Construction of New MRI Contrast Agents for Spatiotemporal Visualization of Nitric Oxide in Ischemia/Reperfusion Organs

Abstract

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