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

Abstract

In this study, 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 [Fe^IIIL]^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. L_III edge EXAFS data on the Th(IV) complexes of both the ligandmore » and a monoclonal antibody conjugate revealed the expected mononuclear 1:1 metal:chelator coordination environment. This was also confirmed by high resolution mass spectrometry. Lastly, 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.« less

Authors:

Deblonde, Gauthier J. -P. ^[1]; Lohrey, Trevor D.  ^[2];

• Search DOE PAGES for author "Lohrey, Trevor D."
• Search DOE PAGES for ORCID "0000-0003-3568-7861"

Booth, Corwin H. ^[1]; Carter, Korey P. ^[1]; Parker, Bernard F. ^[2]; Larsen, Åsmund ^[3]; Smeets, Roger ^[3]; Ryan, Olav B. ^[3]; Cuthbertson, Alan S. ^[3]; Abergel, Rebecca J.  ^[2]

• Search DOE PAGES for author "Abergel, Rebecca J."
• Search DOE PAGES for ORCID "0000-0002-3906-8761"

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+ Show Author Affiliations

1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, Berkeley, CA (United States)
3. Bayer AS, Oslo (Norway)

Publication Date:

Mon Oct 29 00:00:00 EDT 2018

Research Org.:

Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Org.:

USDOE Office of Science (SC), Basic Energy Sciences (BES). Chemical Sciences, Geosciences, and Biosciences Division

OSTI Identifier:

1510758

Grant/Contract Number:  

AC02-05CH11231; AC02-76SF00515

Resource Type:

Accepted Manuscript

Journal Name:

Inorganic Chemistry

Additional Journal Information:

Journal Volume: 57; Journal Issue: 22; Journal ID: ISSN 0020-1669

Publisher:

American Chemical Society (ACS)

Country of Publication:

United States

Language:

English

Subject:

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 62 RADIOLOGY AND NUCLEAR MEDICINE