Study Rationale:
For reasons not yet understood, a protein called alpha-synuclein clumps in the brain cells of people with Parkinson’s disease. Some evidence suggests that a protein called tau also may accumulate. Assessing the accumulation of tau and alpha-synuclein proteins in the living human brain is crucial to better understand the development of progressive supranuclear palsy, Parkinson’s disease and related neurodegenerative disorders. This will aid definitive diagnosis and track the effectiveness of new therapies that target this class of neurodegenerative diseases. Recent progress has been achieved in developing positron emission tomography (PET) imaging agents to determine tau levels in Alzheimer’s disease. But due to disease-specific differences in tau and synuclein, these agents are of unknown effectiveness in non-Alzheimer’s tau-related diseases such as progressive supranuclear palsy and related neurodegenerative disorders including Parkinson’s. At present, we lack a PET imaging agent selective for the predominant form of tau found in progressive supranuclear palsy, called “4R-tau,” as well as alpha-synuclein.
Hypothesis:
Our goal is to concurrently develop and validate selective PET imaging agents for progressive supranuclear palsy and Parkinson’s.
Study Design:
We will carefully test the existing tau-PET Alzheimer’s imaging agents as potential 4R selective tracers, and simultaneously explore new chemical entities that can be used for radiolabeling as PET probes for alpha-synuclein. We (MedChem Imaging, Inc.) in collaboration with the Mathis laboratory (University of Pittsburgh) have been synthesizing and radiolabeling the leading Alzheimer’s tau-PET tracers from laboratories around the world, as well as our new chemical entities as potential 4R-tau and alpha-synuclein PET probes, and evaluating those compounds in the brain tissues of different tau-related diseases and Parkinson’s subjects using sensitive assay methods.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
We will use the data from this study to design and synthesize new chemical entities designed for 4R-tau or alpha-synuclein selectivity for future evaluation PET imaging agents.
Next Steps for Development:
The ultimate goals are compounds that merit further pre-clinical and clinical evaluation as 4R-tau and/or alpha-synuclein selective PET agents, and that can serve as “scaffolds” upon which to base the design of additional selective PET imaging agents. Selective PET agents for these elusive targets will enable better patient selection and imaging-based evaluations of the effectiveness of new progressive supranuclear palsy and Parkinson’s therapies.