The Dopamine Stabilizer (−)-OSU6162 Occupies a Subpopulation of Striatal Dopamine D2/D3 Receptors: An [11C]Raclopride PET Study in Healthy Human Subjects

Abstract

(-)-OSU6162 is a dopamine stabilizer that can counteract both hyperdopaminergic and hypodopaminergic states. In this study, D2/D3 receptor occupancy of (-)-OSU6162 in the human brain was investigated using positron emission tomography (PET). Twelve male healthy volunteers underwent [(11)C]raclopride PET scanning before and 1 h after a single oral dose of (-)-OSU6162 (15-90 mg). Blood samples for determination of (-)-OSU6162 and prolactin plasma levels were collected at Tmax. Parametric images of [(11)C]raclopride binding potential relative to nondisplaceable tissue (cerebellar grey matter) uptake (BPND) at baseline and after (-)-OSU6162 administration were generated using the simplified reference tissue model. MRI-based regions of interest were defined for the striatum, composed of caudate nucleus and putamen, and projected onto the co-registered parametric [(11)C]raclopride BPND image. Furthermore, three striatal subregions, ie, anterior dorsal caudate, anterior dorsal putamen, and ventral striatum, were defined manually and additionally analyzed. Plasma concentrations of (-)-OSU6162, ranging from 0.01 to 0.9 μM, showed a linear relationship with prolactin levels, reflecting blockade of pituitary D2 receptors. A concentration-dependent increase in striatal D2/D3 receptor occupancy was observed, reaching a value of about 20% at an (-)-OSU6162 plasma level of 0.2 μM, and which for higher concentrations leveled off to a maximal occupancy of about 40%. Findings were similar in the striatal subregions. The present data corroborate the notion that (-)-OSU6162 binds preferentially to a subpopulation of D2/D3 receptors, possibly predominantly extrasynaptic, and this may form the basis for the dopamine-stabilizing properties of (-)-OSU6162.

Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses

“…Human occupancy data for pridopidine have not yet been reported, but a recent 11 C-raclopride study (Tolboom et al 2015 ) examined D 2 R occupancy by (−)-OSU6162 and observed a 2 to 33 % occupancy in human subjects that received doses ranging from 15 to 90 mg (between 0.14 and 1.25 mg/kg). Since the dose-occupancy curve appeared to level off at 40 %, the authors suggested that (−)-OSU6162 selectively occupies a subset of striatal D 2 Rs, a property which could potentially account for some of the characteristics of dopamine stabilizers.…”

Open study with (−)-OSU6162 in multiple sclerosis-related fatigue

“…To estimate adherence, samples for measurements of (−)‐OSU6162 plasma concentrations were drawn on all patients at days 14 and 84 about 90 minutes after medication intake in the morning. Plasma concentrations of (−)‐OSU6162 were determined by high performance liquid chromatography/tandem mass spectrometry as described previously …”

Argument for a non‐linear relationship between severity of human obesity and dopaminergic tone

“…If there is indeed an increase in tonic DA signalling in morbid obesity, would this result in the recruitment of extra-synaptic DA receptors? It appears at least from a recent PET study on humans that [ 11 C]raclopride binds to an appreciable level of extra-synaptic D2Rs (52). This raises the tantalizing possibility that the findings from Wang et al are a result of decreased occupancy of extrasynaptic D2Rs as a consequence of increased tonic DA signalling.…”