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

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.