Targeting MAO-A With Ultrafast Kinetics: Affinity Probes for Precision Imaging of Brain Pathologies and Depression...

Major depressive disorder (MDD) lacks objective biomarkers, hindering diagnosis. Monoamine oxidase A (MAO-A)-upregulated in depressed brains and degrading monoamine neurotransmitters-is a key pathological biomarker. To address limitations of current MAO-A probes (reliance on enzymatic reactions, > 1 h), we designed JBDs: near-infrared (λ_em>700 nm) probes with large Stokes shifts (> 200 nm), using affinity-based recognition (independent of enzymatic reactions), a purine core for superior MAO-A affinity, and showing long conjugated system and negatively charged tails do not enhance affinity. Among them, JBD stands out with extraordinary performance: < 5 s response (2-3 orders faster than reported) and exceptional specificity for MAO-A. It enables precise targeted MAO-A imaging in overexpressing live cells and visualizes MAO-A in orthotopic glioma mice. Critically, JBD achieves non-invasive imaging of MAO-A upregulation in depressive mouse brains, directly bridging the gap between MAO-A detection and MDD-associated biomarker visualization. RNA-seq further confirms MAO-A elevation aligns with MDD pathways, supporting JBD's role in detecting and dissecting MAO-A-mediated depressive mechanisms.