Construction\nof New MRI Contrast Agents for Spatiotemporal\nVisualization of Nitric Oxide in Ischemia/Reperfusion Organs

Noninvasive and real-time nitric oxide (NO) visualization <i>in vivo</i> is still a challenge. Herein, we constructed a series\nof NO-responsive magnetic resonance imaging (MRI) contrast agents <b>Gd1b</b>–<b>e</b> by modifying Gd-DO3A using a bis-pyridyl-ethylamine\nside chain as a signal-amplifying moiety and <i>o</i>-phenylenediamine\nas a NO-responsive linker. It was found that <b>Gd1b</b>, <b>d</b>, and <b>e</b> can form macromolecular ternary complexes\n(Gd-Zn<sup>2+</sup>-HSA) with high longitudinal relaxivity (<i>r</i><sub>1</sub>) (12.2–16.2 mM<sup>–1</sup> s<sup>–1</sup>). Once reacting with NO, the <i>o</i>-phenylenediamine\nlinker was hydrolyzed to produce a small molecular Gd complex with\nsharply decreased <i>r</i><sub>1</sub> (4.7–6.3 mM<sup>–1</sup> s<sup>–1</sup>). Among them, <b>Gd1d</b> with a desirable pharmacokinetic profile (<i>t</i><sub>1/2</sub> = 5.91 h) could clearly distinguish the ischemia–reperfusion\n(IR) liver with excessive NO in rats. Meanwhile, the temporarily reduced\namount of NO in the IR liver and brain by the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl\ncould enhance the signal of <b>Gd1d</b>, suggesting anticipated\nNO-responsive property. This research offers a new avenue for insight\ninto the NO spatiotemporal property in multiple IR organs.