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

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 [ 11 C]O‐methylreboxetine ([ 11 C]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)‐[ 11 C]MRB and (S,S)‐[ 11 C]MRB. Here we report an evaluation of the racemate and individual enantiomers of [ 11 C]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 [ 11 C]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 [ 11 C]MRB, with an even more dramatic effect after injection of (S,S)‐[ 11 C]MRB. These results, along with the fact that there was no regional specificity and no blocking effect by nisoxetine for (R,R)‐[ 11 C]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)‐[ 11 C]MRB, but not the (R,R)‐isomer. These studies demonstrate that the use of (S,S)‐[ 11 C]MRB would allow a better understanding of the role that NET plays in living systems. Synapse 50:345–352, 2003. © 2003 Wiley‐Liss, Inc.