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

Journal Article · · Inorganic Chemistry
 [1];  [2];  [1];  [1];  [2];  [3];  [3];  [3];  [3];  [2]
  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)
+ Show Author Affiliations
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 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. 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.
Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Chemical Sciences, Geosciences & Biosciences Division
Grant/Contract Number:
AC02-05CH11231; AC02-76SF00515
OSTI ID:
1510758
Journal Information:
Inorganic Chemistry, Journal Name: Inorganic Chemistry Journal Issue: 22 Vol. 57; ISSN 0020-1669
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
English

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Cited By (3)

Ultra-selective ligand-driven separation of strategic actinides journal June 2019
Synergistic Effect of a Mesothelin-Targeted 227 Th Conjugate in Combination with DNA Damage Response Inhibitors in Ovarian Cancer Xenograft Models journal March 2019
A Thorium Metal‐Organic Framework with Outstanding Thermal and Chemical Stability journal April 2019

Figures / Tables (12)

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