A General Approach Based on “Recognizing–Releasing” Strategy to Design Norepinephrine-Responsive Photoacoustic Probes for Depression Detection

The precise detection of norepinephrine (NE) is critically important for understanding depression pathology and improving clinical diagnosis. Current strategies for designing NE-responsive photoacoustic (PA) probes, such as the "protect-deprotect" and the "hunting-shooting", are limited by slow kinetics, susceptibility to interference, or poor generalizability. Here, we report a novel "Recognizing-Releasing" strategy for designing NE-responsive photoacoustic (PA) probes and present QSH-NE as a proof-of-concept probe to demonstrate the generalizability of this strategy for in vivo imaging of depression. This rationally designed probe incorporates a quinolinium-derived sulfur-substituted hemicyanine (QSH-OH) as the PA reporter and a 2-hydroxy-5-(hydroxymethyl) benzaldehyde-derived unit as the recognition moiety. The PA activation mechanism initiates with aldehyde-amino recognition to form a five-membered ring, followed by a releasing step through carbamate cleavage and 1,6-elimination. QSH-NE exhibited favorable sensitivity, high activation fold, and a good response rate for NE in vitro. Notably, QSH-NE enabled noninvasive monitoring of depression progression and drug intervention efficacy through quantitative PA signal analysis in live animal brains. This general design strategy not only advances NE detection specificity but also provides a versatile platform for depression research and clinical diagnosis.