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 [³H]flortaucipir (a.k.a. TauvidTM, AV-1451, T807), [³H]MK-6240 (a.k.a. florquinitau), [³H]PI-2620, [³H]APN-1607 (a.k.a. PM-PBB3) and [³H]CBD-2115 (a.k.a. [³H]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 [³H]flortaucipir. Results: [³H]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 [³H]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. [³H]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. [³H]MK-6240 and [³H]PI-2620 showed elevated binding in one-third of the CTE IV cases and the variability may be attributed to mixed AD/CTE pathology. [³H]CBD-2115 showed moderate binding, displaced under homologous blockade, and aligned with 4R-tau immunostaining. Conclusion: In human CTE tissues, [³H]flortaucipir and [³H]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. [³H]MK-6240 and [³H]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.

慢性创伤性脑病 (CTE) 是一种与头部受伤相关的神经系统疾病。CTE 的诊断发生在尸检时，并且基于过度磷酸化 tau 蛋白的血管周围积聚。为阿尔茨海默病成像而开发的 Tau-PET 放射性药物正在经历过脑损伤的人群中进行评估。本研究的目的是对病理诊断为 CTE 的受试者中的五种 tau-PET 放射性示踪剂进行头对头的体外比较。方法：采用薄切片放射自显影来评估 [ ³ H]flortaucipir（又名 TauvidTM、AV-1451、T807）、[ ³ H]MK-6240（又名 florquinitau）、[ ³ H]PI-2620的特异性结合和分布, [ ³H]APN-1607（又名 PM-PBB3）和 [ ³ H]CBD-2115（又名 [ ³ H]OXD-2115）在来自病理诊断的 CTE 病例（I-IV 期）的新鲜冷冻人死后脑组织中）。对带有 AT8 的磷酸化 tau、带有 RD3 的 3R tau、带有 RD4 的 4R tau 和带有 6F/3D 抗体的淀粉样蛋白-β 进行免疫组织化学。^{用[ 3} H]flortaucipir通过饱和度分析量化死后组织切片中的Tau靶密度(Bmax) 。结果： [ ³ H]Flortaucipir 在所有检查的 CTE 病例中均显示出阳性信号，具有不同程度的特异性结合 (68.7 ± 10.5%; n = 12)，由同源阻断定义，在较小程度上由 MK-6240 的异源阻断定义 (27.3 ± 13.6%；n= 12)。[ ³ H]flortaucipir 信号也被单胺氧化酶 (MAO)-A 抑制剂 clorgyline (43.9 ± 4.6%; n = 3) 取代，表明与 MAO-A 的脱靶结合。[ ³ H]APN-1607 在同源阻断研究中发生了中度置换，并且没有被 flortaucipir 置换，然而，当用 β-淀粉样蛋白靶向化合物 NAV-4694 阻断时观察到显着置换。[ ³ H]MK-6240 和 [ ³ H]PI-2620 在三分之一的 CTE IV 病例中显示出结合升高，并且变异性可能归因于混合的 AD/CTE 病理学。[ ³ H]CBD-2115 显示出中度结合，在同源阻断下发生置换，并与 4R-tau 免疫染色对齐。结论：在人类 CTE 组织中，[ ³ H]flortaucipir 和 [ ³ H]APN-1607 分别显示与 MAO-A 和淀粉样蛋白-β 的脱靶结合，应在脑损伤患者的 PET 成像研究中予以考虑。[ ³ H]MK-6240 和 [ ³ H]PI-2620 在严重和/或混合病理病例中与 CTE-tau 结合，它们各自的 fluorine-18 PET 放射性示踪剂需要对严重疑似 CTE 的患者进行进一步评估。