In vivo evaluation of [(123)I]MNI-420: a novel single photon emission computed tomography radiotracer for imaging of adenosine 2A receptors in brain.

INTRODUCTION: Dysregulation of adenosine 2A (A2A) receptor function in brain has been implicated in multiple psychiatric and neurodegenerative disorders, including schizophrenia and Parkinson's disease, making the development of an imaging agent to study A2A receptors in both healthy brain and disease states desirable. In this study, [(123)I]MNI-420 was evaluated as a potential single photon emission computed tomography (SPECT) radiotracer for imaging A2A receptors in brain. METHODS: Two adult male monkeys (Macaca fascicularis) and three adult female baboons (Papio anubis) were anesthetized and imaged on Neurofocus SPECT cameras. Baboons underwent baseline and displacement studies using varying doses of caffeine (2.0-20mg/kg). Baseline and pre-blocking experiments with multiple doses of preladenant (0.01-1.2mg/kg), a highly selective A2A antagonist, were performed in cynomolgus monkeys. RESULTS: Following bolus intravenous (i.v.) injection, [(123)I]MNI-420 rapidly entered the non-human primate brain. The regional brain accumulation of [(123)I]MNI-420 matched the known distribution of A2A receptors in brain (highest in the striatum). Striatum to cerebellum ratios and binding potentials of around 3.0-3.5 and 2.0-2.5, respectively, were measured in monkey and baboon brain. A dose-dependent occupancy was observed following i.v. injection of caffeine at pseudo-equilibrium conditions during displacement experiments. Pre-treatment with preladenant blocked specific binding in A2A rich regions in a dose-dependent fashion. CONCLUSIONS: The data indicate that [(123)I]MNI-420 holds promise as a SPECT radiotracer for imaging A2A receptors in brain and further evaluation is warranted, in order to determine its utility as a SPECT radiotracer for imaging of A2A in brain.

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

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.