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

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

doi:10.1021/acs.inorgchem.8b02430

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

Journal Article · Mon Oct 29 00:00:00 EDT 2018 · Inorganic Chemistry

DOI:https://doi.org/10.1021/acs.inorgchem.8b02430· OSTI ID:1510758

Deblonde, Gauthier J. -P. ^[1];

^[2]; 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];

^[2]

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

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 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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

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

Grant/Contract Number:: AC02-05CH11231; AC02-76SF00515

OSTI ID:: 1510758

Journal Information:: Inorganic Chemistry, Vol. 57, Issue 22; ISSN 0020-1669

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 30 works

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References (37)

Advancements in cancer therapy with alpha-emitters: a review Imam, Seyed K. International Journal of Radiation OncologyBiologyPhysics, Vol. 51, Issue 1 https://doi.org/10.1016/S0360-3016(01)01585-1	journal	September 2001
DNA Double Strand Breaks as Predictor of Efficacy of the Alpha-Particle Emitter Ac-225 and the Electron Emitter Lu-177 for Somatostatin Receptor Targeted Radiotherapy Graf, Franziska; Fahrer, Jörg; Maus, Stephan PLoS ONE, Vol. 9, Issue 2 https://doi.org/10.1371/journal.pone.0088239	journal	February 2014
The Radiochemical and Radiopharmaceutical Applications of Radium Gott, Matthew; Steinbach, Jörg; Mamat, Constantin Open Chemistry, Vol. 14, Issue 1 https://doi.org/10.1515/chem-2016-0011	journal	January 2016
Revised effective ionic radii and systematic studies of interatomic distances in halides and chalcogenides Shannon, R. D. Acta Crystallographica Section A, Vol. 32, Issue 5, p. 751-767 https://doi.org/10.1107/S0567739476001551	journal	September 1976
The size of actinoid(III) ions – structural analysis vs. common misinterpretations Lundberg, Daniel; Persson, Ingmar Coordination Chemistry Reviews, Vol. 318 https://doi.org/10.1016/j.ccr.2016.04.003	journal	July 2016
Abundance of chemical elements in the continental crust: a new table Taylor, S. R. Geochimica et Cosmochimica Acta, Vol. 28, Issue 8 https://doi.org/10.1016/0016-7037(64)90129-2	journal	August 1964
Recovery of Uranium from Wet Phosphoric Acid by Solvent Extraction Processes Beltrami, Denis; Cote, Gérard; Mokhtari, Hamid Chemical Reviews, Vol. 114, Issue 24 https://doi.org/10.1021/cr5001546	journal	November 2014
Thorium Metallacycle Facilitates Catalytic Alkyne Hydrophosphination Garner, Mary E.; Parker, Bernard F.; Hohloch, Stephan Journal of the American Chemical Society, Vol. 139, Issue 37 https://doi.org/10.1021/jacs.7b08323	journal	September 2017
Solution thermodynamic evaluation of hydroxypyridinonate chelators 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO) for UO ₂ (VI) and Th(IV) decorporation Sturzbecher-Hoehne, M.; Deblonde, G. J. -P.; Abergel, R. J. Radiochimica Acta, Vol. 101, Issue 6 https://doi.org/10.1524/ract.2013.2047	journal	June 2013
Solution Thermodynamic Stability of Complexes Formed with the Octadentate Hydroxypyridinonate Ligand 3,4,3-LI(1,2-HOPO): A Critical Feature for Efficient Chelation of Lanthanide(IV) and Actinide(IV) Ions Deblonde, Gauthier J-P.; Sturzbecher-Hoehne, Manuel; Abergel, Rebecca J. Inorganic Chemistry, Vol. 52, Issue 15 https://doi.org/10.1021/ic4010246	journal	July 2013
Rational Design of Sequestering Agents for Plutonium and Other Actinides Gorden, Anne E. V.; Xu, Jide; Raymond, Kenneth N. Chemical Reviews, Vol. 103, Issue 11 https://doi.org/10.1021/cr990114x	journal	November 2003
Using the Antenna Effect as a Spectroscopic Tool: Photophysics and Solution Thermodynamics of the Model Luminescent Hydroxypyridonate Complex [Eu ^III (3,4,3-LI(1,2-HOPO))] ⁻ Abergel, Rebecca J.; D’Aléo, Anthony; Ng Pak Leung, Clara Inorganic Chemistry, Vol. 48, Issue 23 https://doi.org/10.1021/ic9013703	journal	December 2009
Chelation and stabilization of berkelium in oxidation state +IV Deblonde, Gauthier J. -P.; Sturzbecher-Hoehne, Manuel; Rupert, Peter B. Nature Chemistry, Vol. 9, Issue 9 https://doi.org/10.1038/nchem.2759	journal	April 2017
Highly Luminescent and Stable Hydroxypyridinonate Complexes: A Step Towards New Curium Decontamination Strategies Sturzbecher-Hoehne, Manuel; Kullgren, Birgitta; Jarvis, Erin E. Chemistry - A European Journal, Vol. 20, Issue 32 https://doi.org/10.1002/chem.201402103	journal	July 2014
Toxic heavy metal – Pb, Cd, Sn – complexation by the octadentate hydroxypyridinonate ligand archetype 3,4,3-LI(1,2-HOPO) Deblonde, Gauthier J. -P.; Lohrey, Trevor D.; An, Dahlia D. New Journal of Chemistry, Vol. 42, Issue 10 https://doi.org/10.1039/C7NJ04559J	journal	January 2018
From early prophylaxis to delayed treatment: Establishing the plutonium decorporation activity window of hydroxypyridinonate chelating agents An, Dahlia D.; Kullgren, Birgitta; Jarvis, Erin E. Chemico-Biological Interactions, Vol. 267 https://doi.org/10.1016/j.cbi.2016.03.034	journal	April 2017
p -SCN-Bn-HOPO: A Superior Bifunctional Chelator for ⁸⁹ Zr ImmunoPET Deri, Melissa A.; Ponnala, Shashikanth; Kozlowski, Paul Bioconjugate Chemistry, Vol. 26, Issue 12 https://doi.org/10.1021/acs.bioconjchem.5b00572	journal	November 2015
Gd−Hydroxypyridinone (HOPO)-Based High-Relaxivity Magnetic Resonance Imaging (MRI) Contrast Agents Datta, Ankona; Raymond, Kenneth N. Accounts of Chemical Research, Vol. 42, Issue 7 https://doi.org/10.1021/ar800250h	journal	July 2009
In Vitro and In Vivo Efficacy of a Novel CD33-Targeted Thorium-227 Conjugate for the Treatment of Acute Myeloid Leukemia Hagemann, U. B.; Wickstroem, K.; Wang, E. Molecular Cancer Therapeutics, Vol. 15, Issue 10 https://doi.org/10.1158/1535-7163.MCT-16-0251	journal	August 2016
Targeted alpha therapy using a novel CD70 targeted thorium-227 conjugate in <i>in vitro</i> and <i>in vivo</i> models of renal cell carcinoma Hagemann, Urs B.; Mihaylova, Dessislava; Uran, Steinar R. Oncotarget, Vol. 8, Issue 34 https://doi.org/10.18632/oncotarget.16910	journal	April 2017
An efficient chelator for complexation of thorium-227 Ramdahl, Thomas; Bonge-Hansen, Hanne T.; Ryan, Olav B. Bioorganic & Medicinal Chemistry Letters, Vol. 26, Issue 17 https://doi.org/10.1016/j.bmcl.2016.07.034	journal	September 2016
GLEE, a new computer program for glass electrode calibration Gans, P. Talanta, Vol. 51, Issue 1 https://doi.org/10.1016/S0039-9140(99)00245-3	journal	January 2000
Investigation of equilibria in solution. Determination of equilibrium constants with the HYPERQUAD suite of programs Gans, P.; Sabatini, A.; Vacca, A. Talanta, Vol. 43, Issue 10 https://doi.org/10.1016/0039-9140(96)01958-3	journal	October 1996
A short history of SHELX Sheldrick, George M. Acta Crystallographica Section A Foundations of Crystallography, Vol. 64, Issue 1, p. 112-122 https://doi.org/10.1107/S0108767307043930	journal	December 2007
WinGX and ORTEP for Windows : an update Farrugia, Louis J. Journal of Applied Crystallography, Vol. 45, Issue 4 https://doi.org/10.1107/S0021889812029111	journal	July 2012
X-ray-absorption fine-structure standards: A comparison of experiment and theory Li, G. G.; Bridges, F.; Booth, C. H. Physical Review B, Vol. 52, Issue 9 https://doi.org/10.1103/PhysRevB.52.6332	journal	September 1995
Parameter-free calculations of X-ray spectra with FEFF9 Rehr, John J.; Kas, Joshua J.; Vila, Fernando D. Physical Chemistry Chemical Physics, Vol. 12, Issue 21 https://doi.org/10.1039/b926434e	journal	January 2010
Thorium(IV) Complexes of Bidentate Hydroxypyridinonates ¹ Xu, Jide; Whisenhunt, Donald W.; Veeck, Alan C. Inorganic Chemistry, Vol. 42, Issue 8 https://doi.org/10.1021/ic0259888	journal	April 2003
Confirmation of standard error analysis techniques applied to EXAFS using simulations Booth, Corwin H.; Hu, Yung-Jin Journal of Physics: Conference Series, Vol. 190 https://doi.org/10.1088/1742-6596/190/1/012028	journal	November 2009
Number of relevant independent points in x-ray-absorption fine-structure spectra Stern, Edward A. Physical Review B, Vol. 48, Issue 13 https://doi.org/10.1103/PhysRevB.48.9825	journal	October 1993
Gadolinium complex of tris[(3-hydroxy-1-methyl- 2-oxo-1,2-didehydropyridine-4-carboxamido)ethyl]-amine: A New Class of gadolinium magnetic resonance relaxation agents Xu, Jide; Franklin, Sonya J.; Whisenhunt, Donald W. Journal of the American Chemical Society, Vol. 117, Issue 27, p. 7245-7246 https://doi.org/10.1021/ja00132a025	journal	July 1995
Plutonium(IV) Sequestration: Structural and Thermodynamic Evaluation of the Extraordinarily Stable Cerium(IV) Hydroxypyridinonate Complexes¹ Xu, Jide; Radkov, Emil; Ziegler, Marco Inorganic Chemistry, Vol. 39, Issue 18, p. 4156-4164 https://doi.org/10.1021/ic000063i	journal	September 2000
A Macrocyclic Chelator with Unprecedented Th ⁴⁺ Affinity Pham, Tiffany A.; Xu, Jide; Raymond, Kenneth N. Journal of the American Chemical Society, Vol. 136, Issue 25 https://doi.org/10.1021/ja503456r	journal	June 2014
3,4,3-LI(1,2-HOPO): In vitro formation of highly stable lanthanide complexes translates into efficacious in vivo europium decorporation Sturzbecher-Hoehne, Manuel; Ng Pak Leung, Clara; D'Aléo, Anthony Dalton Transactions, Vol. 40, Issue 33 https://doi.org/10.1039/c1dt10840a	journal	January 2011
Hexadentate Hydroxypyridonate Iron Chelators Based on TREN-Me-3,2-HOPO: Variation of Cap Size¹ Xu, Jide; O'Sullivan, Brendon; Raymond, Kenneth N. Inorganic Chemistry, Vol. 41, Issue 25 https://doi.org/10.1021/ic025610+	journal	November 2002
Ferric ion sequestering agents. 13. Synthesis, structures, and thermodynamics of complexation of cobalt(III) and iron(III) tris complexes of several chelating hydroxypyridinones Scarrow, Robert C.; Riley, Paul E.; Abu-Dari, Kamal Inorganic Chemistry, Vol. 24, Issue 6 https://doi.org/10.1021/ic00200a030	journal	March 1985
N-Carboxyalkyl derivatives of 3-hydroxy-4-pyridinones: synthesis, complexation with Fe(III), Al(III) and Ga(III) and in vivo evaluation Santos, M. Amélia; Gil, Marco; Marques, Sérgio Journal of Inorganic Biochemistry, Vol. 92, Issue 1 https://doi.org/10.1016/S0162-0134(02)00483-X	journal	September 2002

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