Synthesis, Characterization, and Evaluation of Chelators for Radium-223.

Abstract

The stable coordination of radium-223 (²²³Ra) for targeted alpha therapy remains elusive. Herein, 17 chelators were investigated for the complexation of ²²³Ra, of which 13 have previously not been reported. MacroPa was used as a reference and control for the studies, and by a process of systematic modifications to this chelator and a range of other chelator scaffolds, a library of structurally related compounds was obtained, each differing from another by a single functional group or change in the backbone. The radiolabeling of each chelator was assessed by radio-thin layer chromatography to determine radiochemical conversion. Fourteen of the synthesized chelators provided quantitative coordination of ²²³Ra at room temperature and neutral pH (or close to). The stability of these complexes in human serum at 37 °C was analyzed using radio-size exclusion chromatography, where results corresponding to [²²³Ra][Ra(MacroMePhos)] were encouraging. However, radio-thin layer chromatography analysis of the 'small molecule' fractions revealed the presence of free ²²³Ra, indicating instability within 1 h. In fact, even [²²³Ra][Ra(MacroPa)] dissociated within 1 h, albeit at higher dilutions. Overall, this work shows that the search for a suitable ²²³Ra-chelator for applications in radiopharmaceuticals still requires significant attention and effort.