[18F]THK-5117 PET for assessing neurofibrillary pathology in Alzheimer’s disease

Abstract

These findings suggest that [(18)F]THK-5117 provides regional information on neurofibrillary pathology in living subjects.

Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies

“…Alzheimer's disease tau aggregates composed of all six tau isoforms are dominated by paired helical filaments (Goedert et al, 1992), while straight filaments are present as the major morphology of tau filaments in a large subset of tau-positive frontotemporal lobar degenerations (FTLDs) characterized by deposition of tau isoforms (FTLD-Tau) with 4-repeat domains, such as progressive supranuclear palsy (PSP) and CBD (Flament et al, 1991;Ksiezak-Reding et al, 1994), and FTLD-Tau disorders with 3-repeat domains, such as Pick's disease (Kato and Nakamura, 1990). It has also been documented that other groups of tau radioligands, including 18 F-AV-1451 (also known as 18 F-T807), THK-5117 and THK-5351, react with Alzheimer's disease tau tangles as well as a some FTLD-Tau non-Alzheimer's disease tau deposits (Chien et al, 2013;Okamura et al, 2013;Harada et al, 2014Harada et al, , 2015Harada et al, , 2016Rabinovici et al, 2015;Vettermann et al, 2016). Meanwhile, a recent study has raised the possibility that 18 F-AV-1451 selectively binds to Alzheimer's disease paired helical filaments but binds less avidly to other tau fibril types (Marquié et al, 2015;Lowe et al, 2016;Sander et al, 2016).…”

Structure–Activity Relationship of 2-Arylquinolines as PET Imaging Tracers for Tau Pathology in Alzheimer Disease

“…Tau PET imaging is expected to provide a better indication of the severity and prognosis of AD given the stronger association between neurodegeneration and tau pathology (10). Similar to Ab probes, most tau probes are small molecules radiolabeled with 11 C or 18 F and have planar aromatic rings that enable them to bind to the b-sheet structure of tau aggregates. First-in-human PET studies in AD or other tauopathies of some tau probes have already been performed using novel tau tracers (11)(12)(13).…”

“…The probes mainly consist of lipophilic heterocyclic rings, which allow them to cross the blood-brain barrier, and are labeled with 11 C or 18 F. Although 11 C-Pittsburgh compound B is the most prevalent Ab probe, 3 18 F-labeled probes have already been approved by the Food and Drug Administration and the European Medicines Agency (8). The development of tau PET probes has been of increasing interest over the past few years (9).…”

“…Since then, we have been developing 2-arylquinoline (2-AQ) derivatives for tau PET imaging (15-17) and 3 18 F-labeled derivatives, 18 F-THK-523, 18 F-THK-5105, and 18 F-THK-5117, have already been evaluated in clinical studies (13,18,19). In recent basic and clinical studies, 18 F-THK-5117 demonstrated high binding selectivity and affinity for tau over Ab pathology and better pharmacokinetics in the living brain than other THK probes (18). However, 18 F-THK-5117 showed marked white matter retention in both healthy controls and AD patients (18).…”

Is Tau Imaging More Than Just Upside-Down 18F-FDG Imaging?

“…Elevated binding to melanin and monoaminooxydase may explain some of the off-target binding (30)(31)(32). Particularly worrisome are recent findings demonstrating a potential contribution of monoaminooxydase-B binding to tau PET imaging not only in subcortical but also in cortical brain regions (33).…”