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Kinetic modeling and occupancy measures of the norepinephrine transporters in baboons using single photon emission computed tomography with (123)I-INER

Author(s): A. A. Tavares, O. Barret, J. Batis, D. Alagille, A. Koren, C. Papin, G. Kudej, K. Nice, J. H. Kordower, K. P. Cosgrove, T. Kloczynski, E. Brenner, J. Seibyl, G. Tamagnan

This study aims to investigate the pharmacokinetics of a recently developed radiotracer for imaging of the norepinephrine transporter (NET) in baboon brain, (123)I-INER, using single photon emission computed tomography (SPECT). In addition, it also aims to determine NET occupancy by atomoxetine and reboxetine, two selective norepinephrine reuptake inhibitors, using (123)I-INER in baboons. Baseline and preblocking studies with a high dose of atomoxetine (0.85 mg/kg) were conducted in three baboons using SPECT with (123)I-INER administered as a bolus. Kinetic modeling analysis was investigated for different models, namely invasive and reference tissue models. Bolus plus constant infusion experiments with displacement at equilibrium using six different doses of atomoxetine (0.03-0.85 mg/kg) and four different doses of reboxetine (0.5-3.0 mg/kg) were carried out in several baboons to obtain occupancy measurements as a function of dose for the two NET selective drugs. Results showed that reference tissue models can be used to estimate binding potential values and occupancy measures of (123)I-INER in different brain regions. In addition, the apparent volume of distribution was estimated by dividing concentration in tissue by the concentration in blood at 3 hours postinjection. After administration of atomoxetine or reboxetine, a dose-dependent occupancy was observed in brain regions known to contain high densities of NET. In conclusion, pharmacokinetic properties of (123) I-INER were successfully described, and obtained results may be used to simplify future data acquisition and image processing. Dose-dependent NET occupancy for two selective norepinephrine reuptake inhibitors was successfully measured in vivo in baboon brain using SPECT and (123) I-INER.

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ISBN: 1098-2396 (Electronic) 0887-4476 (Linking)
Publication Year: 2013
Periodical: Synapse
Periodical Number: 1
Volume: 67
Pages: 30-41
Author Address: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom. atavares@mnimaging.com