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

We report the synthesis and evaluation of the first PYTA bifunctional chelators (BFCs) designed for actinium-225 coordination. Methods: Three PYTA bifunctional chelators, PY3A, PYTA-GA, and PYTA-PE, were synthesized. A comparative radiolabeling study with current gold standards, MacropaTM, DOTA and Crown derivatives, was performed. Conjugation to PSMA ligand and antibodies exemplified the applicability of the BFCs. In vivo evaluation investigated the biodistribution and long-term stability of radiocomplexes. Results: PYTA derivatives demonstrate excellent radiochemical properties with quantitative radiolabeling under smooth conditions (37°C, low concentration) and prolonged in vitro stability. In vivo evaluation of radioimmunoconjugates confirmed the prolonged stability of PYTA conjugates, yielding results comparable to Macropa™, while revealing clear instability of Crown derivative. Conclusion: These findings set PYTA as the next gold-standard chelator for actinium-225, comparable to Macropa™, with the advantages of easier bifunctional derivatives syntheses and greater versatility of radionuclides.