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An Eighteen‐Membered Macrocyclic Ligand for Actinium‐225 Targeted Alpha Therapy
Author(s) -
Thiele Nikki A.,
Brown Victoria,
Kelly James M.,
AmorCoarasa Alejandro,
Jermilova Una,
MacMillan Samantha N.,
Nikolopoulou Anastasia,
Ponnala Shashikanth,
Ramogida Caterina F.,
Robertson Andrew K. H.,
RodríguezRodríguez Cristina,
Schaffer Paul,
Williams Clarence,
Babich John W.,
Radchenko Valery,
Wilson Justin J.
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201709532
Subject(s) - chemistry , chelation , lncap , ligand (biochemistry) , alpha (finance) , bifunctional , conjugated system , stereochemistry , pharmacology , receptor , medicine , prostate cancer , biochemistry , cancer , surgery , construct validity , polymer , organic chemistry , patient satisfaction , catalysis
The 18‐membered macrocycle H 2 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.