title: A Metal-Free Method for Producing MRI Contrast at Amyloid-β.
abstract: Alzheimer's disease (AD) is characterized by depositions of the amyloid-β (Aβ) peptide in the brain. The disease process develops over decades, with substantial neurological loss occurring before a clinical diagnosis of dementia can be rendered. It is therefore imperative to develop methods that permit early detection and monitoring of disease progression. In addition, the multifactorial pathogenesis of AD has identified several potential avenues for AD intervention. Thus, evaluation of therapeutic candidates over lengthy trial periods also demands a practical, noninvasive method for measuring Aβ in the brain. Magnetic resonance imaging (MRI) is the obvious choice for such measurements, but contrast enhancement for Aβ has only been achieved using Gd(III)-based agents. There is great interest in gadolinium-free methods to image the brain. In this study, we provide the first demonstration that a nitroxide-based small-molecule produces MRI contrast in brain specimens with elevated levels of Aβ. The molecule is comprised of a  fluorene (a molecule with high affinity for Aβ) and a nitroxide spin label (a paramagnetic MRI contrast species). Labeling of brain specimens with the spin-labeled fluorene produces negative contrast in samples from AD model mice whereas no negative contrast is seen in specimens harvested from wild-type mice. Injection of spin-labeled fluorene into live mice resulted in good brain penetration, with the compound able to generate contrast 24-h post injection. These results provide a proof of concept method that can be used for early, noninvasive, gadolinium-free detection of amyloid plaques by MRI.
authors.affiliation: Department of Biochemistry & Molecular Medicine, University of California Davis, Sacramento, CA, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Hilt
authors.affiliation: Department of Chemistry, University of California Davis, Davis, CA, USA.
authors.forename: Tang
authors.initials: T
authors.lastname: Tang
authors.affiliation: UCD NMR Facility & and Biomedical Engineering Graduate Group, University of California Davis, Davis, CA, USA.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Walton
authors.affiliation: Department of Biochemistry & Molecular Medicine, University of California Davis, Sacramento, CA, USA.
authors.forename: Madhu
authors.initials: M
authors.lastname: Budamagunta
authors.affiliation: M.I.N.D. Institute and Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA.
authors.forename: Izumi
authors.initials: I
authors.lastname: Maezawa
authors.affiliation: Institute of Organic and Medicinal Chemistry, University of Pécs, Pécs, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Kálai
authors.affiliation: Institute of Organic and Medicinal Chemistry, University of Pécs, Pécs, Hungary.
authors.forename: Kálmán
authors.initials: K
authors.lastname: Hideg
authors.affiliation: Department of Pharmacology, University of California Davis, Davis, CA, USA.
authors.forename: Vikrant
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Pharmacology, University of California Davis, Davis, CA, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.affiliation: Department of Cell Biology and Human Anatomy, School of Medicine, University of California Davis, Davis, CA, USA.
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Gong
authors.affiliation: M.I.N.D. Institute and Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA.
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
authors.affiliation: Department of Biomedical Engineering and Chemistry Graduate Group, University of California Davis, Davis, CA, USA.
authors.forename: Angelique
authors.initials: A
authors.lastname: Louie
authors.affiliation: Department of Biochemistry & Molecular Medicine, University of California Davis, Sacramento, CA, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Voss
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000473:pathology; D003287:Contrast Media / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008670:Metals / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003287:Contrast Media; D008670:Metals; D053764:Presenilin-1
keywords: Alzheimer’s disease; amyloid MRI contrast; amyloid-β; magnetic resonance imaging; nitroxide spin label; spin-labeled fluorene