Assessing the accumulation of tau (protein associated with dementia) and alpha-synuclein (sticky protein associated with Parkinson's) in the living human brain is crucial to better understanding Progressive Supranuclear Palsy (movement disorder that causes impaired balance and vision; PSP), Parkinson's disease (PD) and related neurodegenerative disorders, in addition to aiding in diagnosis and tracking the effectiveness of new therapies. Recent progress has been made in developing positron emission tomography (method to image the living brain; PET) agents to determine tau pathology load in Alzheimer's disease (type of dementia that impairs memory; AD); however, due to disease-specific differences in tau and alpha-synuclein forms, these agents are of unknown effectiveness in PSP and PD. At present, we lack a PET imaging agent selective for the predominant form of tau in PSP, "4R-tau," as well as alpha-synuclein in PD.
Our goal is to develop and validate selective PET imaging agents for PSP and PD.
We (MedChem Imaging LLC) will carefully evaluate existing tau-PET AD imaging agents as potential 4R selective tracers and simultaneously explore additional chemical compounds that can be labeled as PET probes for alpha-synuclein. In collaboration with the Mathis laboratory at the University of Pittsburgh, we will synthesize and radiolabel leading AD tau-PET tracers from laboratories around the world, as well as new chemical compounds, as potential alpha-synuclein PET probes. We will then evaluate these compounds in the brain tissues of those with different tauopathies and those with PD using sensitive assays (tests).
Impact on Diagnosis/Treatment of Parkinson's disease:
Our goals are to provide a reference database comparing the binding of current AD tau-PET tracers in different non-AD tauopathies and new chemical entities for alpha-synuclein and radiolabeling precursors and corresponding non-radioactive and radioactive reference standards for the Tau Consortium and The Michael J. Fox Foundation. Using these data, we will then design and synthesize new chemical compounds designed for 4R-tau or alpha-synuclein for future evaluation PET imaging studies.
Next Steps for Development:
Our ultimate goals are to develop compounds that merit further pre-clinical and clinical evaluation as 4R-tau- and/or alpha-synuclein-selective PET agents that can serve as "scaffolds" upon which to design additional imaging agents. Selective PET agents for these targets will enable better clinical trial participant selection and imaging-based evaluations of the effectiveness of new PSP and PD therapies.