Evaluation of Tau Radiotracers in Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurologic disorder associ-ated with head injuries, diagnosed by the perivascular accumulation of hyperphosphorylated tau protein (phospho-tau) identified at autopsy. Tau PET radiopharmaceuticals developed for imaging Alzheimer dis-ease are under evaluation for brain injuries. The goal of this study was to conduct a head-to-head in vitro evaluation of 5 tau PET radiotracers in subjects pathologically diagnosed with CTE. Methods: Autoradiography was used to assess the specific binding and distribution of 3H-flortauci-pir (also known as Tauvid, AV-1451, and T807), 3H-MK-6240 (also known as florquinitau), 3H-PI-2620, 3H-APN-1607 (also known as PM-PBB3 and florzolotau), and 3H-CBD-2115 (also known as 3H-OXD-2115) in fresh-frozen human postmortem CTE brain tissue (stages I-IV). Immunohistochemistry was performed for phospho-tau with AT8, 3R tau with RD3, 4R tau with RD4 and amyloid-I3 with 6F/3D antibodies. Tau target density (maximum specific binding) was quantified by satura-tion analysis with 3H-flortaucipir in tissue sections. Results: 3H-flortauci-pir demonstrated a positive signal in all CTE cases examined, with varying degrees of specific binding (68.7% +/- 10.5%; n = 12) defined by homologous blockade and to a lesser extent by heterologous block-ade with MK-6240 (27.3% +/- 13.6%; n = 12). The 3H-flortaucipir signal was also displaced by the monoamine oxidase (MAO)-A inhibitor clorgy-line (43.9% +/- 4.6%; n = 3), indicating off-target binding to MAO-A. 3H-APN-1607 was moderately displaced in homologous blocking studies and was not displaced by 3H-flortaucipir; however, substantial displace-ment was observed when blocking with the I3-amyloid-targeting com-pound NAV-4694. 3H-MK-6240 and 3H-PI-2620 had negligible binding in all but 2 CTE IV cases, and binding may be attributed to pathology severity or mixed Alzheimer disease/CTE pathology. 3H-CBD-2115 showed moderate binding, displaced under homologous blockade, and aligned with 4R-tau immunostaining. Conclusion: In human CTE tis-sues, 3H-flortaucipir and 3H-APN-1607 revealed off-target binding to MAO-A and amyloid-I3, respectively, and should be considered if these radiotracers are used in PET imaging studies of patients with brain injuries. 3H-MK-6240 and 3H-PI-2620 bind to CTE tau in severe-or mixed-pathology cases, and their respective 18F PET radiotracers war-rant further evaluation in patients with severe suspected CTE.