Progress Report
Study Rationale:
Assessing the accumulation of alpha-synuclein (a-synuclein) proteins in living human brain is crucial to better understand the pathophysiology of Parkinson’s disease (PD), and related neurodegenerative disorders, to aid definitive diagnosis, and to track the effectiveness of new therapies that target the class of neurodegenerative diseases. Recent progress has been achieved in developing positron emission tomography (PET) imaging agents to determine tau pathology load in Alzheimer’s Disease (AD), but, due to disease-specific differences in tau isoforms and synuclein, these agents are of unknown effectiveness in other neurodegenerative disorders including PD. At present, we lack a PET imaging agent selective for the predominant form of tau found in another critical aggregated protein in PD known as a-synuclein.
Hypothesis:
Our goal is to develop and validate selective PET imaging agents for PD.
Study Design:
A reasonable starting point is explore new chemical entities that are amenable for radiolabeling as PET probes for a-synuclein. MedChem Imaging, Inc. in collaboration with the Stehouwer laboratory (U. Pittsburgh) have been synthesizing and radiolabeling our new chemical entities as potential a-synuclein PET probes, and evaluating those compounds in the brain tissues of PD subjects using sensitive assay methods.
Impact on Diagnosis/Treatment of Parkinson’s disease:
Our milestones are to provide: (i) new chemical entities for a-synuclein and, (ii) radiolabeling precursors and the corresponding non-radioactive and radioactive (tritium labeled) reference standards to Michael J. Fox Foundation collaborators. Using these data, we will then design and synthesize new chemical entities designed for a-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 a-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 PD therapies.