Design Strategies of Cyanine Dyes Bearing Aryl‐Piperazinyl Groups for Molecular Photoacoustic Imaging

Photoacoustic (PA) imaging offers the potential for deep‐tissue visualization, but the development of dyes specifically responsive to diverse lesion environments remains insufficient. To address this problem, we synthesized cyanine dyes incorporating various aryl‐piperazinyl groups at the central carbon of the polymethine chain, aiming to modulate their PA signals in response to various biological processes such as enzyme activity or reactions induced by reactive oxygen species (ROS). When various aryl substituents were incorporated into the piperazinyl cyanine scaffold, each dye showed a distinct absorption spectrum depending on the electron‐donating/withdrawing ability of the substituents. Density functional theory (DFT) optimization and natural population analysis (NPA) revealed that dyes with highly electron‐withdrawing aryl substituents exhibit reduced electron localization in the conjugated system and reduced bond‐length alternation. Conformational analysis further showed substituent‐dependent preferences for different low‐energy conformers, suggesting that both electronic structure and molecular conformation contribute to the observed absorption spectral changes. PA spectra of these dyes also changed depending on the aryl substituents, suggesting that the mechanism of these aryl‐piperazinyl cyanine dyes could serve as a design principle for environment‐responsive PA dyes in the future.