This study focuses on the development of a high-affinity, selective PET radiotracer for imaging tau aggregates in non-Alzheimer's disease (non-AD) tauopathies. Over 150 analogues of the first-in-class 4R-tau lead, [18F]OXD-2115, were synthesized and screened for tau affinity. In silico models were used to predict brain uptake. [18F]OXD-2314 was identified as a promising compound with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primates. [18F]OXD-2314 showed high affinity for 4R-tau aggregates in PSP and CBD tissues, and equipotent binding in AD tissues. In vitro binding assays and pharmacology screening showed no significant interaction with CNS receptors or enzymes, indicating its potential as a high-affinity tau PET radiotracer. Radiolabeling studies demonstrated suitable radiochemical purity and molar activity for human PET imaging. Dynamic PET imaging in rats and non-human primates revealed rapid brain uptake and clearance, with an early-to-late brain concentration ratio of ~8 in rats and ~4 in non-human primates. Radiometabolite analysis showed that the radiometabolites formed are not readily passing through the blood-brain barrier. Overall, [18F]OXD-2314 is a promising brain-penetrant PET radiotracer for imaging tau aggregates in non-AD tauopathies, and regulatory submission for first-in-human studies is underway.This study focuses on the development of a high-affinity, selective PET radiotracer for imaging tau aggregates in non-Alzheimer's disease (non-AD) tauopathies. Over 150 analogues of the first-in-class 4R-tau lead, [18F]OXD-2115, were synthesized and screened for tau affinity. In silico models were used to predict brain uptake. [18F]OXD-2314 was identified as a promising compound with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primates. [18F]OXD-2314 showed high affinity for 4R-tau aggregates in PSP and CBD tissues, and equipotent binding in AD tissues. In vitro binding assays and pharmacology screening showed no significant interaction with CNS receptors or enzymes, indicating its potential as a high-affinity tau PET radiotracer. Radiolabeling studies demonstrated suitable radiochemical purity and molar activity for human PET imaging. Dynamic PET imaging in rats and non-human primates revealed rapid brain uptake and clearance, with an early-to-late brain concentration ratio of ~8 in rats and ~4 in non-human primates. Radiometabolite analysis showed that the radiometabolites formed are not readily passing through the blood-brain barrier. Overall, [18F]OXD-2314 is a promising brain-penetrant PET radiotracer for imaging tau aggregates in non-AD tauopathies, and regulatory submission for first-in-human studies is underway.