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Improving the reactivity of hydrazine-bearing MRI probes for in vivo imaging of lung fibrogenesis

Abstract

Pulmonary fibrosis (PF) is the pathologic accumulation of extracellular matrix components in lung tissue that result in scarring following chronic lung injury. PF is typically diagnosed by high resolution computed tomography (HRCT) and/or invasive biopsy. However, HRCT cannot distinguish old injury from active fibrogenesis. We previously demonstrated that allysine residues on oxidized collagen represent an abundant target during lung fibrogenesis, and that magnetic resonance imaging (MRI) with a small-molecule, gadolinium-containing probe, Gd-Hyd, could specifically detect and stage fibrogenesis in a mouse model. In this work, we present an improved probe, Gd-CHyd, featuring an N,N-dialkyl hydrazine which has an order of magnitude both greater reactivity and affinity for aldehydes. In a paired study in mice with bleomycin induced lung injury we show that the improved reactivity and affinity of Gd-CHyd results in significantly higher lung-to-liver contrast, e.g. 77% higher at 45 min post injection, and slower lung clearance than Gd-Hyd. Gd-CHyd enhanced MRI is >60-fold higher in bleomycin injured mouse lungs compared to uninjured mice. Collectively, our data indicate that enhancing hydrazine reactivity and affinity towards allysine is an effective strategy to significantly improve molecular MRI probes for lung fibrogenesis.

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Publication details

The article was received on 24 Sep 2019, accepted on 08 Nov 2019 and first published on 08 Nov 2019


Article type: Edge Article
DOI: 10.1039/C9SC04821A
Chem. Sci., 2019, Accepted Manuscript
  • Open access: Creative Commons BY-NC license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    Improving the reactivity of hydrazine-bearing MRI probes for in vivo imaging of lung fibrogenesis

    E. A. Akam, E. Abston, N. Rotile, H. Slattery, I. Zhou, M. Lanuti and P. Caravan, Chem. Sci., 2019, Accepted Manuscript , DOI: 10.1039/C9SC04821A

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