An Eighteen‐Membered Macrocyclic Ligand for Actinium‐225 Targeted Alpha Therapy

The 18-membered macrocycle H₂ macropa was investigated for ²²⁵ Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all ²²⁵ Ac (26 kBq) in 5 min at RT. [²²⁵ Ac(macropa)]⁺ remained intact over 7 to 8 days when challenged with either excess La³⁺ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled ²²⁵ Ac in just minutes at RT, and macropa-Tmab retained >99 % of its ²²⁵ Ac in human serum after 7 days. In LNCaP xenograft mice, ²²⁵ Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free ²²⁵ Ac over 96 h. These findings establish macropa to be a highly promising ligand for ²²⁵ Ac chelation that will facilitate the clinical development of ²²⁵ Ac TAT for the treatment of soft-tissue metastases.