Pet imaging of two monoaminergic neurotransmitter systems in brain : studies of the norepinephrine transporter and dopamine D©ü receptor

Abstract: Positron emission tomography (PET) has been widely used to study non-invasively function of the brain, pathophysiology of disease and aid in the development of new drugs. PET and selective radiolabeled molecules allow imaging of certain critical components of neurotransmission, such as pre-synaptic transporters and post-synaptic receptors in living brain. The general aim of the present thesis was (i) to measure neuropharmacological interventions using PET (e.g., competition between synaptic neurotransmitters and radiolabeled tracers provide a useful tool to estimate changes in synaptic levels of neurotransmitters), and (ii) PET determination of drug induced receptor occupancy, examined by the curvilinear relationship between drug plasma concentration and receptor occupancy over a wide dose-range in nonhuman primate brain. The aim of Papers 1 and II was to evaluate (S,S)-[18F]FMeNER-D2 as a radiotracer for the norepinephrine transporter (NET). Paper I examined the whole-body biodistribution of (S,S)-[18F]FMeNER-D2 and estimated the resulting radiation exposure to organs of the body in nonhuman primates. The estimated radiation burden of (SS)-[18F]FMeNER-D2 was found to be comparable to that of other 18F radioligands. In Paper II, the aim was to determine if atomoxetine occupies NET in a dose-dependent fashion using (S,S)-[18F]FMeNER-D2in nonhuman primate brain. Previous PET studies have failed to demonstrate the feasibility of measuring a dose-dependent NET occupancy. After administration of increasing doses of atomoxetine, a dose-dependent occupancy from 38% to 82% was observed in brain regions known to contain high densities of NET. The aim of Papers III and IV was to combine PET imaging of the D2 receptor with pharmacological challenges that either increase or decrease concentrations of dopamine In Paper III, the aim was to assess and compare in nonhuman primate brain the sensitivity of the agonist radioligand [11C]MNPA and antagonist [11C]raclopride, to stimulant-induced dopamine release. [11C]MNPA binding potential was ~50% more sensitive than [11C]raclopride to pharmacological induced increases in dopamine. The aim of Paper IV was to estimate the occupancy of D2 receptors in rat brain by endogenous dopamine using PET and [11C]MNPA. The dopamine depletion paradigm increased [11C]MNPA binding potential significantly and the results indicate ~27% of D2 high affinity state receptors are occupied by endogenous dopamine during basal conditions. The aim of Paper V was to determine D2 and 5-HT1A receptor occupancy in brain after administration of RGH-188. In addition, the intrinsic activity of RGH-188 was estimated in vivo using a dopamine D2 agonist and antagonist radioligand. RGH-188 occupied D2 receptors in a dose dependent and saturable manner, with lowest dose occupying ~5% of receptors, and highest dose more than 90%. RGH-188 was equally potent to displace both antagonist and agonist radioligand. 5-HT1A receptor occupancy was much lower compared to D2 occupancy at the same doses, with a maximal value of ~30%. These results suggest that RGH-188 binds to D2 rather than 5-HT1A receptors, and its equal potency to displace agonist and antagonist radiotracers suggests that RGH-188 is an antagonist.