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

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 bis-pyridyl-ethylamine
side chain as a signal-amplifying moiety and o-phenylenediamine
as a NO-responsive linker. It was found that Gd1b, d, and e can form macromolecular ternary complexes
(Gd-Zn2+-HSA) with high longitudinal relaxivity (r1) (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 r1 (4.7–6.3 mM–1 s–1). Among them, Gd1d with a desirable pharmacokinetic profile (t1/2 = 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.