title: Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies.
abstract: 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.
authors.affiliation: National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.|Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Ono
authors.affiliation: National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Naruhiko
authors.initials: N
authors.lastname: Sahara
authors.affiliation: National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kumata
authors.affiliation: National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Bin
authors.initials: B
authors.lastname: Ji
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm 14157, Sweden.
authors.forename: Ruiqing
authors.initials: R
authors.lastname: Ni
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Koga
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Center for Neurodegenerative Disease Research and Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Center for Neurodegenerative Disease Research and Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute 480-1195, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Hozumi
authors.affiliation: Department of Neurology, Chiba-East National Hospital, Chiba 260-8712, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Yoshiyama
authors.affiliation: Department of Neurology, Erasmus Medical Center, Rotterdam 3015 CE, The Netherlands.
authors.forename: John C
authors.initials: JC
authors.lastname: van Swieten
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm 14157, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordberg
authors.affiliation: National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.affiliation: National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.affiliation: National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
mesh_terms: D001345:Autoradiography; D052160:Benzothiazoles / Q000737:chemistry / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D002070:Butadienes / Q000493:pharmacokinetics; D002243:Carbolines / Q000493:pharmacokinetics*; D003933:Diagnosis; D005260:Female; D005453:Fluorescence; D006801:Humans; D008297:Male; D016874:Neurofibrillary Tangles / Q000473:pathology*; D010621:Phenazopyridine / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D024801:Tauopathies / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D013830:Thiadiazoles / Q000493:pharmacokinetics; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D002070:Butadienes; D002243:Carbolines; C000619442:PBB3 compound; D019275:Radiopharmaceuticals; D013830:Thiadiazoles; D016875:tau Proteins; C015700:benzo-1,2,3-thiadiazole; C000591008:7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole; D010621:Phenazopyridine
keywords: Alzheimer’s disease; N279K/G272V FTDP-17-MAPT mutation; PBB3/AV-1451; progressive supranuclear palsy/corticobasal degeneration/Pick’s
                      disease; tau PET ligand