期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 52, 期 1, 页码 62-73出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm800817h
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资金
- NIH [1-R21-MH-66622-01, MH-42088, RR-000039, MH-39415, MH-52899]
Reboxetine analogues with methyl and fluoroalkyl substituents at position 2 of the phenoxy ring 1-4 were synthesized. In vitro competition binding with [H-3]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 [C-11]1 and [C-11]4 is consistent with distribution of the NET in the brain, while [F-18]2 and [F-18]3 showed only slight regional differentiation in brain uptake. Especially, the highest ratios of uptake of [C-11]1in 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 [C]l and [C-11]4. PET imaging in awake monkeys suggested that anesthesia influenced the binding potential of [C-11]1 and [C-11]4 at the NET.
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