A One-Pot Three-Component Double-Click Method for Synthesis of [67Cu]-Labeled Biomolecular Radiotherapeutics

• Published in: Scientific reports 2017-05, Vol.7 (1), p.1912-9, Article 1912
• Main Authors: Fujiki, Katsumasa, Yano, Shinya, Ito, Takeshi, Kumagai, Yuki, Murakami, Yoshinori, Kamigaito, Osamu, Haba, Hiromitsu, Tanaka, Katsunori
• Format: Article
• Language: English
• Subjects: 631/92/2783; 631/92/96; 82; 82/1; 82/58; Albumin; Albumins - chemistry; Antibodies - chemistry; Cancer; Chelation; Click Chemistry - methods; Copper Radioisotopes - chemistry; HEK293 Cells; Humanities and Social Sciences; Humans; Isotope Labeling; Molecular Structure; multidisciplinary; Organometallic Compounds - chemistry; Radiation therapy; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-02123-2

A one-pot three-component double-click process for preparing tumor-targeting agents for cancer radiotherapy is described here. By utilizing DOTA (or NOTA) containing tetrazines and the TCO-substituted aldehyde, the two click reactions, the tetrazine ligation (an inverse electron-demand Diels-Alder cycloaddition) and the RIKEN click (a rapid 6π-azaelectrocyclization), could simultaneously proceed under mild conditions to afford covalent attachment of the metal chelator DOTA or NOTA to biomolecules such as to albumin and anti-IGSF4 antibody without altering their activities. Subsequently, radiolabeling of DOTA- or NOTA-attached albumin and anti-IGSF4 antibody (an anti-tumor-targeting antibody) with [ 67 Cu], a β − -emitting radionuclide, could be achieved in a highly efficient manner via a simple chelation with DOTA proving to be a more superior chelator than NOTA. Our work provides a new and operationally simple method for introducing the [ 67 Cu] isotope even in large quantities to biomolecules, thereby representing an important process for preparations of clinically relevant tumor-targeting agents for radiotherapy.