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Solution Thermodynamics and Kinetics of Metal Complexation with a Hydroxypyridinone Chelator Designed for Thorium-227 Targeted Alpha Therapy

  • Author(s): Deblonde, GJP
  • Lohrey, TD
  • Booth, CH
  • Carter, KP
  • Parker, BF
  • Larsen, Å
  • Smeets, R
  • Ryan, OB
  • Cuthbertson, AS
  • Abergel, RJ
  • et al.
Abstract

© 2018 American Chemical Society. The solution chemistry of a chelator developed for 227Th targeted alpha therapy was probed. The compound of interest is an octadentate ligand comprising four N-methyl-3-hydroxy-pyridine-2-one metal-binding units, two tertiary amine groups, and one carboxylate arm appended for bioconjugation. The seven pKa values of the ligand and the stability constants of complexes formed with Th(IV), Hf(IV), Zr(IV), Gd(III), Eu(III), Al(III), and Fe(III) were determined. The ligand exhibits extreme thermodynamic selectivity toward tetravalent metal ions with a ca. 20 orders of magnitude difference between the formation constant of the Th(IV) species formed at physiological pH, namely [ThL]-, and that of its Eu(III) analogue. Likewise, log β110 values of 41.7 ± 0.3 and 26.9 ± 0.3 (T = 25 °C) were measured for [ThL]- and [FeIIIL]2-, respectively, highlighting the high affinity and selectivity of the ligand for Th ions over potentially competing endogenous metals. Single crystal X-ray analysis of the Fe(III) complex revealed a dinuclear 2:2 metal:chelator complex crystallizing in the space group P1. The formation of this dimeric species is likely favored by several intramolecular hydrogen bonds and the protonation state of the chelator in acidic media. LIII edge EXAFS data on the Th(IV) complexes of both the ligand and a monoclonal antibody conjugate revealed the expected mononuclear 1:1 metal:chelator coordination environment. This was also confirmed by high resolution mass spectrometry. Finally, kinetic experiments demonstrated that labeling the bioconjugated ligand with Th(IV) could be achieved and completed after 1 h at room temperature, reinforcing the high suitability of this chelator for 227Th targeted alpha therapy.

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