Evaluation of a new norepinephrine transporter PET ligand in baboons, both in brain and peripheral organs

Synapse. 2003 Dec 15;50(4):345-52. doi: 10.1002/syn.10281.


Reboxetine is a specific norepinephrine transporter (NET) inhibitor and has been marketed in several countries as a racemic mixture of the (R,R) and (S,S) enantiomers for the treatment of depression. Its methyl analog (methylreboxetine, MRB) has been shown to be more potent than reboxetine itself. We developed a nine-step synthetic procedure to prepare the normethyl precursor, which was used to synthesize [11C]O-methylreboxetine ([11C]MRB). We also developed a convenient resolution method using a chiral HPLC column to resolve the racemic precursor to obtain enantiomerically pure individual precursors that lead to the individual enantiomers (R,R)-[11C]MRB and (S,S)-[11C]MRB. Here we report an evaluation of the racemate and individual enantiomers of [11C]MRB as radioligands for PET imaging studies of NET systems in baboons both in brain and in peripheral organs. The relative regional distribution of the radioactivity after injection of [11C]MRB in baboon brain is consistent with the known distribution of NET. For a NET-poor region such as striatum, there were no significant changes in the striatal uptakes with and without the nisoxetine pretreatment. In contrast, a significant blocking effect was observed in NET-rich regions such as thalamus and cerebellum after injection of racemic [11C]MRB, with an even more dramatic effect after injection of (S,S)-[11C]MRB. These results, along with the fact that there was no regional specificity and no blocking effect by nisoxetine for (R,R)-[11C]MRB, suggest the enantioselectivity of MRB in vivo, consistent with previous in vitro and in vivo studies in rodents. PET studies of baboon torso revealed a blocking effect by desipramine only in the heart, a NET-rich organ, after injection of (S,S)-[11C]MRB, but not the (R,R)-isomer. These studies demonstrate that the use of (S,S)-[11C]MRB would allow a better understanding of the role that NET plays in living systems.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Autoradiography
  • Binding, Competitive
  • Brain / anatomy & histology
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • Brain Chemistry
  • Brain Mapping
  • Carbon Radioisotopes / metabolism
  • Chromatography, High Pressure Liquid
  • Dose-Response Relationship, Drug
  • Heart / drug effects
  • Kidney / drug effects
  • Kidney / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Lung / drug effects
  • Lung / metabolism
  • Morpholines / chemistry
  • Morpholines / metabolism*
  • Norepinephrine Plasma Membrane Transport Proteins
  • Papio / blood
  • Radioligand Assay
  • Reboxetine
  • Stereoisomerism
  • Symporters / chemistry
  • Symporters / metabolism*
  • Time Factors
  • Tissue Distribution
  • Tomography, Emission-Computed / instrumentation
  • Tomography, Emission-Computed / methods*


  • Carbon Radioisotopes
  • Morpholines
  • Norepinephrine Plasma Membrane Transport Proteins
  • Symporters
  • Reboxetine