Versatile Bifunctional PYTA Derivatives for 225Ac Radiolabeling: A Comparison to Gold Standards

We report the synthesis and evaluation of the first 3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane-3,6,10,13-tetraacetic acid (PYTA) bifunctional chelators (BFCs) for ²²⁵Ac coordination. Methods: Three PYTA BFCs (PYTA-triacetate, PYTA-glutaric acid, and PYTA-pyridyl-ether) were synthesized. A comparative radiolabeling study with MACROPA, DOTA, and crown derivatives was performed. Conjugation to prostate-specific membrane antigen ligands and antibodies exemplified the applicability of these BFCs. Biodistribution and long-term stability of radiocomplexes were investigated in vivo. Results: PYTA derivatives demonstrated excellent radiochemical properties with quantitative radiolabeling under mild conditions (37 °C; low concentration) and exhibited prolonged in vitro stability. In vivo evaluation of radioimmunoconjugates confirmed the prolonged stability of PYTA conjugates, yielding results comparable to those seen with MACROPA, and revealed the instability of crown derivatives. Conclusion: PYTA emerges as a promising chelator for ²²⁵Ac, comparable to MACROPA, with the advantages of modular BFC synthesis.

225Ac; bifunctional chelators; radiochemistry; targeted α-therapy; α-emitter.