Specific in vivo binding to the norepinephrine transporter demonstrated with the PET radioligand, (S,S)-[11C]MeNER

Nucl Med Biol. 2003 Oct;30(7):707-14. doi: 10.1016/s0969-8051(03)00079-9.

Abstract

(S,S)-2-(alpha-(2-Methoxyphenoxy)benzyl)morpholine (MeNER), an O-methyl analog of the selective and potent norepinephrine transporter (NET) inhibitor, (S,S)-reboxetine, and its less active enantiomer, (R,R)-MeNER, have each been radiolabeled by O-methylation of their corresponding phenolic precursors in good yields from [(11)C]methyl iodide or [(11)C]methyl triflate. Radiochemical purities were >99% and specific radioactivity at time of injection was about 74 GBq/micromol. Autoradiographic examination of (S,S)-[(11)C]MeNER binding to human brain slices post mortem indicated specific binding in a brain region including the locus coeruleus. PET examination of both [(11)C]MeNER enantiomers in a cynomolgus monkey demonstrated a higher specific binding of the (S,S)-enantiomer with ratios of 1.4-1.6 in the lower brainstem, mesencephalon and thalamus to striatum. Pretreatment with the NET ligand, desipramine, decreased the specific binding of (S,S)-[(11)C]MeNER. Labeled metabolites of [(11)C]MeNER were all more polar. (S,S)-[(11)C]MeNER is a good lead compound in the search for a selective radioligand for quantitation of NET in the human brain in vivo.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Autoradiography / methods*
  • Brain / diagnostic imaging*
  • Brain / metabolism*
  • Cadaver
  • Culture Techniques
  • Humans
  • Isotope Labeling / methods
  • Macaca fascicularis
  • Metabolic Clearance Rate
  • Morpholines / blood
  • Morpholines / pharmacokinetics*
  • Norepinephrine Plasma Membrane Transport Proteins
  • Radiopharmaceuticals / blood
  • Radiopharmaceuticals / pharmacokinetics
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Symporters / metabolism*
  • Tissue Distribution
  • Tomography, Emission-Computed / methods*

Substances

  • 2-(alpha-(2-methoxyphenoxy)benzyl)morpholine
  • Morpholines
  • Norepinephrine Plasma Membrane Transport Proteins
  • Radiopharmaceuticals
  • SLC6A2 protein, human
  • Symporters