実用的ながん診断・治療分子の創製を目指して

—効率的クリック標識法の開発と放射線セラノスティクス—

抄録

Radiation diagnostics and therapeutics are promising to be effective for cancer medicine. In radiodiagnosis, PET is widely used to quantitatively visualize the locations and levels of radiotracer accumulation with high sensitivity. In radiotherapy, in particular, α-emission therapy based on radioimmunoconjugate has attracted attention as a potent cancer therapeutics because radiation of α-particles can damage targeted cancer tissue within a few cell diameters, thereby minimizing damage of other normal tissues. In a few decades, many researchers have devoted much effort to development of radiolabeled cancer-targeting molecules. However, there are few examples of radiolabeled molecules clinically utilized for cancer diagnosis and therapy due to few effective and practical methods for labeling of biofunctional molecule, especially protein and antibody. So far, we have developed an invasive and effective labeling method for protein based on RIKEN click reaction. We have recently developed practical labeling method by using two click reactions, which comprised of strain-promoted [3+2] cyclization for introduction of functional group to unsaturated aldehyde and RIKEN click reaction for protein labeling, named as double click reaction. By utilizing this double click reaction, we established a practical synthetic protocol of gallium-68-labeled cyclic RGDyK peptide, which was applied for PET imaging, from elution of gallium-68 to synthesis of gallium-68-labeled cyclic RGDyK peptide. Furthermore, we developed one-pot three-component double clicks, which conducted tetrazine ligation and RIKEN click reaction as highly reactive click reaction under mild conditions. On the basis of the one-pot three-component double clicks, we accomplished highly effective and practical synthesis of radioimmunoconjugates labeled with copper-67 as β^--emitter and with astatine-211 as α-emitter. In addition, we also succeeded in evaluation of α-emission cancer therapeutic efficacy of the astatine-211-labeled trastuzumab on the A431 cells-xenograft mice.