New compound for cancer targeted radiotherapy

Gauthier J-P Deblonde, Trevor D Lohrey, Corwin H Booth, Korey P Carter, Bernard F Parker, Åsmund Larsen, Roger Smeets, Olav B Ryan, Alan S Cuthbertson, Rebecca J Abergel

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

Authors:
Dr Gauthier J-P Deblonde, PhD
Dr Gauthier J-P Deblonde, PhD
Lawrence Livermore National Laboratory
Staff Scientist
Actinides chemistry, Niobium, Tantale, solution thermodynamics, Separation processes, Radiochemistry
Livermore, California | United States

Inorg Chem 2018 Nov 29;57(22):14337-14346. Epub 2018 Oct 29.

Chemical Sciences Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States.

The solution chemistry of a chelator developed for Th 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 p K 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 β values of 41.7 ± 0.3 and 26.9 ± 0.3 (T = 25 °C) were measured for [ThL] and [FeL], 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. L 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 Th targeted alpha therapy.

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Source
http://pubs.acs.org/doi/10.1021/acs.inorgchem.8b02430
Publisher Site
http://dx.doi.org/10.1021/acs.inorgchem.8b02430DOI Listing
November 2018
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