Journal article
Solution Thermodynamics and Kinetics of Metal Complexation with a Hydroxypyridinone Chelator Designed for Thorium-227 Targeted Alpha Therapy
Inorganic chemistry, Vol.57(22), pp.14337-14346
11/19/2018
DOI: 10.1021/acs.inorgchem.8b02430
PMID: 30372069
Abstract
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 pK a 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 P1̅. 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.
Details
- Title: Subtitle
- Solution Thermodynamics and Kinetics of Metal Complexation with a Hydroxypyridinone Chelator Designed for Thorium-227 Targeted Alpha Therapy
- Creators
- Gauthier J.-P Deblonde - Chemical Sciences DivisionTrevor D Lohrey - Department of ChemistryCorwin H Booth - Chemical Sciences DivisionKorey P Carter - Chemical Sciences DivisionBernard F Parker - Department of ChemistryÅsmund Larsen - Department of Thorium Conjugate ResearchRoger Smeets - Department of Thorium Conjugate ResearchOlav B Ryan - Department of Thorium Conjugate ResearchAlan S Cuthbertson - Department of Thorium Conjugate ResearchRebecca J Abergel - University of California
- Resource Type
- Journal article
- Publication Details
- Inorganic chemistry, Vol.57(22), pp.14337-14346
- Publisher
- American Chemical Society
- DOI
- 10.1021/acs.inorgchem.8b02430
- PMID
- 30372069
- ISSN
- 0020-1669
- eISSN
- 1520-510X
- Grant note
- DOI: 10.13039/100004326, name: Bayer; DOI: 10.13039/100006151, name: Basic Energy Sciences, award: DE-AC02-05CH11231; DOI: 10.13039/100000015, name: U.S. Department of Energy
- Language
- English
- Date published
- 11/19/2018
- Academic Unit
- Chemistry
- Record Identifier
- 9984216587502771
Metrics
138 Record Views