title: 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.
authors.affiliation: Chemistry Department, Brookhaven National Laboratory, Upton, New York 11973, USA. ding@bnl.gov
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Ding
authors.forename: Kuo-Shyan
authors.initials: KS
authors.lastname: Lin
authors.forename: Victor
authors.initials: V
authors.lastname: Garza
authors.forename: Pauline
authors.initials: P
authors.lastname: Carter
authors.forename: David
authors.initials: D
authors.lastname: Alexoff
authors.forename: Jean
authors.initials: J
authors.lastname: Logan
authors.forename: Colleen
authors.initials: C
authors.lastname: Shea
authors.forename: Youwen
authors.initials: Y
authors.lastname: Xu
authors.forename: Payton
authors.initials: P
authors.lastname: King
mesh_terms: D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000378:metabolism*; D001923:Brain Chemistry; D001931:Brain Mapping; D002250:Carbon Radioisotopes / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000737:chemistry / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010215:Papio / Q000097:blood; D011869:Radioligand Assay; D000077593:Reboxetine; D013237:Stereoisomerism; D027981:Symporters / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000295:instrumentation / Q000379:methods*
chemical_list: D002250:Carbon Radioisotopes; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D027981:Symporters; D000077593:Reboxetine