Metallotexaphyrins as MRI-Active Catalytic Antioxidants for Neurodegenerative Disease: A Study on Alzheimer's Disease

James T Brewster 2nd; Gregory D Thiabaud; Peter Harvey; Hadiqa Zafar; James F Reuther; Simone Dell'Acqua; Rachel M Johnson; Harrison D Root; Pedro Metola; Alan Jasanoff; Luigi Casella; Jonathan L Sessler

doi:10.1016/j.chempr.2019.12.016

Metallotexaphyrins as MRI-Active Catalytic Antioxidants for Neurodegenerative Disease: A Study on Alzheimer's Disease

Chem. 2020 Mar 12;6(3):703-724. doi: 10.1016/j.chempr.2019.12.016.

Authors

James T Brewster 2nd¹, Gregory D Thiabaud¹, Peter Harvey^{2

3}, Hadiqa Zafar¹, James F Reuther^{1

4}, Simone Dell'Acqua⁵, Rachel M Johnson⁶, Harrison D Root¹, Pedro Metola⁶, Alan Jasanoff², Luigi Casella⁵, Jonathan L Sessler^{1

7}

Affiliations

¹ Department of Chemistry, the University of Texas at Austin, Austin, TX 78712-1224, USA.
² Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ Sir Peter Mansfield Imaging Centre, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK.
⁴ Department of Chemistry, University of Massachusetts Lowell, Lowell, MA 01854, USA.
⁵ Department of Chemistry, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy.
⁶ Accelerated Research Initiative, University of Texas at Austin, Austin, TX 78712, USA.
⁷ Center for Supramolecular Chemistry and Catalysis, Shanghai University, Shanghai, China.

Abstract

The complex etiology of neurodegeneration continues to stifle efforts to develop effective therapeutics. New agents elucidating key pathways causing neurodegeneration might serve to increase our understanding and potentially lead to improved treatments. Here, we demonstrate that a water-soluble manganese(II) texaphyrin (MMn) is a suitable magnetic resonance imaging (MRI) contrast agent for detecting larger amyloid beta constructs. The imaging potential of MMn was inferred on the basis of in vitro studies and in vivo detection in Alzheimer's disease C. elegans models via MRI and ICP-MS. In vitro antioxidant- and cellular-based assays provide support for the notion that this porphyrin analog shows promise as a therapeutic agent able to mitigate the oxidative and nitrative toxic effects considered causal in neurodegeneration. The present report marks the first elaboration of an MRI-active metalloantioxidant that confers diagnostic and therapeutic benefit in Alzheimer's disease models without conjugation of a radioisotope, targeting moiety, or therapeutic payload.

Keywords: Alzheimer’s disease; C. elegans AD models; MRI; amyloid aggregation; amyloid beta; amyloid beta modifications by ROS and RNS; expanded porphyrin; metalloantioxidant; neurodegeneration; texaphyrin.

Abstract

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