reboxetine analogs as potential PET radioligands for imaging the norepinephrine transporter

Fanxing Zeng, Nachwa Jarkas, Jeffrey S. Stehouwer, Ronald J. Voll, Michael J. Owens, Clinton D. Kilts, Charles B. Nemeroff, Mark M. Goodman

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Six new (S, S)-enantiomers of reboxetine derivatives were synthesized and their binding affinities were determined via competition binding assays in cells expressing the human norepinephrine transporter (NET), serotonin transporter (SERT) or dopamine transporter (DAT). All six compounds prepared exhibit high affinity for the NET (Ki ≤ 2 nM) and selectivity versus the SERT and DAT. Radiolabeling methods were also developed to prepare these ligands in moderate to high radiochemical yield with high radiochemical purity via O- or S-methylation with [11C]CH3I, or O-alkylation with [18F]fluoroethyl brosylate or [18F]fluoropropyl brosylate, and their log P7.4 was measured. These new C-11- and F-18-labeled tracers will be utilized in comparative microPET studies to evaluate their potential as PET radioligands for imaging brain NET in nonhuman primates.

Original languageEnglish (US)
Pages (from-to)783-793
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number2
DOIs
StatePublished - Jan 15 2008
Externally publishedYes

Keywords

  • (S, S)Reboxetine analogs
  • Carbon-11
  • Fluorine-18
  • Norepinephrine transporter
  • Positron Emission Tomography

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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