Biomolecular labeling based on lysine-clickable 6π-azaelectrocyclization toward innovative cancer theranostics

An amino group at side chain of lysine residue can be targeted for protein modification because of the convenience for covalent bond formation. We have achieved an efficient protein modification by utilizing amine-clickable 6π-azaelectrocyclization, termed RIKEN click reaction recently, which enabled direct click labeling of protein without any introduction of specific functional groups such as alkynes and azides. On the basis of the RIKEN click reaction, we established the double click labeling method. The double click methods composed of copper-free strain-promoted [3 + 2] cyclization or tetrazine ligation and RIKEN click reaction were developed. The double click method realized highly effective proteins including radiolabeling of bioactive peptides and anti-tumor antibodies. In this personal review, the development of double click probes, practical radiolabeling of biological active molecules such as cyclic RGDyK peptides, proteins, and antibodies with α-emission or β-emission radionuclides, and their applications for PET imaging and α-emission cancer treatment are summarized.