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

doi:10.1093/brain/aww339 BRAIN 2017: 140; 764–780 | 764 Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies Maiko Ono,1,2 Naruhiko Sahara,1 Katsushi Kumata,1 Bin Ji,1 Ruiqing Ni,3 Shunsuke Koga,4 Dennis W. Dickson,4 John Q. Trojanowski,5 Virginia M-Y. Lee,5 Mari Yoshida,6 Isao Hozumi,7 Yasumasa Yoshiyama,8 John C. van Swieten,9 Agneta Nordberg,3 Tetsuya Suhara,1 Ming-Rong Zhang1 and Makoto Higuchi1 Diverse neurodegenerative disorders are characterized by deposition of tau fibrils composed of conformers (i.e. strains) unique to each illness. The development of tau imaging agents has enabled visualization of tau lesions in tauopathy patients, but the modes of their binding to different tau strains remain elusive. Here we compared binding of tau positron emission tomography ligands, PBB3 and AV-1451, by fluorescence, autoradiography and homogenate binding assays with homologous and heterologous blockades using tauopathy brain samples. Fluorescence microscopy demonstrated intense labelling of non-ghost and ghost tangles with PBB3 and AV-1451, while dystrophic neurites were more clearly detected by PBB3 in brains of Alzheimer’s disease and diffuse neurofibrillary tangles with calcification, characterized by accumulation of all six tau isoforms. Correspondingly, partially distinct distributions of autoradiographic labelling of Alzheimer’s disease slices with 11C-PBB3 and 18F-AV-1451 were noted. Neuronal and glial tau lesions comprised of 4-repeat isoforms in brains of progressive supranuclear palsy, corticobasal degeneration and familial tauopathy due to N279K tau mutation and 3-repeat isoforms in brains of Pick’s disease and familial tauopathy due to G272V tau mutation were sensitively detected by PBB3 fluorescence in contrast to very weak AV-1451 signals. This was in line with moderate 11C-PBB3 versus faint 18F-AV-1451 autoradiographic labelling of these tissues. Radioligand binding to brain homogenates revealed multiple binding components with differential affinities for 11C-PBB3 and 18F-AV-1451, and higher availability of binding sites on progressive supranuclear palsy tau deposits for 11C-PBB3 than 18F-AV-1451. Our data indicate distinct selectivity of PBB3 compared to AV-1451 for diverse tau fibril strains. This highlights the more robust ability of PBB3 to capture wide-range tau pathologies. 1 National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan 2 Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan 3 Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm 14157, Sweden 4 Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA 5 Center for Neurodegenerative Disease Research and Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA 6 Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute 480-1195, Japan 7 Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu 501-1196, Japan 8 Department of Neurology, Chiba-East National Hospital, Chiba 260-8712, Japan 9 Department of Neurology, Erasmus Medical Center, Rotterdam 3015 CE, The Netherlands Received June 14, 2016. Revised November 15, 2016. Accepted November 16, 2016. Advance Access publication January 12, 2017 ß The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: Comparison of PET ligands PBB3 and AV-1451 BRAIN 2017: 140; 764–780 | 765 Correspondence to: Makoto Higuchi, MD, PhD, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan E-mail: Keywords: tau PET ligand; PBB3/AV-1451; Alzheimer’s disease; N279K/G272V FTDP-17-MAPT mutation; progressive supranuclear palsy/corticobasal degeneration/Pick’s disease Abbreviations: CBD = corticobasal degeneration; DNTC = diffuse neurofibrillary tangles with calcification; FTDP-17 = frontotemporal dementia and parkinsonism linked to chromosome 17; FTLD = frontotemporal lobar degeneration; GB = Gallyas-Braak silver stain; PSP = progressive supranuclear palsy Introduction Accumulation of filamentous tau protein aggregates in the brain is characteristic of Alzheimer’s disease and allied neurodegenerative disorders collectively referred to as tauopathies (Lee et al., 2001). The discovery of tau gene mutations in familial tauopathy termed frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and investigations of various tau transgenic mouse lines provided compelling evidence for the mechanistic implication of tau abnormalities in neurotoxic insults (Lee et al., 2001). Composition of tau isoforms may give rise to conformational diversity of tau fibrils, which are ultrastructurally identified as paired helical filaments and straight filaments or ribbons (Bibow et al., 2011; Murray et al., 2014). These and other minor conformational variants, dubbed ‘strains’, determine subcellular, cellular and regional localizations of tau aggregates in close association with pathological and clinical phenotypes of each tauopathy (Feany and Dickson, 1995; Murray et al., 2014). To date, converging experimental evidence supports the view that misfolding of tau can propagate intercellularly similar to prion proteins, with an original tau strain being preserved during the transmission process (Goedert et al., 2014; Sanders et al., 2014). As there has been growing demand for diagnostic and therapeutic approaches to tau pathologies, small-molecule agents for PET have been developed to visualize tau deposits in the brains of living subjects. These tracers are in principle ligands that bind to a b-pleated sheet secondary structure forming in tau filaments, and are likely to dock a binding pocket on the b-sheet of tau, which may differ structurally from binding pockets in amyloid-b fibrils (Berriman et al., 2003). Similarly, there may be conformational and structural differences among tracer binding components on distinct tau fibril strains, particularly in with respect to tau isoform compositions (Hasegawa et al., 2014; Taniguchi-Watanabe et al., 2016), since an alternative splicing domain, exon 10, is a constituent of the b-sheet domain of fibrillary tau assemblies (Li et al., 2002; von Bergen et al., 2006; Daebel et al., 2012). Among three classes of tau PET tracers, 11C-pyridinylbutadienyl-benzothiazole 3 (11C-PBB3) was the first reported to detect a broad range of tau inclusions, and in vivo PET data supported its utility for detecting tau lesions not only in patients with Alzheimer’s disease but also in subjects with non-Alzheimer’s disease dementias as exemplified by corticobasal degene (...truncated)