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

摘要

(?)-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 [11C]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 [11C]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 [11C]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.