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

Abstract

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.

Presence of Specific 11C-meta-Hydroxyephedrine Retention in Heart, Lung, Pancreas, and Brown Adipose Tissue

“…The observation of lower HED retention in the lungs as compared with the heart supports earlier reports (9,11). By contrast, the selective NET inhibitor (R,R)-11 C-methyl-reboxetine displayed similar binding levels for lung and heart (27). This apparently high lung uptake of (R,R)-11 C-methyl-reboxetine may result from the greater lipophilicity and, hence, nonspecific binding of this tracer in comparison with HED.…”

Cerebellar Vermis Involvement in Cocaine-Related Behaviors

“…For example, frontal lobe dopamine uptake occurs primarily via NET activity (Moron et al, 2002). NET is present in cerebellum including vermis (Ding et al, 2003). Accordingly, some cerebellar regions containing NET might mediate effects of cocaine and its cues.…”

(R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

“…In comparison to (S,S)-[ 11 C]MeNER 2, the corresponding (R)-[O- 11 CH 3 ] -nisoxetine derivative 6 ( Fig.1) exhibited very high non-specific binding in vivo [12,13]. None of the other 11 C labeled ligands for NET were as suitable as (S,S)-[ 11 C]MeNER 2 [14,15].…”

“…Up to this point, the most promising NET specific radiotracer has been a methyl derivative of reboxetine, (S,S)-[ 11 C]-(α-(2-methoxyphenoxy)benzyl)morpholine (MeNER) 2 ( Fig.1), which is a PET imaging agent [9][10][11]. (S,S)-[ 11 C]MeNER 2 showed the highest hypothalamus to striatum (target to non-target) ratio of 2.5 at 60 min post-iv injection in rats.…”