University of Pittsburgh and University of Pennsylvania researchers have designed and synthesized a series of substituted–indoles as positron emission tomography (PET) radiotracers for use in imaging 4-repeat tau (4R-tau) in non-Alzheimer’s disease (AD) tauopathies. Imaging of 4R-tau will allow for earlier diagnosis of many non-AD tauopathies, support the discovery of therapeutics targeting 4R-tau, and could allow clinicians to monitor treatment progress in patients on anti-tau therapies.
Description
Aggregates of tau, either possessing three microtubule binding repeats (3R) or four repeats (4R) are key features of several neurodegenerative conditions. Examples include progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), both 4R-tauopathies, as well as AD which is a mixed 3R/4R-tauopathy. Identification of 4R-tau using PET could be used as a definitive diagnostic biomarker for 4R-tauopathies and could exclude or indicate clinically similar 3R-tauopathies. Overall, 4R-tau imaging could improve the lives and outcomes of many patients with 4R-tauopathies including PSP and CBD.
Applications
• Progressive supranuclear palsy
• Corticobasal degeneration
• Non-Alzheimer’s disease tauopathies
Advantages
Several tau PET tracers are in use for AD diagnosis; however, for other tauopathies a definitive diagnosis remains challenging. While efforts have been made to develop PET tracers specifically targeting 3R- or 4R-tau, to date these have not been selective and have produced low PET signals limiting their clinical usefulness. This new series of PET tracers bind with high affinity in post-mortem PSP and CBD brain tissue.
Invention Readiness
A library of substituted-indoles has been synthesized and evaluated for binding in post-mortem human brain tissue. Thirteen compounds were found to have Ki values of 5 – 14 nM in PSP and CBD tissue samples. [18F]JSS20-183A can be readily radiolabeled, rapidly crosses the blood-brain barrier, and shows no evidence of off-target binding.
IP Status
https://patents.google.com/patent/WO2024233875A2Related Publication(s)
Stehouwer, J. S., Huang, G., Saturnino Guarino, D., Debnath, M. L., Polu, A., Geib, S. J., Lopresti, B., Ikonomovic, M. D., Mason, N., Mach, R. H., & Mathis, C. A. (2025). Structure–Activity Relationships and Evaluation of 2-(Heteroaryl-cycloalkyl)-1H-indoles as Tauopathy Positron Emission Tomography Radiotracers. Journal of Medicinal Chemistry, 68(6), 6462–6492. https://doi.org/10.1021/acs.jmedchem.4c02988
