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 Norepinep

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：January 8, 2009
• 年：2009
• 卷：52
• 期：1
• 页码：62-73
• 全文大小：339K
• 年卷期：v.52,no.1(January 8, 2009)
• ISSN：1520-4804

文摘

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_i’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.