title: Novel Fluorinated 8-Hydroxyquinoline Based Metal Ionophores for Exploring the Metal Hypothesis of Alzheimer's Disease.
abstract: Zinc, copper, and iron ions are involved in amyloid-beta (Aβ) deposition and stabilization in Alzheimer's disease (AD). Consequently, metal binding agents that prevent metal-Aβ interaction and lead to the dissolution of Aβ deposits have become well sought therapeutic and diagnostic targets. However, direct intervention between diseases and metal abnormalities has been challenging and is partially attributed to the lack of a suitable agent to determine and modify metal concentration and distribution in vivo. In the search of metal ionophores, we have identified several promising chemical entities by strategic fluorination of 8-hydroxyquinoline drugs, clioquinol, and PBT2. Compounds 15-17 and 28-30 showed exceptional metal ionophore ability (6-40-fold increase of copper uptake and >2-fold increase of zinc uptake) and inhibition of zinc induced Aβ oligomerization (EC50s < ∼5 μM). These compounds are suitable for further development as drug candidates and/or positron emission tomography (PET) biomarkers if radiolabeled with (18)F.
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital , Boston, Massachusetts 02114, United States ; Department of Radiology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Liang
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne , Parkville, Victoria 3010, Australia.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Southon
authors.affiliation: Radiopharmaceutical Research and Development, Life Sciences, Australian Nuclear Science and Technology Organisation , Kirrawee, New South Wales 2232, Australia.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Fraser
authors.affiliation: Radiopharmaceutical Research and Development, Life Sciences, Australian Nuclear Science and Technology Organisation , Kirrawee, New South Wales 2232, Australia.
authors.forename: Anwen M
authors.initials: AM
authors.lastname: Krause-Heuer
authors.affiliation: Radiopharmaceutical Research and Development, Life Sciences, Australian Nuclear Science and Technology Organisation , Kirrawee, New South Wales 2232, Australia.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital , Boston, Massachusetts 02114, United States ; Department of Radiology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Shoup
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital , Boston, Massachusetts 02114, United States.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lewis
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne , Parkville, Victoria 3010, Australia.
authors.forename: Irene
authors.initials: I
authors.lastname: Volitakis
authors.affiliation: The Key Laboratory of Advanced Textile Materials and Manufacturing Technology, Department of Chemistry, Zhejiang Sci-Tech University , Hangzhou 310018, China.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Han
authors.affiliation: Radiopharmaceutical Research and Development, Life Sciences, Australian Nuclear Science and Technology Organisation , Kirrawee, New South Wales 2232, Australia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Greguric
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne , Parkville, Victoria 3010, Australia.
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital , Boston, Massachusetts 02114, United States ; Department of Radiology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Neil
authors.initials: N
authors.lastname: Vasdev
keywords: 8-Hydroxyquinoline; Alzheimer’s disease; metal ionophore; positron emission tomography