A Concise Synthetic Approach to Highly Reactive Click-to-Release Trans-Cyclooctene Linkers

An increase of the click-to-release reaction rate between cleavable trans-cyclooctenes (TCO) and tetrazines would be beneficial for drug delivery applications. In this work, we developed a short and stereoselective synthesis route towards highly reactive sTCOs that serve as cleavable linkers, affording quantitative tetrazine-triggered payload release. In addition, the 5-fold more reactive sTCO exhibited the same in vivo stability as the parent TCO linker when used as antibody linker in circulation in mice.