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

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 σ1 and dopamine D2 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 σ1 occupancy (>80%), suggesting that σ1 engagement alone is unlikely to account for the antidyskinetic benefits of pridopidine. Exposures following effective doses (20‐30 mg/kg), while providing full σ1 occupancy, provide only modest dopamine D2 occupancy (