Open problems for the preparation and quality control of Ac-225 radiopharmaceuticals

The aim of this brief review is to analyze the persistent chemical and radiochemical hurdles that still hinder the development of clinically useful actinium-225 ( 225 Ac) radiopharmaceuticals for alpha-targeted radionuclide therapy (TAT). The absence of useful gamma photons emitted during the decay of the 225 Ac radionuclide and the lack of data on the actual molecular structure of 225 Ac complexes make it difficult to determine the exact radiochemical purity (RCP) of this class of radiopharmaceuticals. Analysis of published experimental data on radiolabeling reactions has revealed critical differences in radionuclide-to-ligand molar ratios and labeling conditions between 225 Ac and other therapeutic radionuclides, particularly 177 Lu, to achieve the radionuclidic purity (RP) required for in vivo studies (99.5 %). The impact of the secular equilibrium in the 225 Ac decay chain, combined with the disruptive effect of alpha recoil, causing the dissociation of the radionuclide from the chelating group, and the constant growth of dangerous radionuclide impurities, are discussed. Finally, the difficulty of obtaining preclinical real-time quantitative SPECT images for dosimetry calculations is briefly considered.