(R,S)-2-Iodo-reboxetine: development as a novel SPECT radiotracer for imaging the noradrenaline transporter in brain

Tavares, A., Dewar, D. , Sutherland, A. and Pimlott, S. (2010) (R,S)-2-Iodo-reboxetine: development as a novel SPECT radiotracer for imaging the noradrenaline transporter in brain. NeuroImage, 52(S1), S115-S115. (doi: 10.1016/j.neuroimage.2010.04.094)

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Abstract

Introduction: Dysregulation of noradrenergic function has been implicated in multiple brain disorders, including: depression, post-traumatic stress, anxiety, attention-deficit/hyperactivity disorder, Alzheimer's disease and Parkinson's disease. Despite this, few attempts have been made to develop radiotracers for imaging the noradrenaline transporter (NAT) in vivo using either positron emission tomography or single photon emission computerised tomography (SPECT). We set out to develop a novel SPECT radiotracer, based on the selective noradrenaline re-uptake inhibitor, reboxetine, for imaging the NAT in brain. Methods: The lead candidate, (R,S)-2-iodo-reboxetine [1], was radiolabelled via electrophillic iododestannylation of the corresponding tin precursor using peracetic acid as an oxidant. In vitro binding assays, in vitro and ex vivo brain autoradiography, in vivo biodistribution and pharmacokinetics studies using whole body dynamic planar imaging and ex vivo displacement studies, were performed in rats in order to evaluate radiolabelled (R,S)-2-iodo-reboxetine as a NAT SPECT radiotracer. Results: (R,S)-2-Iodo-reboxetine against 3H-Nisoxetine has nanomolar affinity for the NAT in homogenates of whole rat brain (Ki = 8.4 ± 1.7 nM, mean ± SEM, n = 5). 123I and 125I radiolabelling of (R,S)-2-iodo-reboxetine was successfully accomplished. The percentage non specific binding (of total binding), as measured by in vitro autoradiography with 123I-(R,S)-2-iodo-reboxetine in rat brain sections (mean ± SEM, n = 3), was 26 ± 2% in the locus coeruleus, 97 ± 3% in the corpus callosum, 98 ± 2% in the caudate putamen, 97 ± 2% in the hippocampus, 87 ± 6% in the anterior thalamus, 75 ± 2% in the raphe and 85 ± 8% in the cerebral cortex. Ex vivo autoradiography showed a specific to non-specific binding ratio (locus coeruleus:striatum) of 2.7. In vivo brain uptake was 2.96 ± 0.33% (mean ± SEM, n = 4) of the injected dose, as measured by whole body dynamic planar imaging. The elimination route of 123I-(R,S)-2-iodo-reboxetine, determined by both in vivo whole body dynamic planar imaging and ex vivo studies, was mainly intestinal. Conclusion: The data indicate that 123I-(R,S)-2-iodo-reboxetine may have potential as a radiotracer for imaging the NAT in brain.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dewar, Dr Deborah and Sutherland, Professor Andrew
Authors: Tavares, A., Dewar, D., Sutherland, A., and Pimlott, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
College of Science and Engineering > School of Chemistry
Journal Name:NeuroImage
Publisher:Elsevier
ISSN:1053-8119
ISSN (Online):1095-9572
Published Online:07 July 2010

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