Structure-guided design of pyridinyl-indole 4R-tau PET radiotracers: Development of [18F]OXD-2314 for human use

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 4-repeat (4R)-tau PET radiopharmaceutical for imaging non-AD tauopathies exists. Herein, the properties of analogues of a first-in-class 4R-tau lead, [18F]OXD-2115, are described. Over 150 analogues of OXD-2115 were synthesized and screened for tau affinity in vitro 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.