title: Kinetic modeling and occupancy measures of the norepinephrine transporters in baboons using single photon emission computed tomography with (123)I-INER.
abstract: 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.
authors.affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom. atavares@mnimaging.com
authors.forename: Adriana Alexandre dos Santos
authors.initials: AA
authors.lastname: Tavares
authors.forename: Olivier
authors.initials: O
authors.lastname: Barret
authors.forename: Jeffery
authors.initials: J
authors.lastname: Batis
authors.forename: David
authors.initials: D
authors.lastname: Alagille
authors.forename: Andrei
authors.initials: A
authors.lastname: Koren
authors.forename: Caroline
authors.initials: C
authors.lastname: Papin
authors.forename: Greg
authors.initials: G
authors.lastname: Kudej
authors.forename: Katie
authors.initials: K
authors.lastname: Nice
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Kordower
authors.forename: Kelly P
authors.initials: KP
authors.lastname: Cosgrove
authors.forename: Tracy
authors.initials: T
authors.lastname: Kloczynski
authors.forename: Eric
authors.initials: E
authors.lastname: Brenner
authors.forename: John
authors.initials: J
authors.lastname: Seibyl
authors.forename: Gilles
authors.initials: G
authors.lastname: Tamagnan
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001921:Brain / Q000000981:diagnostic imaging; D005260:Female; D007700:Kinetics; D008954:Models, Biological; D009025:Morpholines / Q000493:pharmacokinetics*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D010215:Papio; D011437:Propylamines / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: C518627:(123I)INER; D018759:Adrenergic Uptake Inhibitors; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011437:Propylamines; D019275:Radiopharmaceuticals; D000069445:Atomoxetine Hydrochloride