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 Nemeroff, Mark M. Goodman

Research output: Contribution to journal › Article

15 Citations (Scopus)

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

Fingerprint

Norepinephrine Plasma Membrane Transport Proteins
Serotonin Plasma Membrane Transport Proteins
Dopamine Plasma Membrane Transport Proteins
Imaging techniques
Methylation
Enantiomers
Alkylation
Neuroimaging
Primates
Assays
Brain
Cells
Ligands
Derivatives
reboxetine
In Vitro Techniques

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

Cite this

Synthesis, in vitro characterization, and radiolabeling of reboxetine analogs as potential PET radioligands for imaging the norepinephrine transporter. / Zeng, Fanxing; Jarkas, Nachwa; Stehouwer, Jeffrey S.; Voll, Ronald J.; Owens, Michael J.; Kilts, Clinton D.; Nemeroff, Charles; Goodman, Mark M.

In: Bioorganic and Medicinal Chemistry, Vol. 16, No. 2, 15.01.2008, p. 783-793.

Research output: Contribution to journal › Article

Zeng, F, Jarkas, N, Stehouwer, JS, Voll, RJ, Owens, MJ, Kilts, CD, Nemeroff, C & Goodman, MM 2008, 'Synthesis, in vitro characterization, and radiolabeling of reboxetine analogs as potential PET radioligands for imaging the norepinephrine transporter', Bioorganic and Medicinal Chemistry, vol. 16, no. 2, pp. 783-793. https://doi.org/10.1016/j.bmc.2007.10.025
Zeng F, Jarkas N, Stehouwer JS, Voll RJ, Owens MJ, Kilts CD et al. Synthesis, in vitro characterization, and radiolabeling of reboxetine analogs as potential PET radioligands for imaging the norepinephrine transporter. Bioorganic and Medicinal Chemistry. 2008 Jan 15;16(2):783-793. https://doi.org/10.1016/j.bmc.2007.10.025
Zeng, Fanxing ; Jarkas, Nachwa ; Stehouwer, Jeffrey S. ; Voll, Ronald J. ; Owens, Michael J. ; Kilts, Clinton D. ; Nemeroff, Charles ; Goodman, Mark M. / Synthesis, in vitro characterization, and radiolabeling of reboxetine analogs as potential PET radioligands for imaging the norepinephrine transporter. In: Bioorganic and Medicinal Chemistry. 2008 ; Vol. 16, No. 2. pp. 783-793.
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