Enzyme-Instructed CBT-Cys-like Click Cyclization Reactions for Bioimaging

Abstract

With high efficiency, mild conditions, and rapid reaction rate, click reactions have garnered much attention in the field of bioimaging since proposed by Sharpless et al. in 2001 ( Angew. Chem., Int. Ed. 2001, 40, 2004−2021). Inspired by the regenerative pathway of d-luciferin in fireflies, Liang et al. ( Nat. Chem. 2010, 2, 54−60) raised a 2-cyanobenzothiazole (CBT)-cysteine (Cys) click condensation reaction in 2010, which exhibits a higher second-order reaction rate (9.19 M^–1 s^–1) and superior biocompatibility. As it has been developed in the past decade, remarkable progress has been made in the construction of enzyme-instructed CBT-Cys-based bioimaging probes. This review introduces the concept of the CBT-Cys click reaction, elucidates the mechanism of the CBT-Cys click reaction, and concerns the development progress of CBT-Cys reaction and its derived reactions [i.e., 2-cyano-6-hydroxyquinoline (CHQ)-Cys reaction and 2-pyrimidinecarbonitrile (PMN)-Cys reaction]. Furthermore, we give a comprehensive and up-to-date review of enzyme-instructed CBT-Cys-like click reaction-based probes with significantly enhanced imaging signal and contrast for various bioimaging modes, including fluorescence imaging, photoacoustic imaging, magnetic resonance imaging, and positron emission tomography. In the end, we discuss the possible challenges and opportunities that may arise in the future.