Synthesis, Radiosynthesis, and Biological evaluation of carbon-11 and fluorine-18 labeled reboxetine analogues: Potential positron emission tomography radioligands for in vivo imaging of the norepinephrine transporter

Reboxetine analogues with methyl and fluoroalkyl substituents at position 2 of the phenoxy ring 1-4 were synthesized. In vitro competition binding with [ ³H]nisoxetine demonstrated that 1-4 have a high affinity for the norepinephrine transporter (NET) with K _is = 1.02, 3.14, 3.68, and 0.30 nM, respectively. MicroPET imaging in rhesus monkeys showed that the relative regional distribution of [ ¹¹C]1 and [ ¹¹C]4 is consistent with distribution of the NET in the brain, while [ ¹⁸F]2 and [ ¹⁸F]3 showed only slight regional differentiation in brain uptake. Especially, the highest ratios of uptake of [ ¹¹C]1 in NET-rich regions to that in caudate were obtained at 1.30-1.45 at 45 min and remained relatively constant over 85 min. Pretreatment of the monkey with the selective NET inhibitor, desipramine, decreased the specific binding for both [ ¹¹C]1 and [ ¹¹C]4. PET imaging in awake monkeys suggested that anesthesia influenced the binding potential of [ ¹¹C]1 and [ ¹¹C]4 at the NET.