Dual tracer tau PET imaging reveals different molecular targets for ¹¹C-THK5351 and ¹¹C-PBB3 in the Alzheimer brain

Purpose: Several tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (¹¹C-THK5351 and ¹¹C-PBB3) in a head-to-head, in vivo, multimodal design. Methods: Nine patients with a diagnosis of mild cognitive impairment or probable Alzheimer’s disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer’s disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers ¹¹C-THK5351 and ¹¹C-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer ¹¹C-AZD2184, a T1-MRI sequence, and neuropsychological assessment. Results: The load and regional distribution of binding differed between ¹¹C-THK5351 and ¹¹C-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of ¹¹C-PBB3, but not that of ¹¹C-THK5351, in the temporal lobe resembled that of ¹¹C-AZD2184, with strong correlations detected between ¹¹C-PBB3 and ¹¹C-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with ¹¹C-THK5351 than with ¹¹C-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with ¹¹C-THK5351 than with ¹¹C-PBB3 binding. Conclusion: This research suggests different molecular targets for these tracers; while ¹¹C-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of ¹¹C-THK5351 fitted the expected distribution of tau pathology in Alzheimer’s disease better and was more closely related to downstream disease markers.