Radioiodinated reboxetine analogues for imaging of the norepinephrine transporters in brain using single photon emission computed tomography

Tavares, A. A. S., Jobson, N. K., Dewar, D. , Sutherland, A. , Pimlott, S. L. , Batis, J., Barret, O., Baldwin, R., Seibyl, J. and Tamagnan, G. (2012) Radioiodinated reboxetine analogues for imaging of the norepinephrine transporters in brain using single photon emission computed tomography. 9th International Symposium on Functional Neuroreceptor Mapping of the Living Brain (NRM), Baltimore, Maryland, USA, 09-11 Aug 2012. S103-S104. (doi: 10.1038/jcbfm.2012.79)

Abstract

Background: 123I-INER, a radioiodinated (S,S) reboxetine analogue, and123I-NKJ64, a radioiodinated(R,S) stereoisomer of123I-INER, are the most promising radiotracers developed to date for in vivo imaging of the norepinephrine transporter (NET) using single photon emission computed tomography (SPECT)[1–4]. The present study aimed to compare the brain distribution and pharmacokinetics of123I-NKJ64 with that of123I-INER in baboons and to investigate the occupancy of NET in baboons using SPECT in order to determine the most promising radioiodinated reboxetine analogue. Methods: Adult female baboons (Papio anubis) were anesthetized and imaged on a Neurofocus SPECT camera (NeuroPhysics, Sharon, MA, USA). For the first experiments, baboons received a bolus of either123I-INER or123I-NKJ64 intravenously and arterial blood was sampled during the SPECT acquisition. Image analysis; invasive and noninvasive kinetic modelling were performed using PMOD 3.203 soft-ware (PMOD technologies, Zurich, Switzerland).123I-INER was also used to estimate receptor occupancy by bolus plus constant infusion studies with displacement at equilibrium using six different doses of atomoxetine (0.03 to 0.85 mg/kg) and four different doses of reboxetine (0.5 to 3.0 mg/kg). Results: Following bolus injection, both radiotracers rapidly and avidly entered the baboon brain. The regional brain accumulation of123I-NKJ64 did not match the known distribution of NET in baboon brain (highest in brain stem), contrasting with previous results obtained in rats [4]. Conversely, the regional distribution of123I-INER was consistent with the known distribution of NET in baboon brain (Table). Since123I-INER was found to be the preferred radioiodinated reboxetine analogue, occupancy measures of NET in baboon brain were determined using SPECT. After administration of atomoxetine or reboxetine, a dose-dependent occupancy was observed in brain regions known to contain high densities of NET (atomoxetine ED50=0.10mg/kg and reboxetine ED50=1.07mg/kg). Conclusions: These data suggest that123I-NKJ64 may lack affinity and selectivity for NET in baboon brain.123I-INER is the most promising SPECT radioiodinated reboxetine analogue developed to date for in vivo imaging of NET in brain. Dose-dependent NET occupancy for two selective norepinephrine reuptake inhibitors was successfully measured in vivo in baboon brain using SPECT and123I-INER.These results highlight the importance of species differences during radiotracer development and the enantioselectivity of radioiodinated analogues of reboxetine in vivo.

• Item Type: Conference or Workshop Item
• Additional Information: Abstract - list of abstracts available in Journal of Cerebral Blood Flow & Metabolism 32(1_suppl): S103-S104.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Pimlott, Dr Sally and Sutherland, Professor Andrew and Dewar, Dr Deborah
• Authors: Tavares, A. A. S., Jobson, N. K., Dewar, D., Sutherland, A., Pimlott, S. L., Batis, J., Barret, O., Baldwin, R., Seibyl, J., and Tamagnan, G.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing; College of Science and Engineering > School of Chemistry
• Journal Name: Journal of Cerebral Blood Flow and Metabolism
• ISSN: 0271-678X

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