Second-generation tau PET tracer in situ binding assessed with fluorescence imaging

Brain positron emission tomography (PET) imaging is a valuable tool which allows visualization of the pathological structures inside the living patients' brains. While amyloid-β PET tracers have been in use with Alzheimer's disease patients in clinics, tau PET tracers have still not entered the clinical routine. Second-generation tau PET tracers have been developed with the aim to overcome the limitations of the first-generation tau PET tracers, such as low sensitivity and off-target binding. However, the detailed pathological characterization of these tracers' binding is still needed for fully understanding their potential as accurate markers of pathogenic tau. Herein, we focused on the second-generation tau PET tracer Genentech Tau Probe 1 ([ ¹⁸ F]GTP1) and made use of the fluorescent properties of its non-radioactive unlabeled variant GTP1 for correlative fluorescence microscopy. The results show that GTP1 binds to tau tangles and neuropil threads (NPTs), but not amyloid-β plaques. Importantly, our results indicate that there is a strong correlation between the fluorescent GTP1 signal and the [ ¹⁸ F]GTP1 signal detected with autoradiography, which is currently the standard way of studying the tau PET tracer binding in situ . Together, this data shows the robust application of a non-radioactive tau PET tracer in binding studies in post-mortem tissue and sheds new light on the tau binding properties of GTP1.