title: Candidate PET Radioligand Development for Neurofibrillary Tangles: Two Distinct Radioligand Binding Sites Identified in Postmortem Alzheimer's Disease Brain.
abstract: [(18)F]THK-523 and [(18)F]807 are promising radioligands for imaging neurofibrillary tangles (NFTs) with positron emission tomography (PET) in neurodegenerative diseases, such as Alzheimer's disease (AD) and traumatic brain injury. Although [(18)F]THK-523 and [(18)F]T807 are considered high-affinity selective radioligands for NFTs, uncertainty has existed as to whether PET radioligands for imaging NFTs bind to the same molecular site because in vitro assays for ligands binding to NFTs have been lacking. We labeled THK-523 and T807 with tritium to serve as reference radioligands for in vitro binding assays with AD brain homogenates for newly synthesized ligands. With these radioligands, we identified two distinct binding sites for small molecules, one site with high affinity for THK-523 and the other with high affinity for T807. Moreover, binding assays with [(3)H]PIB confirmed that the two newly identified binding sites are also distinct from the thioflavin-T binding site where all current clinically useful PET radioligands for imaging β-amyloid plaque bind with high affinity. The two newly identified binding sites are considered to reside on NFTs rather than on β-amyloid plaques. Furthermore, we applied all three binding assays to a set of newly prepared compounds, based on chain modifications to THK-523. Some compounds with high affinity and selectivity for the THK-523 binding site emerged from this set, including one with amenability to labeling with fluorine-18, namely, ligand 10b.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Cai
authors.affiliation: Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences , Rockville, Maryland 20851, United States.
authors.forename: Baoxi
authors.initials: B
authors.lastname: Qu
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Hurtle
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Sureshbabu
authors.initials: S
authors.lastname: Dadiboyena
authors.affiliation: Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences , Rockville, Maryland 20851, United States.
authors.forename: Ramon
authors.initials: R
authors.lastname: Diaz-Arrastia
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000473:pathology*; D000814:Aniline Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D001345:Autoradiography; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002243:Carbolines / Q000493:pharmacokinetics; D003933:Diagnosis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D016874:Neurofibrillary Tangles / Q000473:pathology*; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000737:chemistry / Q000493:pharmacokinetics; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; C559040:2-(4-aminophenyl)-6-(2-fluoroethoxy)quinoline; D000814:Aniline Compounds; D002243:Carbolines; D011804:Quinolines; D019275:Radiopharmaceuticals; D013844:Thiazoles; D016875:tau Proteins; C000591008:7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole
keywords: Alzheimer’s disease; PET; Radioligand; in vitro assay; tangle; tau