Research & Teaching Faculty

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

TitleAn Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy
Publication TypeJournal Article
Year of Publication2017
AuthorsThiele, NA, Brown, V, Kelly, JM, Amor-Coarasa, A, Jermilova, U, MacMillan, SN, Nikolopoulou, A, Ponnala, S, Ramogida, CF, Robertson, AKH, Rodríguez-Rodríguez, C, Schaffer, P, Jr., CWilliams, Babich, JW, Radchenko, V, Wilson, JJ
JournalAngewandte Chemie International Edition
Keywordsactinium, CANCER, Chelates, macrocycles, RADIOPHARMACEUTICALS

Abstract The 18-membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225Ac (26 kBq) in 5 min at RT. [225Ac(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 225Ac in just minutes at RT, and macropa-Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft-tissue metastases.