A Nitric Oxide-Sensing T1 Contrast Agent for In Vivo Molecular MR Imaging of Inflammatory Disease

Abstract

Nitric oxide (NO) is a signaling molecule that not only appears in the very early stage of inflammatory disease but also persists in chronic conditions. Its detection in vivo can, therefore, potentially enable early disease detection and treatment monitoring. Due to its transient nature and low abundance, however, noninvasive and deep-tissue imaging of NO dynamics is challenging. In this study, we present a magnetic resonance imaging (MRI) contrast agent based on a manganese porphyrin for specific imaging of NO. This agent is activated by NO, binds to tissue protein, accumulates so long as NO is actively produced, and confers a substantial bright contrast on T₁-weighted MRI. In vitro tests confirm the specificity of activation by NO over other reactive oxygen or nitrogen species, absence of inflammation induced by the contrast agent, and sensitivity to NO levels in the tens of micromolar. In vivo demonstration in a mouse model of stress-induced acute myocardial inflammation revealed an over 2.2-times increase in T₁ reduction in the inflamed heart compared to a healthy heart. This new NO-activatable T₁ contrast agent holds the potential to provide early diagnosis of inflammatory disease, characterize different stages of inflammation, and ultimately guide the design of novel anti-inflammation therapeutics.