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Tau PET has attracted increasing interest as an imaging biomarker for 4-repeat (4R)-tauopathy progressive supranuclear palsy (PSP). However, the translation of in vitro 4R-tau binding to in vivo tau PET signals is still unclear. Therefore, we performed a translational study using a broad spectrum of advanced methodologies to investigate the sources of [ 18 F]PI-2620 tau PET signals in individuals with 4R-tauopathies, including a pilot PET autopsy study in patients. First, we conducted a longitudinal [ 18 F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and detected elevated [ 18 F]PI-2620 PET signals in the presence of high levels of neuronal tau. An innovative approach involving cell sorting after radiotracer injection in vivo revealed higher tracer uptake in single neurons than in the astrocytes of PS19 mice. Regional [ 18 F]PI-2620 tau PET signals during the lifetime correlated with the abundance of fibrillary tau and with autoradiography signal intensity in PSP patients and disease controls who underwent autopsy 2-63 months after tau PET. In autoradiography, tau-positive neurons and oligodendrocytes with a high AT8 density, but not tau-positive astrocytes, were the drivers of [ 18 F]PI-2620 autoradiography signals in individuals with PSP. The high tau abundance in oligodendrocytes at the boundary of gray and white matter facilitated the identification of an optimized frontal lobe target region to detect the tau burden in patients with PSP. In summary, neuronal and oligodendroglial tau constitutes the dominant source of tau PET radiotracer binding in 4-repeat-tauopathies, translating to an in vivo signal., Competing Interests: Declarations. Conflict of interest: MB is a member of the Neuroimaging Committee of the EANM. MB has received speaker honoraria from Roche, GE Healthcare, and Life Molecular Imaging; has advised Life Molecular Imaging; and is currently on the advisory board of MIAC. NF received speaker honoraria from Eisai and Life Molecular Imaging and consulting honoraria from MSD. CP and JL are inventors in the patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6) filed by LMU Munich. JL reports speaker fees from Bayer Vital, Biogen and Roche; consulting fees from Axon Neuroscience and Biogen; author fees from Thieme Medical Publishers and W. Kohlhammer GmbH Medical Publishers; nonfinancial support from AbbVie; and compensation for duty as part-time CMO from MODAG, all outside the submitted work. TvE reports speaker/consultant fees from Eli Lilly, Shire, H. Lundbeck A/S, and Orion Corporation, and author fees from Thieme Medical Publishers, all without conflicts of interest with regard to the submitted work. Gesine Respondek has been a full-time employee at Roche Pharmaceuticals since July 2021 and has consulted for UCB, all outside of the submitted work. AZ reports speaker fees and research support from Dr. Willmar Schwabe GmbH and author fees from Thieme Medical Publishers, Springer Medical Publishers and W. Kohlhammer GmbH Medical Publishers. In addition to the submitted work, TG received consulting fees from AbbVie, Alector, Anavex, Biogen, BMS, Cogthera, Eli Lilly, Functional Neuromodulation, Grifols, Iqvia, Janssen, Noselab, Novo Nordisk, NuiCare, Orphanzyme, Roche Diagnostics, Roche Pharma, UCB, and Vivoryon; lecture fees from Biogen, Eisai, Grifols, Medical Tribune, Novo Nordisk, Roche Pharma, Schwabe, and Synlab; and grants to his institution from Biogen, Eisai, and Roche Diagnostics. LB is a Novartis Pharma GmbH employee, unrelated to this work. All the other authors declare that no conflicts of interest exist., (© 2024. The Author(s).)