Ligand-based design of [18F]OXD-2314 for PET imaging in non-Alzheimer’s disease tauopathies

Anton Lindberg, Emily Murrell, Junchao Tong, N. Scott Mason, Daniel Sohn, Johan Sandell, Peter Ström, Jeffrey S. Stehouwer, Brian J. Lopresti, Jenny Viklund, Samuel Svensson (), Chester A. Mathis () and Neil Vasdev ()
Additional contact information
Anton Lindberg: Centre for Addiction and Mental Health
Emily Murrell: Centre for Addiction and Mental Health
Junchao Tong: Centre for Addiction and Mental Health
N. Scott Mason: University of Pittsburgh
Daniel Sohn: Oxiant Discovery
Johan Sandell: Novandi Chemistry AB
Peter Ström: Novandi Chemistry AB
Jeffrey S. Stehouwer: University of Pittsburgh
Brian J. Lopresti: University of Pittsburgh
Jenny Viklund: Oxiant Discovery
Samuel Svensson: Oxiant Discovery
Chester A. Mathis: University of Pittsburgh
Neil Vasdev: Centre for Addiction and Mental Health

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Positron emission tomography (PET) imaging of tau aggregation in Alzheimer’s disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [18F]OXD-2115, using ligand-based design. Over 150 analogues of OXD-2115 were synthesized and screened in post-mortem brain tissue for tau affinity against [3H]OXD-2115, and in silico models were used to predict brain uptake. [18F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies.

Date: 2024
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DOI: 10.1038/s41467-024-49258-1

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