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

• Published in: Synapse (New York, N.Y.) N.Y.), 2011-07, Vol.65 (7), p.658-667
• Main Authors: Tavares, Adriana Alexandre S., Jobson, Nicola K., Dewar, Deborah, Sutherland, Andrew, Pimlott, Sally L.
• Format: Article
• Language: English
• ISSN: 0887-4476; 1098-2396
• DOI: 10.1002/syn.20895

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, 123/125 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. 125 I‐NKJ64 displayed saturable binding with high affinity for NAT in cortical homogenates ( K D = 4.82 ± 0.87 nM, mean ± SEM, n = 3). In vitro and ex vivo autoradiography showed the regional distribution of 123 I‐NKJ64 binding to be consistent with the known density of NAT in brain. Following i.v. injection there was rapid uptake of 123 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 123 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 123 I‐NKJ64 in the locus coeruleus (>50% blocking). The data indicate that further evaluation of 123 I‐NKJ64 in nonhuman primates is warranted in order to determine its utility as a SPECT radiotracer for imaging of NAT in brain. Synapse , 2011. © 2010 Wiley‐Liss, Inc.