Zirconium tetraazamacrocycle complexes display extraordinary stability and provide a new strategy for zirconium-89-based radiopharmaceutical development

Abstract

We report our initial investigations into the use of tetraazamacrocycles as zirconium-89 chelators. We describe the synthesis and complete characterization of several Zr tetraazamacrocycle complexes, and definitively describe the first crystal structure of zirconium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Zr-DOTA) using single crystal X-ray diffraction analysis. After evaluating several radioactive analogs, we found that ⁸⁹Zr-DOTA is superior to ⁸⁹Zr-DFO, the only ⁸⁹Zr-complex to be used clinically in ⁸⁹Zr-radiopharmaceutical applications. Finally, we provide a rationale for the unanticipated and extraordinary stability of these complexes <i>in vitro</i> and <i>in vivo</i>. These results may inform the development of safer and more robust immuno-PET agents for precision medicine applications.