The goal of this proposal is to develop an imaging test, 18F-PEB PET, to assess glutamate function in the brain of individuals with Parkinson disease (PD) and determine if the medication, fenobam impacts glutamate function. 18F-PEB is a chemical that binds to the glutamate receptor mGluR5 allowing us to measure the activity of the receptor using PET imaging. Studies have suggested an increased activity of glutamate in the brain may be important in the development of dyskinesias in PD.
Six PD subjects with dyskinesia, 6 early-untreated PD subjects and 6 healthy subjects will undergo dyskinesia ratings and imaging evaluation using 18F-PEB PET a measure of mGluR5 activity. The data in PD subjects with dyskinesia will be compared with early-untreated PD subjects and healthy subjects to evaluate if those with dyskinesia have increased mGluR5 activity. In addition, 12 PD subjects with dyskinesia will undergo baseline 18F-PEB imaging. Subjects will be randomized to one of three doses of fenobam, followed by a 3 week treatment period and a second 18F-PEB PET imaging session. Clinical evaluations will be performed to determine if there is a reduction in dyskinesia in the fenobam treated subjects.
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-PEB PET will provide an extremely useful tool to improve our understanding of the role of glutamate 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 dyskineasia.
We expect 18F-PEB PET imaging will be a useful tool to assess glutamate activity in PD. We anticipate finding increased glutamate activity in dyskinetic PD subjects. We anticipate that 18F-PEB PET imaging will provide the critical information regarding whether fenobam is binding directly to the mGluR5 receptor and the dose needed to provide a clinical effect. Our hope is that the individuals with PD will have a reduction in dyskinesia as a result of Fenobam administration.
Long-term administration of levodopa in Parkinson’s disease (PD) induces disabling involuntary movements recognized as levodopa-induced dyskinesia (LIDs). The development of effective therapies for LIDs is an unmet need in PD. There is now evidence that upregulation of the metabotroic glutamate receptors, such as mGluR5, may play an important role in LIDs. Further confirmation of this has come from studies administering NMDA receptor antagonists in pre-clinical models resulting in prevention or reduction of LID.
In this study, we are comparing mGluR5 activity using 18F-PEB PET imaging in early PD patients, PD patients with LIDs and healthy volunteers. Thus far, there does not appear to be a difference in mGluR5 activity in early PD patients and healthy volunteers. 18F-PEB PET imaging of the PD patients with LID is currently being performed. The LID patients will also undergo treatment with a glutamate antagonist to determine the dose occupancy of this medication and evaluate the clinical effect of the medication on dyskinesia. At the completion of the study, we should have a better understanding of the role of the mGluR5 receptor activity in LID and have initial data regarding the role of glutamate antagonists in the treatment of LID.
Specific Aim 1 has been completed with imaging performed in eight healthy controls (HC), eight early PD subjects and nine PD-LID subjects. Results of this study indicate an increase in mGluR5 activity in the PD-LID subjects relative to the HC and early PD subjects with the exception that subjects with late PD (n=2, >15 yrs from diagnosis) who have a reduction in FPEB uptake. This finding is unexpected and may represent a reduction in mGluR5 activity with more advanced disease, possibly related to more severe neurodegeneration.
We have been unable to accomplish the initially proposed Specific Aim 2 as there is currently no access to an mGluR5 antagonist to perform the study. While we will continue to try to obtain access to an mGluR5 antagonist to complete the dose occupancy study as proposed in the future, there are other studies critical to the development of the mGluR5 tracer, FPEB that will further our understanding of mGluR5 activity at specific PD stages and therapeutic conditions. We have provided a proposal for revision of the initial proposal to address two important questions that have been realized through the completion of Specific Aim 1:
1) Among PD-LID subjects is there a change in mGluR5 activity with increasing duration or severity of disease?
2) Does treatment with dopamine replacement agents (levodopa, dopamine agonists) have a short-term influence on mGluR5 activity?