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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

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posted on 08.01.2009 by Fanxing Zeng, Jiyoung Mun, Nachwa Jarkas, Jeffrey S. Stehouwer, Ronald J. Voll, Gilles D. Tamagnan, Leonard Howell, John R. Votaw, Clinton D. Kilts, Charles B. Nemeroff, Mark M. Goodman
Reboxetine analogues with methyl and fluoroalkyl substituents at position 2 of the phenoxy ring 14 were synthesized. In vitro competition binding with [3H]nisoxetine demonstrated that 14 have a high affinity for the norepinephrine transporter (NET) with Ki’s = 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.

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