trans-Cyclooctene (TCO)

trans-Cyclooctene (TCO) is a highly strained eight-membered carbocyclic ring containing a trans-double bond, making it one of the most reactive dienophiles used in bioorthogonal chemistry (Blackman et al., 2008, J. Am. Chem. Soc.). It is not a biological target such as a receptor or enzyme, but rather a synthetic chemical moiety used as a handle for site-specific labeling and drug delivery (Oliveira et al., 2022, Chem. Soc. Rev.). TCO's primary utility lies in its ability to undergo an exceptionally fast inverse electron-demand Diels-Alder (IEDDA) reaction with 1,2,4,5-tetrazines under physiological conditions without cross-reactivity with endogenous functional groups (Devaraj, 2018, ACS Cent. Sci.). In therapeutic contexts, TCO is often conjugated to a targeting vector, like a monoclonal antibody, in a pre-targeting strategy. This allows a tetrazine-linked payload—such as a radiopharmaceutical or a cytotoxic drug—to be administered later, clicking onto the TCO-tagged antibody at the tumor site to minimize systemic toxicity (Rossin et al., 2010, Angew. Chem. Int. Ed.). This approach is currently being evaluated in clinical trials, such as those involving the Click-to-Release platform for localized chemotherapy (Wu et al., 2021, Chem. Sci.).

Other names

(E)-cycloocteneTCO moietyStrained alkene handle

Acts as a bioorthogonal dienophile that undergoes an exceptionally rapid inverse electron-demand Diels-Alder (IEDDA) reaction with 1,2,4,5-tetrazines to form a stable covalent linkage or trigger drug release.