In situ identification of cellular in mammalian tissue

The lack of tools to observe drug-target interactions at cellular resolution in intact tissue has been a major barrier to understanding in vivo drug actions. Here, we develop clearing-assisted tissue click chemistry (CATCH) to optically image covalent drug targets in intact mammalian tissues. CATCH permits specific and robust in situ fluorescence imaging of target-bound drug molecules at subcellular resolution and enables the identification of target cell types. Using well-established inhibitors of endocannabinoid hydrolases and monoamine oxidases, direct or competitive CATCH not only reveals distinct anatomical distributions and predominant cell targets of different drug compounds in the mouse brain but also uncovers unexpected differences in drug engagement across and within brain regions, reflecting rare cell types, as well as dose dependent target shifts across tissue, cellular, and subcellular compartments that are not accessible by conventional methods. CATCH represents a valuable platform for visualizing in vivo interactions of small molecules in tissue.

Automated summary

This study develops a clearing-assisted tissue click chemistry (CATCH) technique for optically imaging covalent drug targets in intact mammalian tissues. The researchers find that CATCH enables specific and robust imaging of target-bound drug molecules at subcellular resolution, and it can also identify the target cell types. By using inhibitors of endocannabinoid hydrolases and monoamine oxidases, the study not only reveals distinct anatomical distributions and predominant cell targets of different drug compounds in the mouse brain, but it also uncovers unexpected differences in drug engagement across and within brain regions, reflecting rare cell types and dose-dependent target shifts that cannot be accessed by conventional methods.