Study Rationale:
Assessing the accumulation of tau proteins in living human brain is crucial to better understand the pathophysiology of Progressive Supranuclear Palsy (PSP), 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 non-AD tauopathies such as PSP and related neurodegenerative disorders including PD. At present, we lack a PET imaging agent selective for the predominant form of tau found in PSP, “4R-tau” which is also likely related to other critical aggregated proteins in PD.
Hypothesis:
Our goal is to concurrently develop and validate selective PET imaging agents for PSP and PD.
Study Design:
A reasonable starting point is to carefully test the existing tau-PET AD imaging agents as potential 4R selective tracers, and simultaneously 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 the leading AD tau-PET tracers from laboratories around the world, as well as our new chemical entities as potential 4R-tau PET probes, and evaluating those compounds in the brain tissues of different tauopathies and PD subjects using sensitive assay methods.
Impact on Diagnosis/Treatment of Parkinson’s disease:
Our milestones are to provide: (i) a reference database comparing the binding of current AD tau-PET tracers in different non-AD tauopathies as well as PD, and new chemical entities for 4R-tau and, (ii) radiolabeling precursors and the corresponding non-radioactive and radioactive (tritium labeled) reference standards to the Tau Consortium and the Michael J. Fox Foundation collaborators. Using these data, we will then design and synthesize new chemical entities designed for 4R-tau 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 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 PSP and PD therapies.