Pridopidine, a clinic‐ready compound, reduces 3,4‐dihydroxyphenylalanine‐induced dyskinesia in Parkinsonian macaques

Abstract

ABSTRACT Background Pridopidine, in development for Huntington's disease, may modulate aberrant l ‐dopa‐induced effects including l ‐dopa‐induced dyskinesia (LID). Objective This study investigated whether pridopidine could reduce LID in the MPTP macaque model of Parkinson's disease and characterized the observed behavioral effects in terms of receptor occupancy. Methods The pharmacokinetic profile and effects of pridopidine (15‐30 mg/kg) on parkinsonism, dyskinesia, and quality of on‐time, in combination with l ‐dopa, were assessed in MPTP macaques with LID. Pridopidine receptor occupancy was estimated using known in vitro binding affinities to σ 1 and dopamine D 2 receptors, in vivo PET imaging, and pharmacokinetic profiling across different species. Results Pridopidine produced a dose‐dependent reduction in dyskinesia (up to 71%, 30 mg/kg) and decreased the duration of on‐time with disabling dyskinesia evoked by l ‐dopa by 37% (20 mg/kg) and 60% (30 mg/kg). Pridopidine did not compromise the anti‐parkinsonian benefit of l ‐dopa. Plasma exposures following the ineffective dose (15 mg/kg) were associated with full σ 1 occupancy (>80%), suggesting that σ 1 engagement alone is unlikely to account for the antidyskinetic benefits of pridopidine. Exposures following effective doses (20‐30 mg/kg), while providing full σ 1 occupancy, provide only modest dopamine D 2 occupancy (<40%). However, effective pridopidine doses clearly engage a range of receptors (including adrenergic‐α 2C , dopamine‐D 3 , and serotoninergic‐5‐HT 1A sites) to a higher degree than D 2 and might contribute to the antidyskinetic actions. Conclusions In MPTP macaques, pridopidine produced a significant decrease in LID without compromising the antiparkinsonian benefit of l ‐dopa. Although the actions of pridopidine were associated with full σ 1 occupancy, effective exposures are more likely associated with occupancy of additional, non‐sigma receptors. This complex pharmacology may underlie the effectiveness of pridopidine against LID. © 2018 International Parkinson and Movement Disorder Society