The goal of this proposal is to develop two imaging tests, [18F]MK-9470 and [18F]MPPF, to assess the function of two receptors (cannabinoid – CB-1 and serotonin receptor – 5-HT1a) in the brain of individuals with Parkinson's disease (PD). There is evidence to suggest that these receptors may play an important role in levodopa-induced dyskinesia. The development of imaging tests to evaluate the activity of these receptors (CB-1 And 5-HT1a) provides the opportunity to understand the changes that occur in individuals with levodopa-induced dyskinesia and the potential to develop medications that more effectively treat dyskinesias.
Six PD subjects with levodopa-induced dyskinesia, 5 early PD subjects and 5 healthy subjects will undergo clinical evaluations including dyskinesia ratings and imaging evaluations using [18F]MK-9470 (a measure of CB-1 activity) and [18F]MPPF (a measure of 5-HT1a activity). The data in PD subjects with dyskinesia will be compared with early PD subjects and healthy subjects to evaluate if subjects with dyskinesia have decreased CB-1 activity and increased 5-HT1a activity. In addition, all subjects will undergo dopamine transporter imaging and the degree of dopaminergic neuronal loss will be compared with the activity of CB-1 and 5-HT1a to more fully characterize the neurochemical changes that occur in individuals with levodopa-induced dyskinesia.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
While a decrease in dopamine is the most recognized neurochemical change in the brain in PD, studies have recently shown that other non-dopamine neurochemicals also play an important role. The development of [18F]MK-9470 and [18F]MPPF PET will provide an extremely useful tools to improve our understanding of the role of cannabinoids and serotonin in the development of dykinesias in individuals with PD and will be a critical component of drug development of medications to improve the treatment of dyskinesia.
The primary imaging outcomes will be the striatal binding potential (BPnd) for [18F]MPPF, the fractional uptake rate for [18F]MK-9470 and the striatal binding ratio for [123I]β-CIT. Imaging outcomes will be compared among PD with LID subjects, early untreated PD subjects and healthy subjects. While the proposed studies are exploratory and the planned sample size is designed as a pilot study requiring further studies to confirm results, a priori criteria for assessing a difference among these cohorts will require at least a 25% signal difference in the PD with LID subjects compared with early untreated PD subjects and healthy subjects.