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

  • Angew Chem Int Ed Engl. 2017 Nov 13;56(46):14712-14717. doi: 10.1002/anie.201709532.
Nikki A Thiele  1 ,  Victoria Brown  2 ,  James M Kelly  3 ,  Alejandro Amor-Coarasa  3 ,  Una Jermilova  2 ,  Samantha N MacMillan  1 ,  Anastasia Nikolopoulou  3 ,  Shashikanth Ponnala  3 ,  Caterina F Ramogida  2 ,  Andrew K H Robertson  2 ,  Cristina Rodríguez-Rodríguez  4 ,  Paul Schaffer  2 ,  Clarence Williams Jr  3 ,  John W Babich  3 ,  Valery Radchenko  2 ,  Justin J Wilson  1
Affiliations
  • 1. Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, USA.
  • 2. Life Science Division, TRIUMF, Vancouver, BC, V6T 2A3, Canada.
  • 3. Radiology, Weill Cornell Medicine, New York, NY, 10065, USA.
  • 4. Fac. of Pharmaceutical Sciences, Dept. of Physics and Astronomy and Centre for Comparative Medicine, University of British Columbia, Vancouver, BC, V6T 1W5, Canada.
PMID: 28963750 DOI: 10.1002/anie.201709532
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 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.

Keywords
actinium; cancer; chelates; macrocycles; radiopharmaceuticals.
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