Multi‐tracer comparison in Alzheimer’s disease, Corticobasal Degeneration and Progressive Supranuclear Palsy brains

Abstract Background Recent CryoEM studies in tauopathies clearly bought forward one more time the complexity of these pathologies, and showed that it goes beyond the tau isoforms. Tau PET tracers play an important role in the understanding of this aspect. We have observed in post‐mortem brain tissue from Alzheimer’s disease (AD) patients that the second‐generation of tau PET tracers 3 H‐PI2620, 3 H‐MK6240, 3 H‐RO948, all show similar regional distribution, but also comparable binding affinities to multiple binding sites in AD brain large hemispherical tissue section autoradiography and homogenates. In vitro autoradiography can mirror the in vivo binding pattern of PET tracers and be useful in pre‐clinical validations. The aim of this study was to perform a comparative multi‐tracer study in AD, PSP, CBD and control brains with several second generation tau‐tracers to obtain a deeper insight into tau spatial distribution and discriminative power of tau tracers in degenerative proteinopathies. We also want to study how the binding of the tracers correlate with other pathological hallmarks such as amyloid‐β and reactive astrogliosis. Methods we performed radioligand binding assays in brain homogenates, in small tissue sections and large frozen hemispherical brain sections autoradiography using tau PET tracers ( 3 H‐PI2620, 3 H‐MK6240, 3 H‐RO948, and 3 H‐JNJ067) in comparison to reactive astrogliosis PET tracers ( 3 H‐BU99008 and 3 H‐Deprenyl) and amyloid tracer ( 3 H‐PIB). Results In ongoing studies, 3 H‐PI2620, 3 H‐MK6240 and 3 H‐RO948 clearly followed a two binding sites model in AD brains. 3 H‐PI2620 bound to two binding sites in the frontal cortex of both AD and CBD but to one site in PSP brains, but in similar high affinity range in the three pathologies. 3 H‐RO948 and 3 H‐MK6240 showed low binding in comparison to 3 H‐PI2620 in CBD and PSP. Conclusion Tau PET tracers showed similar affinities to multiple binding sites and similar regional distribution in AD brains. 3 H‐MK6240 and 3 H‐RO948 displayed selectivity for AD brains, while 3 H‐PI2620 also showed similar binding affinity for CBD and PSP brains. Ongoing studies with several PET tracers targeting different pathological hallmarks will increase possible discriminative properties and provide new knowledge on the spatial distribution of tau and its correlation with other biomarkers in different tauopathies.