A reaction-based Iridium(III) phosphorescent probe for selective imaging of methylglyoxal and its correlation with amyloid-β pathology in Alzheimer’s disease

Methylglyoxal (MGO), a reactive dicarbonyl metabolite generated during glycolysis, has been implicated in oxidative stress and neuroinflammation associated with Alzheimer’s disease (AD), but its spatial relationship with amyloid-β (Aβ) pathology in brain tissue remains incompletely characterized. Here, we report two cyclometalated iridium(III) complexes, Ir-MA and Ir-DA, for reaction-based phosphorescent sensing of MGO. Ir-DA contains an ortho-diamino recognition unit that reacts with MGO to form the quinoxaline product Ir-DA-Qx, producing a pronounced phosphorescence turn-on response consistent with attenuation of photoinduced electron-transfer-mediated quenching. Compared with the mono-amino analogue Ir-MA, Ir-DA exhibited a preferential response toward MGO over structurally related dicarbonyl species under the tested conditions, with a regression-derived detection limit of 0.32 μM and nonlinear optical properties suitable for multiphoton imaging. Ir-DA enabled imaging of exogenous and endogenous MGO-related changes in living cells and revealed increased phosphorescence signals under inflammatory and amyloidogenic stress. In APP/PS1 mouse brain sections, Ir-DA-associated signals were elevated at 6 months relative to wild-type controls and further increased at 12 months, with quantitative colocalization analysis demonstrating a close spatial association with Aβ-positive plaque core and peri-plaque regions. Collectively, these results establish Ir-DA as a reaction-based phosphorescent platform for imaging MGO-associated carbonyl stress and provide quantitative imaging evidence linking MGO dysregulation with amyloid pathology.