Synthesis, in vitro characterization, and radiolabeling of reboxetine analogs as potential PET radioligands for imaging the norepinephrine transporter

Abstract Six new ( S ,  S )-enantiomers of reboxetine derivatives were synthesized and their binding affinities were determined via competition binding assays in cells expressing the human norepinephrine transporter (NET), serotonin transporter (SERT) or dopamine transporter (DAT). All six compounds prepared exhibit high affinity for the NET ( K i  ⩽ 2 nM) and selectivity versus the SERT and DAT. Radiolabeling methods were also developed to prepare these ligands in moderate to high radiochemical yield with high radiochemical purity via O- or S-methylation with [ 11 C]CH 3 I, or O-alkylation with [ 18 F]fluoroethyl brosylate or [ 18 F]fluoropropyl brosylate, and their log  P 7.4 was measured. These new C-11- and F-18-labeled tracers will be utilized in comparative microPET studies to evaluate their potential as PET radioligands for imaging brain NET in nonhuman primates.