University of Pittsburgh researchers have designed and synthesized several substituted-alkenyl-indazoles capable of assessing accumulation of 4R-tau, a key biomarker for a variety of neurodegenerative conditions. Improving imaging of 4R-tau will allow for earlier diagnosis of these conditions and allow clinicians to monitor treatment progress.
Description
Tau is a protein which plays a vital role in healthy nerve cells. However, aggregates of tau have been linked to several neurodegenerative conditions including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) and could be used as diagnostic biomarker for these conditions. These novel agents have been found to bind with high affinity to 4R-tau, an isoform of tau, and have the potential to aid clinicians in making a definitive diagnosis earlier, better determine treatment paths and allow researchers to understand the underlying pathophysiology of tauopathies.
Applications
• Progressive supranuclear palsy (PSP)
• Corticobasal degeneration (CBD)
• Other neurodegenerative conditions involving tau
Advantages
The FDA has previously approved amyloid-β plaque positron emission tomography (PET) imaging, widely used to image plaques in Alzheimer’s Disease (AD). In AD, another type of aggregated protein is present and consists of a mixture of isoforms of tau, 3R- and 4R- tau. In contrast, PSP and CBD brains predominantly contain 4R-tau aggregates. A PET imaging agent designed for the tau found in AD may not be suitable for tau aggregates in PSP and CBD tauopathies. Some 4R-tau binding PET agents have been developed, but provide poor in vivo specific signals.
These novel agents are photostable unlike some other PET agents and bind with a high affinity to 4R-tau aggregates in human brain tissue, suggesting these could be useful PET imaging agents for patients with PSP or CBD.
Invention Readiness
A library of novel substituted-alkenyl-indazoles have been synthesized and purified. Nine of these were screened in post-mortem AD, PSP, CBD, and Parkinson’s disease (PD) brain tissue. These compounds were found to have a high binding affinity to 4R-tau in PSP and CBD brain samples, but a low binding affinity to alpha-synuclein in PD and amyloid-β in AD brain samples. This high affinity for 4R-tau isoforms could prove a useful diagnostic tool for various tauopathies.
IP Status
Patent Pending
