Levodopa provides effective symptomatic treatment for Parkinson’s disease. However, non-motor symptoms are often insufficiently relieved, and its long-term use is complicated by motor fluctuations and dyskinesia. To clarify mechanisms of levodopa-induced dyskinesia and pharmacological interventions aimed at reducing dyskinetic symptoms, we have here characterized the neurophysiological activity patterns in sensorimotor and cognitive-limbic circuits in dyskinetic rats, comparing the effects of amantadine, pimavanserin and the novel prospective antidyskinetic and antipsychotic treatment mesdopetam. Parallel recordings of local field potentials from eleven cortical and sub-cortical regions revealed suppression of narrowband gamma oscillations (NBGs) in sensorimotor structures by amantadine and mesdopetam in conjunction with alleviation of dyskinetic signs. Concomitant gamma oscillations in cognitive-limbic circuits were not directly linked to dyskinesia and were not affected by antidyskinetic treatments to the same extent, although treatment-induced reductions in functional coupling was observed in both sensorimotor and cognitive-limbic circuits, in parallel. In a broad frequency spectrum (1-200Hz), mesdopetam treatment displayed greater similarities to pimavanserin than to amantadine. These findings point to reduction of NBGs as a valuable biomarker for characterization of antidyskinetic treatment effects and provide systems-level mechanistic insights into the antidyskinetic efficacy of mesdopetam, with potential additional benefits for the treatment of Parkinson’s-related psychosis.

The management of Parkinson’s disease (PD) is frequently compromised by complications induced by dopaminergic treatment such as involuntary movements (dyskinesias) and psychosis. Mesdopetam (IRL790) is a novel dopamine D3 receptor antagonist developed for the management of complications of therapy in PD. Aim To evaluate safety, tolerability and pharmacokinetics of escalating single and multiple doses of mesdopetam Method We conducted a prospective, single-centre, randomized, double-blind, placebo-controlled phase I, first in human (FIH) study with mesdopetam administered to healthy male subjects. Results Overall, mesdopetam was well tolerated up to 120 mg single dose and up to 80 mg upon multiple dosing. AEs were mainly related to the nervous system and were dose dependent. No SAEs occurred and no AEs led to withdrawal. The results of the SAD and the MAD parts indicated dose- and time-independent pharmacokinetics with rapid absorption, maximum plasma levels generally reached within 2 hours after dosing. The average terminal half-life of mesdopetam ranged from 6.4 to 7.1 hours in the SAD part, and 6.3 to 7.3 hours in the MAD part. No accumulation was observed upon multiple dosing. Safety findings were unremarkable with no changes demonstrated in vital signs, ECG parameters or physical examination. Mesdopetam produced a dose-dependent increase in plasma prolactin, compatible with target engagement. Conclusion Mesdopetam was safe and well tolerated in healthy male volunteers. Pharmacokinetic analysis indicated rapid absorption and dose-linear pharmacokinetics of mesdopetam, with a plasma half-life around 7 hours, upon single and repeated dosing. The pharmacokinetics of mesdopetam supports twice daily use in patients.