123I-NKJ64: A novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain

Tavares, A.A.S., Jobson, N.K., Dewar, D. , Sutherland, A. and Pimlott, S.L. (2011) 123I-NKJ64: A novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain. Synapse, 65(7), pp. 658-667. (doi: 10.1002/syn.20895)

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Publisher's URL: http://dx.doi.org/10.1002/syn.20895

Abstract

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, <sup>123/125</sup>I-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. <sup>125</sup>I-NKJ64 displayed saturable binding with high affinity for NAT in cortical homogenates (<i>K</i><sub>D</sub> = 4.82 ± 0.87 nM, mean ± SEM, n = 3). In vitro and ex vivo autoradiography showed the regional distribution of <sup>123</sup>I-NKJ64 binding to be consistent with the known density of NAT in brain. Following i.v. injection there was rapid uptake of <sup>123</sup>I-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 <sup>123</sup>I-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 <sup>123</sup>I-NKJ64 in the locus coeruleus (>50% blocking). The data indicate that further evaluation of <sup>123</sup>I-NKJ64 in nonhuman primates is warranted in order to determine its utility as a SPECT radiotracer for imaging of NAT in brain.

Item Type:Articles
Keywords:Noradrenaline transporter, reboxetine, brain imaging, SPECT, 123I-NKJ64
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Pimlott, Dr Sally and Dewar, Dr Deborah and Sutherland, Professor Andrew
Authors: Tavares, A.A.S., Jobson, N.K., Dewar, D., Sutherland, A., and Pimlott, S.L.
Subjects:Q Science > QD Chemistry
Q Science > QP Physiology
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Synapse
Publisher:John Wiley & Sons, Inc.
ISSN:0887-4476

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