Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([(18)F]AV-133)

Abstract

The 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP)-induced parkinsonism model, particularly in non-human primates, remains the gold-standard for studying the pathogenesis and assessing novel therapies for Parkinson's disease. However, whether the loss of dopaminergic neurons in this model is progressive remains controversial, mostly due to the lack of objective in vivo assessment of changes in the integrity of these neurons. In the present study, parkinsonism was induced in cynomolgus monkeys by intravenous administration of MPTP (0.2 mg/kg) for 15 days; stable parkinsonism developed over 90 days, when the symptoms were stable. Noninvasive positron emission tomographic neuroimaging of vesicular monoamine transporter 2 with 9-[(18)F] fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]AV-133) was used before, and 15 and 90 days after the beginning of acute MPTP treatment. The imaging showed evident progressive loss of striatal uptake of [(18)F]AV-133. The dopaminergic denervation severity had a significant linear correlation with the clinical rating scores and the bradykinesia subscores. These findings demonstrated that [(18)F]AV-133 PET imaging is a useful tool to noninvasively evaluate the evolution of monoaminergic terminal loss in a monkey model of MPTP-induced parkinsonism.