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      Candidate PET Radioligand Development for Neurofibrillary Tangles: Two Distinct Radioligand Binding Sites Identified in Postmortem Alzheimer’s Disease Brain

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          Abstract

          [ 18F]THK-523 and [ 18F]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 [ 18F]THK-523 and [ 18F]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 [ 3H]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.

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          Author and article information

          Journal
          101525337
          37346
          ACS Chem Neurosci
          ACS Chem Neurosci
          ACS chemical neuroscience
          1948-7193
          9 August 2017
          19 May 2016
          20 July 2016
          01 September 2017
          : 7
          : 7
          : 897-911
          Affiliations
          []Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, United States
          []Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, Rockville, Maryland 20851, United States
          Author notes
          [* ] Corresponding Author: Mailing Address: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Building 10, Room B3 C346, Bethesda, MD 20892, USA. Tel: (301) 451-3905. Fax: (301) 480-5112. LishengCai@ 123456mail.nih.gov
          [§]

          Author Contributions

          L.C. and B.Q. contributed equally. L.C. contributed to syntheses, development of binding assays, and radiosyntheses. B.Q. contributed to development and implementation of assays. B.T.H. contributed to syntheses and radiosyntheses. S.D. contributed to syntheses. R.D.-A. contributed to assay development. V.W.P., L.C., and R.D.-A. conceived the project, and V.W.P. provided overall supervision. The manuscript was written through contributions of all the authors. All authors have given approval to the final version of the manuscript.

          Article
          PMC5580238 PMC5580238 5580238 nihpa898013
          10.1021/acschemneuro.6b00051
          5580238
          27171905
          7d3335fc-2a8e-47c7-8984-03a1da509743
          History
          Categories
          Article

          Alzheimer’s disease,Radioligand,in vitro assay,tangle,tau,PET
          Alzheimer’s disease, Radioligand, in vitro assay, tangle, tau, PET

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