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I-123-NKJ64: A Novel Single Photon Emission Computed Tomography Radiotracer for Imaging the Noradrenaline Transporter in Brain

Author(s): A. A. S. Tavares, N. K. Jobson, D. Dewar, A. Sutherland, S. L. Pimlott

Dysregulation of noradrenergic function has been implicated in a variety of psychiatric and neurodegenerative disorders, including depression and Alzheimer's disease. The noradrenaline transporter (NAT) is a major target for antidepressant drugs, including reboxetine, a selective noradrenaline reuptake inhibitor. Therefore, the development of a radiotracer for imaging of the NAT is desirable. In this study, NKJ64, a novel iodinated analog of reboxetine, was radiolabeled and evaluated as a potential single photon emission computerized tomography (SPECT) radiotracer for imaging the NAT in brain. Biological evaluation of the novel radiotracer, I-123/125-NKJ64, was carried out in rats using: in vitro ligand binding assays; in vitro and ex vivo autoradiography; in vivo biodistribution studies and ex vivo pharmacological blocking studies. I-125-NKJ64 displayed saturable binding with high affinity for NAT in cortical homogenates (K-D 5 4.82 +/- 0.87 nM, mean +/- SEM, n = 3). In vitro and ex vivo autoradiography showed the regional distribution of I-123-NKJ64 binding to be consistent with the known density of NAT in brain. Following i.v. injection there was rapid uptake of I-123-NKJ64 in brain, with maximum uptake of 2.93% +/- 0.14% (mean +/- SEM, n = 3) of the injected dose. The specific to nonspecific ratio (locus coeruleus: caudate putamen) of I-123-NKJ64 uptake measured by ex vivo autoradiography was 2.8 at 30 min post i.v. injection. The prior administration of reboxetine significantly reduced the accumulation of I-123-NKJ64 in the locus coeruleus (> 50% blocking). The data indicate that further evaluation of I-123-NKJ64 in nonhuman primates is warranted in order to determine its utility as a SPECT radiotracer for imaging of NAT in brain. Synapse 65: 658-667, 2011. (C) 2010 Wiley-Liss, Inc.

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ISBN: 0887-4476
Publication Year: 2011
Periodical: Synapse
Periodical Number: 7
Volume: 65
Pages: 658-667
Author Address: