Imaging of Tau Pathology in Neurodegenerative Diseases: An Update

Pathological accumulated misfolded tau underlies various neurodegenerative diseases and associated clinical syndromes. To diagnose those diseases reliable before death or even at early stages, many different tau-specific radiotracers have been developed in the last decade to be used with positron-emission-tomography. In contrast to amyloid-β imaging, different isoforms of tau exist further complicating radiotracer development. First-generation radiotracers like [¹¹C]PBB3, [¹⁸F]AV1451 and [¹⁸F]THK5351 have been extensively investigated in vitro and in vivo. In Alzheimer's disease (AD), high specific binding could be detected, and evidence of clinical applicability recently led to clinical approval of [¹⁸F]flortaucipir ([¹⁸F]AV1451) by the FDA. Nevertheless, absent or minor binding to non-AD tau isoforms and high off-target binding to non-tau brain structures limit the diagnostic applicability especially in non-AD tauopathies demanding further tracer development. In vitro assays and autoradiography results of next-generation radiotracers [¹⁸F]MK-6240, [¹⁸F]RO-948, [¹⁸F]PM-PBB3, [¹⁸F]GTP-1 and [¹⁸F]PI-2620 clearly indicate less off-target binding and high specific binding to tau neurofibrils. First in human studies have been conducted with promising results for all tracers in AD patients, and also some positive experience in non-AD tauopathies. Overall, larger scaled autoradiography and human studies are needed to further evaluate the most promising candidates and support future clinical approval.