Versatile bifunctional PYTA derivatives for actinium-225 radiolabeling: a comparison to gold standards

We report the synthesis of the first PYTA bifunctional chelators designed for the coordination of actinium-225 and their bioconjugation to biovectors of interest. Three PYTA bifunctional chelators, PY3A, PYTA-GA, and PYTA-PE, were synthesized. A comparative study with current gold standards, MacropaTM, DOTA and Crown derivatives, highlights the excellent radiochemical properties and prolonged in vitro stability of PYTA derivatives. These exceptional performances were validated further through conjugation to a small PSMA ligand and two antibodies with quantitative radiolabeling under smooth conditions (37°C, low concentration). In vivo evaluation of radioimmunoconjugates further confirmed the prolonged stability of PYTA conjugates, yielding pharmacokinetic results comparable to Macropa™, while revealing clear in vivo instability of the Crown derivative. These findings underscore the potential of PYTA to emerge as the next gold-standard chelator for actinium-225, comparable to Macropa™, with the added advantages of easier synthesis of bifunctional derivatives and greater versatility for radiolabeling with other radionuclides.