Evaluation of Tau Radiotracers in Chronic Traumatic Encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurological disorder associated with head injuries. Diagnosis of CTE occurs upon autopsy and is based on the perivascular accumulation of hyperphosphorylated tau protein. Tau-PET radiopharmaceuticals developed for imaging Alzheimer's disease are under evaluation in populations who have experienced brain injuries. The goal of this study is to conduct a head-to-head in vitro comparison of five tau-PET radiotracers in subjects pathologically diagnosed with CTE. Methods: Thin-section autoradiography was employed to assess specific binding and distribution of [ 3 H]flortaucipir (a.k.a. TauvidTM, AV-1451, T807), [ 3 H]MK-6240 (a.k.a. florquinitau), [ 3 H]PI-2620, [ 3 H]APN-1607 (a.k.a. PM-PBB3) and [ 3 H]CBD-2115 (a.k.a. [ 3 H]OXD-2115) in fresh-frozen human post-mortem brain tissue from pathologically diagnosed cases of CTE (stages I-IV). Immunohistochemistry was performed for phospho-tau with AT8, 3R tau with RD3, 4R tau with RD4 and amyloid-β with 6F/3D antibodies. Tau target density (Bmax) in post-mortem tissue sections was quantified by saturation analysis with [ 3 H]flortaucipir. Results: [ 3 H]Flortaucipir demonstrated 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 blockade with MK-6240 (27.3 ± 13.6%; n = 12). The [ 3 H]flortaucipir signal was also displaced by the monoamine oxidase (MAO)-A inhibitor clorgyline (43.9 ± 4.6%; n = 3), indicating off-target binding to MAO-A. [ 3 H]APN-1607 was moderately displaced in homologous blocking studies and was not displaced by flortaucipir, however, substantial displacement was observed when blocking with the β-amyloid targeting compound, NAV-4694. [ 3 H]MK-6240 and [ 3 H]PI-2620 showed elevated binding in one-third of the CTE IV cases and the variability may be attributed to mixed AD/CTE pathology. [ 3 H]CBD-2115 showed moderate binding, displaced under homologous blockade, and aligned with 4R-tau immunostaining. Conclusion: In human CTE tissues, [ 3 H]flortaucipir and [ 3 H]APN-1607 revealed off-target binding to MAO-A and amyloid-β, respectively, and should be considered in PET imaging studies of patients with brain injuries. [ 3 H]MK-6240 and [ 3 H]PI-2620 bind CTE-tau in severe and/or mixed pathology cases and their respective fluorine-18 PET radiotracers warrant further evaluation in patients with severe suspected-CTE.