title: ¹²³I-NKJ64: a novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain.
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, ¹²³/¹²⁵I-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. ¹²⁵I-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 ¹²³I-NKJ64 binding to be consistent with the known density of NAT in brain. Following i.v. injection there was rapid uptake of ¹²³I-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 ¹²³I-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 ¹²³I-NKJ64 in the locus coeruleus (>50% blocking). The data indicate that further evaluation of ¹²³I-NKJ64 in nonhuman primates is warranted in order to determine its utility as a SPECT radiotracer for imaging of NAT in brain.
authors.affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, G128QQ Glasgow, Scotland, United Kingdom. a.tavares.1@research.gla.ac.uk
authors.forename: Adriana Alexandre S
authors.initials: AA
authors.lastname: Tavares
authors.forename: Nicola K
authors.initials: NK
authors.lastname: Jobson
authors.forename: Deborah
authors.initials: D
authors.lastname: Dewar
authors.forename: Andrew
authors.initials: A
authors.lastname: Sutherland
authors.forename: Sally L
authors.initials: SL
authors.lastname: Pimlott
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D007462:Iodobenzenes / Q000493:pharmacokinetics*; D008297:Male; D009025:Morpholines / Q000493:pharmacokinetics*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077593:Reboxetine; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: C560257:2-((2-iodophenoxy)phenylmethyl)morpholine; D007457:Iodine Radioisotopes; D007462:Iodobenzenes; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; D000077593:Reboxetine