BACKGROUND: Levodopa remains the gold-standard treatment for PD. However, it 
becomes less effective as the disease progresses and produces debilitating side 
effects, such as motor fluctuations and l-dopa-induced dyskinesia. Modulation of 
metabotropic glutamate receptor 4 represents a promising antiparkinsonian 
approach in combination with l-dopa, but it has not been demonstrated in 
primates.
OBJECTIVE: We studied whether a novel positive allosteric modulator of the 
metabotropic glutamate receptor 4, PXT002331 (foliglurax), could reduce 
parkinsonism in primate models.
METHODS: We assessed the therapeutic potential of PXT002331 in three models of 
MPTP-induced parkinsonism in macaques. These models represent three different 
stages of disease evolution: early stage and advanced stage with and without 
l-dopa-induced dyskinesia.
RESULTS: As an adjunct to l-dopa, PXT002331 induced a robust and dose-dependent 
reversal of parkinsonian motor symptoms in macaques, including bradykinesia, 
tremor, posture, and mobility. Moreover, PXT002331 strongly decreased dyskinesia 
severity, thus having therapeutic efficacy on both parkinsonian motor impairment 
and l-dopa-induced dyskinesia. PXT002331 brain penetration was also assessed 
using PET imaging in macaques, and pharmacodynamic analyses support target 
engagement in the therapeutic effects of PXT002331.
CONCLUSIONS: This work provides a demonstration that a positive allosteric 
modulator of metabotropic glutamate receptor 4 can alleviate the motor symptoms 
of PD and the motor complications induced by l-dopa in primates. PXT002331 is 
the first compound of its class to enter phase IIa clinical trials. © 2018 
International Parkinson and Movement Disorder Society.