title: Synthesis, enantiomeric resolution, and selective C-11 methylation of a highly selective radioligand for imaging the norepinephrine transporter with positron emission tomography.
abstract: Reboxetine, 2-[alpha-(2-ethoxyphenoxy)benzyl]morpholine, is a highly selective norepinephrine transporter (NET) blocker that has been used for the treatment of depression. Its methyl analogue, 2-[alpha-(2-methoxyphenoxy)benzyl]morpholine (MRB), has been radiolabeled with C-11 for studies of the NET system with positron emission tomography (PET). The normethyl precursor, 2-[alpha-(2-hydroxyphenoxy)benzyl]morpholine (desethylreboxetine), was synthesized in 6% overall yield via a multi-step regio- and stereo-specific synthesis, starting from a mono-O-protected catechol. The resulting racemic mixture of desethylreboxetine was resolved by chiral HPLC to provide the (2S,3S) and (2R,3R) enantiomers in >98% enantiomeric excess. These enantiomers were then used as precursors for radiosynthesis to prepare enantiomerically pure individual 11C-labeled MRB enantiomers for comparative PET studies in baboons. Selective C-11 methylation at the phenolic oxygen with [11C]CH3I was achieved in the presence of excess base. After HPLC purification, racemic ((2S,3S)/(2R,3R)) or enantiomerically pure ((2S,3S) or (2R,3R)) [11C]MRB was obtained in 61-74% decay-corrected radiochemical yields from [11C]CH3I in a synthesis time of 40 min with a radiochemical purity of >96% and a specific activity of 1.7-2.3 Ci/micromol (63-85 GBq/micromol) corrected from the end of bombardment (EOB).
authors.affiliation: Chemistry Department, Brookhaven National Laboratory, Upton, New York 11973-5000, USA.
authors.forename: Kuo-Shyan
authors.initials: KS
authors.lastname: Lin
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Ding
mesh_terms: D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D008024:Ligands; D008745:Methylation; D015394:Molecular Structure; D009025:Morpholines / Q000032:analysis / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D013237:Stereoisomerism; D027981:Symporters / Q000378:metabolism*; D014055:Tomography, Emission-Computed / Q000379:methods*
chemical_list: D002250:Carbon Radioisotopes; D008024:Ligands; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D027981:Symporters; C037574:morpholine