A Metal-Free Method for Producing MRI Contrast at Amyloid-β

Article type: Research Article

Authors: Hilt, Silvia^{a; 1} | Tang, Tang^{b; 1} | Walton, Jeffrey H.^c | Budamagunta, Madhu^a | Maezawa, Izumi^d | Kálai, Tamás^e | Hideg, Kálmán^e | Singh, Vikrant^f | Wulff, Heike^f | Gong, Qizhi^g | Jin, Lee-Way^d | Louie, Angelique^h | Voss, John C.^{a; *}

Affiliations: [a] Department of Biochemistry & Molecular Medicine, University of California Davis, Sacramento, CA, USA | [b] Department of Chemistry, University of California Davis, Davis, CA, USA | [c] UCD NMR Facility & and Biomedical Engineering Graduate Group, University of California Davis, Davis, CA, USA | [d] M.I.N.D. Institute and Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA | [e] Institute of Organic and Medicinal Chemistry, University of Pécs, Pécs, Hungary | [f] Department of Pharmacology, University of California Davis, Davis, CA, USA | [g] Department of Cell Biology and Human Anatomy, School of Medicine, University of California Davis, Davis, CA, USA | [h] Department of Biomedical Engineering and Chemistry Graduate Group, University of California Davis, Davis, CA, USA

Correspondence: [*] Correspondence to: John C. Voss, Department of Biochemistry & Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA. Tel.: +1 530 754 7583; Fax:+1 530 752 3516; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

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.

Keywords: Alzheimer’s disease, amyloid-β, amyloid MRI contrast, magnetic resonance imaging, nitroxide spin label, spin-labeled fluorene

DOI: 10.3233/JAD-160279

Journal: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1667-1681, 2017