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To whom correspondence should be addressed. Address: Department of Radiology, 1364 Clifton Road NE, Atlanta, GA 30322. Phone: (404) 727-9366. Fax: (404) 727-3488. E-mail: mgoodma@emory.edu

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Research Funding:

National Institute of Mental Health : NIMH

Synthesis, Radiosynthesis, and Biological Evaluation of Carbon-11 and Fluorine-18 Labeled Reboxetine Analogs: Potential Positron Emission Tomography Radioligands for in Vivo Imaging of the Norepinephrine Transporter

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Journal Title:

Journal of Medicinal Chemistry

Volume:

Volume 52, Number 1

Publisher:

, Pages 62-73

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Reboxetine analogs with methyl and fluoroalkyl substituents at position 2 of the phenoxy ring 1–4 were synthesized. In vitro competition binding demonstrated that 1–4 have a high affinity for the norepinephrine transporter (NET) with Ki’s = 1.02, 3.14, 3.68, and 0.30 nM (vs [3H]nisoxetine), 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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