A new technology called CATCH, which combines organizational transparency with click chemistry.
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Release time：2023-07-20
Summary： After drug treatment, the authors performed NeuN immunostaining and found that PF7845‑yne and BIA10‑2474‑yne predominantly colocalized with NeuN‑positive neurons in the neocortex, hippocampus, and amygdala. In contrast, a small population of neuron‑like structures was observed in the pons; these were NeuN‑negative yet targeted by pargyline‑yne (Fig. 3A–D). The authors then eluted NeuN and re‑probed with an anti‑TH antibody to validate this observation, confirming that the NeuN‑negative, pargyline‑yne‑positive cells indeed corresponded to LC‑NA neurons (Fig. 3E). These results demonstrate that CATCH can be combined with fluorescent labeling to reveal the cellular types bound by drugs and to distinguish distinct subcellular sites of drug target engagement within neurons, thereby facilitating iterative identification of drug‑targeted cell types.
Tools for observing drug–target interactions in intact tissues have long been a major hurdle in understanding drug action in vivo. A groundbreaking study published in Cell in 2022, titled “In situ identification of cellular drug targets in mammalian tissue,” reported significant progress: by modifying and integrating click chemistry (CC) with tissue‑clearing techniques, the authors developed a method—Clearing-Assisted TissueClick Chemistry (CATCH)—that enables the labeling and imaging of small‑molecule–target interactions at subcellular resolution (Figure 1A). This approach provides a powerful platform for visualizing in vivo small‑molecule interactions within tissues and allows for the identification of drug distribution and functional contributions in mammalian tissues. 
Figure 1: Method Development for CATCH Technology
1. Tissue transparency has greatly improved chemical labeling in mammalian tissues.
The authors administered to mice the fatty acid amide hydrolase (FAAH) inhibitor PF7845‑yne, which bears an alkyne group at its terminal end. Using the CuAAC click chemistry reaction, the alkyne reacted with the azide on a fluorescent label to form an azide‑alkyne cycloadduct, thereby introducing a fluorescent moiety. Initially, they attempted to directly image the drug–FAAH complex; however, due to a poor signal‑to‑noise ratio, cellular targets remained undetectable. They hypothesized that the complexity of brain tissue and its dense lipid membranes might interfere with the click chemistry reaction. To address this, the authors tested CLARITY, a polyacrylamide‑based hydrogel‑based tissue clearing method, and found that lipid removal significantly improved the imaging signal‑to‑noise ratio (Fig. 1C, D). They also confirmed that other tissue‑clearing approaches yielded comparable results (Fig. 1E). Furthermore, the authors compared the reaction efficiencies of different click‑chemistry ligands—TBTA, BTTAA, and BTTP—at various copper ion concentrations, demonstrating that using BTTP in the presence of 150 μM copper sulfate enabled high‑signal‑to‑noise, stable imaging (Fig. 1B).
2. CATCH enables whole-brain, subcellular in situ imaging of drug–target interactions.
To validate the broad applicability of CATCH, the authors performed CATCH imaging on three small-molecule drugs: the FAAH inhibitor PF7845‑yne, BIA10‑2474‑yne, and the monoamine oxidase (MAO) inhibitor Pargyline‑yne. The results clearly revealed the distribution of these drug–target interactions across distinct brain regions in mice (Fig. 2A–E). Furthermore, the approach enabled visualization of the predominant cell types targeted by each compound: the FAAH inhibitors primarily labeled neuron‑like structures in the neocortex and hippocampus, whereas Pargyline‑yne predominantly bound vascular‑like structures throughout the brain, with sparse but specific labeling of neuron‑like structures in the hypothalamus and pons (Fig. 2F).
Figure 2. Visualization of whole-brain drug binding
3. CATCH can be conjugated with fluorescent labels to identify target cell types.
After drug treatment, the authors performed NeuN immunostaining and found that PF7845‑yne and BIA10‑2474‑yne predominantly colocalized with NeuN‑positive neurons in the neocortex, hippocampus, and amygdala. In contrast, a small population of neuron‑like structures was observed in the pons; these were NeuN‑negative but targeted by pargyline‑yne (Fig. 3A–D). Subsequently, the authors eluted NeuN and re‑incubated with a TH antibody to validate this observation, confirming that the NeuN‑negative, pargyline‑yne‑positive cells indeed corresponded to LC‑NA neurons (Fig. 3E). These findings demonstrate that CATCH can be combined with fluorescent labeling to reveal the cellular types bound by drugs and to distinguish distinct subcellular sites of drug target engagement, thereby facilitating iterative identification of cell types targeted by therapeutics.
Figure 3. Cell-type identification of drug targets
The tissue‑clearing kit independently developed by the Nuohai team enables efficient decolorization and delipidation. Designed with a mild, hydrophilic environment, it demonstrates superior performance in preserving tissue fluorescence, maintaining sample morphology, and reducing autofluorescence. It offers broad applicability, simple operation, rapid processing, and high efficiency.
Keywords:
Click chemistry,Organizational Transparency
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