Activatable Small‐Molecule Photoacoustic Probes that Cross the Blood–Brain Barrier for Visualization of Copper(II) in Mice with Alzheimer's Disease

Copper enrichment in the brain is highly related to Alzheimer?sdisease (AD) pathogenesis,but in vivotracing of Cu2+ in the brain by imaging techniques is stilla great challenge.Inthis work, we developed aseries of activatable photoacoustic (PA) probes withlow molecular weights (less than 438 Da), RPS1–RPS4,whichcan specifically chelate with Cu2+ to form radicals with turn-on PA signals in the near- infrared (NIR) region. Introducing the electron-donating group N,N-dimethylaniline into the probewas found to significantly enhance the radical stability and PA intensity. The best probein the series, RPS1,showed afast response (within seconds) to Cu2+ with high selectivity and alow PA detectionlimit of 90.9 nm.Owing to the lowmolecular weight and amphiphilic structure, RPS1 couldeffectively crossthe blood–brain barrier (BBB)and thus allowed us,for the first time,tovisualizeCu2+ in vivo via PA imaging in the brains ofAD mice.