An Eighteen‐Membered Macrocyclic Ligand for Actinium‐225 Targeted Alpha Therapy. (16th October 2017)

• Record Type: Journal Article
• Authors: Thiele, Nikki A.; Brown, Victoria; Kelly, James M.; Amor‐Coarasa, Alejandro; Jermilova, Una; MacMillan, Samantha N.; Nikolopoulou, Anastasia; Ponnala, Shashikanth; Ramogida, Caterina F.; Robertson, Andrew K. H.; Rodríguez‐Rodríguez, Cristina; Schaffer, Paul; Williams, Clarence; Babich, John W.; Radchenko, Valery; Wilson, Justin J.
• Is Part Of: Angewandte Chemie. Volume 129:Number 46(2017)
• Page Start: 14904
• Page End: 14909
• Publication Date: 2017-10-16
• Subjects: Actinium -- Chelate -- Krebs -- Makrocyclen -- Radiopharmaka; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201709532
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: 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 La 3+ 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.