Abstract
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.
Original language | English (US) |
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Pages (from-to) | 62-73 |
Number of pages | 12 |
Journal | Journal of Medicinal Chemistry |
Volume | 52 |
Issue number | 1 |
DOIs | |
State | Published - Jan 8 2009 |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery