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

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 (89)Zr–DOTA is superior to (89)Zr–DFO, the only (89)Zr-complex to be used clinically in (89)Zr-radiopharmaceutical applications. Finally, we provide a rationale for the unanticipated and extraordinary stability of these complexes in vitro and in vivo. These results may inform the development of safer and more robust immuno-PET agents for precision medicine applications.