Merged Molecular Switches Excel as Optoacoustic Dyes: Azobenzene–Cyanines Are Loud and Photostable NIR Imaging Agents

Abstract Optoacoustic (or photoacoustic) imaging promises micron‐resolution noninvasive bioimaging with much deeper penetration (>cm) than fluorescence. However, optoacoustic imaging of enzyme activity would require loud, photostable, NIR‐absorbing molecular contrast agents, which remain unknown. Most organic molecular contrast agents are repurposed fluorophores, with severe shortcomings of photoinstability or phototoxicity under optoacoustic imaging, as consequences of their slow S 1 →S 0 electronic relaxation. We now report that known fluorophores can be rationally modified to reach ultrafast S 1 →S 0 rates, without much extra molecular complexity, simply by merging them with molecular switches. Here, we merge azobenzene switches with cyanine dyes to give ultrafast relaxation (100‐fold faster). Without even adapting instrument settings, these azohemicyanines display outstanding improvements in signal longevity (>1000‐fold increase of photostability) and signal loudness (>3‐fold even at time zero). We show why this simple but unexplored design strategy can still offer stronger performance in the future, and can also increase the spatial resolution and the quantitative linearity of photoacoustic response over extended longitudinal imaging. By bringing the world of molecular switches and rotors to bear on problems facing optoacoustic agents, this practical strategy will help to unleash the full potential of optoacoustic imaging in fundamental studies and translational uses.