Acyl imidazole derivatives have been applied as activitybased sensing probes to detect intracellular metal ions by leveraging catalytic activity of the ions (Scheme 12A, 12B). Metal ions serve as chemical signals in cells, and chemical probes that detect these ions are useful for understanding their biological functions. In particular, reactivity-based sensing approaches offer advantages that traditional reversible binding sensors do not possess. An acyl transfer-based approach originally developed by Hamachi and co-workers relies on coordination of tetradentate acyl imidazole derivatives to metal ions (Lewis acid), which makes the carbonyl group more electrophilic to trigger a substitution reaction of the complex with nucleophiles on intracellular proteins. The original report developed a zinc-selective probe with dipicolylamine as the zinc-binding site. Although the binding affinity of the probe to Zn 2+ was shown to be quite strong (0.7 nM) for this particular system, the approach could function as catalysis as long as there is a certain degree of dissociation process. Later, Chang and co-workers designed a copper-selective sensor through the incorporation of thioethers enabling detection of labile brain copper. The same group recently applied the catalytic system to multiplex imaging of Cu(I) and Cu(II) by stimulated Raman scattering using isotopically lableled nitrile vibration tags. The development of the zinc-and copper-targeting acyl imidazole sensors indicates that ligand design would be able to modulate the binding selectivity to produce new catalytic chemical probes toward different intracellular metal ions.