A new PET radiotracer, [¹⁸F]OXD-2314, has been developed for imaging tau aggregation in non-Alzheimer's disease (non-AD) tauopathies. This compound was designed using ligand-based approaches to optimize binding to tau aggregates, particularly 4R-tau, which is prevalent in non-AD tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Over 150 analogs of the lead compound [¹⁸F]OXD-2115 were synthesized and tested for tau affinity in post-mortem brain tissue. [¹⁸F]OXD-2314 was identified as a high-affinity, selective PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primates, and is being translated for first-in-human PET studies. Tauopathies are a group of neurodegenerative diseases characterized by the accumulation of tau protein in the brain. These include Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). Tau exists in six isoforms, primarily distinguished by the number of microtubule-binding regions (3R or 4R). Different tauopathies are characterized by the relative abundance of 3R or 4R tau in their respective filaments. The development of PET radiotracers for tau imaging in AD has led to the approval of [¹⁸F]Tauvid™, which is the first and only PET radiopharmaceutical approved for imaging tau deposits in cognitively impaired subjects. However, no high-affinity tau-PET radiopharmaceutical has been optimized for non-AD tauopathies. [¹⁸F]OXD-2314 was developed as a first-in-class PET radiotracer optimized for 4R-tau, showing high affinity for tau aggregates in PSP and CBD tissues, with a binding affinity that is 10-fold higher than in CBD tissue compared to other radiotracers. In vitro binding assays showed that [³H]OXD-2314 binds to 4R-tau aggregates in PSP and CBD tissues with high affinity, and to 3R-tau aggregates in PiD tissues. It also showed high affinity for tau aggregates in AD tissues, indicating its potential for use in both AD and non-AD tauopathies. The compound was also found to have low binding to other CNS targets such as α-synuclein and Aβ plaques, suggesting high selectivity for tau. In vivo studies in rats and non-human primates showed that [¹⁸F]OXD-2314 has favorableA new PET radiotracer, [¹⁸F]OXD-2314, has been developed for imaging tau aggregation in non-Alzheimer's disease (non-AD) tauopathies. This compound was designed using ligand-based approaches to optimize binding to tau aggregates, particularly 4R-tau, which is prevalent in non-AD tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Over 150 analogs of the lead compound [¹⁸F]OXD-2115 were synthesized and tested for tau affinity in post-mortem brain tissue. [¹⁸F]OXD-2314 was identified as a high-affinity, selective PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primates, and is being translated for first-in-human PET studies. Tauopathies are a group of neurodegenerative diseases characterized by the accumulation of tau protein in the brain. These include Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). Tau exists in six isoforms, primarily distinguished by the number of microtubule-binding regions (3R or 4R). Different tauopathies are characterized by the relative abundance of 3R or 4R tau in their respective filaments. The development of PET radiotracers for tau imaging in AD has led to the approval of [¹⁸F]Tauvid™, which is the first and only PET radiopharmaceutical approved for imaging tau deposits in cognitively impaired subjects. However, no high-affinity tau-PET radiopharmaceutical has been optimized for non-AD tauopathies. [¹⁸F]OXD-2314 was developed as a first-in-class PET radiotracer optimized for 4R-tau, showing high affinity for tau aggregates in PSP and CBD tissues, with a binding affinity that is 10-fold higher than in CBD tissue compared to other radiotracers. In vitro binding assays showed that [³H]OXD-2314 binds to 4R-tau aggregates in PSP and CBD tissues with high affinity, and to 3R-tau aggregates in PiD tissues. It also showed high affinity for tau aggregates in AD tissues, indicating its potential for use in both AD and non-AD tauopathies. The compound was also found to have low binding to other CNS targets such as α-synuclein and Aβ plaques, suggesting high selectivity for tau. In vivo studies in rats and non-human primates showed that [¹⁸F]OXD-2314 has favorable