Thorium chelators for targeted alpha therapy: Rapid chelation of thorium-226

Ferrier, Maryline G.; Li, Yawen; Chyan, Ming‐Kuan; Wong, Roger; Li, Lily; Spreckelmeyer, Sarah; Hamlin, Donald K.; Mastren, Tara; Fassbender, Michael E.; Orvig, Chris; Wilbur, D. Scott

doi:10.1002/jlcr.3875

Title: Thorium chelators for targeted alpha therapy: Rapid chelation of thorium-226

Journal Article · Tue Aug 18 00:00:00 EDT 2020 · Journal of Labelled Compounds and Radiopharmaceuticals

DOI:https://doi.org/10.1002/jlcr.3875· OSTI ID:1871380

^[1];

^[2]; Chyan, Ming‐Kuan ^[2]; Wong, Roger ^[2];

^[3]; Spreckelmeyer, Sarah ^[4]; Hamlin, Donald K. ^[2]; Mastren, Tara ^[5]; Fassbender, Michael E. ^[5];

^[4];

^[2]

Univ. of Washington, Seattle, WA (United States); Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Univ. of Washington, Seattle, WA (United States)
Univ. of British Columbia, Vancouver, BC (Canada); TRIUMF,Vancouver (Canada)
Univ. of British Columbia, Vancouver, BC (Canada)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

One of the main challenges in targeted alpha therapy is assuring delivery of the α‐particle dose to the targeted cells. Thus, it is critical to identify ligands for α‐emitting radiometals that will form complexes that are very stable, both in vitro and in vivo. In this investigation, thorium‐227 ( t _1/2 = 18.70 days) chelation of ligands containing hydroxypyridinonate (HOPO) or picolinic acid (pa) moieties and the stability of the resultant complexes were studied. Chelation reactions were followed by reversed‐phased HPLC and gamma spectroscopy. Studies revealed that high ²²⁷ Th chelation yields could be obtained within 2.5 h or less with ligands containing four Me‐3,2‐HOPO moieties, 1 (83%) and 2 (65%), and also with ligands containing pa moieties, H ₄ octapa 3 (65%) and H ₄ py4pa 6 (87%). No reaction occurred with H ₄ neunpa‐ p ‐Bn‐NO ₂ 4 , and the chelation reaction with another pa ligand H ₄ pypa 5 gave inconsistent yields with a very broad radio‐HPLC peak. The ligands spermine‐(Me‐3,2‐HOPO) ₄ 1 , H ₄ octapa 3 , and H ₄ py4pa 6 had high stability (i.e., 87% of ²²⁷ Th still bound to the ligand) in phosphate‐buffered saline at room temperature over a 6‐day period. Preliminary studies with ligand 6 demonstrated efficient chelation of thorium‐226 ( t _1/2 = 30.57 min) when heated to 80°C for 5 min.

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Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States); Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA); USDOE Office of Science (SC), Nuclear Physics (NP); Natural Sciences and Engineering Research Council of Canada (NSERC); Canadian Institutes of Health Research

Grant/Contract Number:: AC52-07NA27344; SC0015220; FOA LAB-14-1099; RGPIN-42394-13; CHRP 493725-16; CPG-146482; FOA LAB 14‐1099

OSTI ID:: 1871380

Alternate ID(s):: OSTI ID: 1786499

Report Number(s):: LLNL-JRNL-793879; 993943; TRN: US2306746

Journal Information:: Journal of Labelled Compounds and Radiopharmaceuticals, Vol. 63, Issue 12; ISSN 0362-4803

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: English

References (28)

Production of ²³⁰ U/ ²²⁶ Th for Targeted Alpha Therapy via Proton Irradiation of ²³¹ Pa Morgenstern, Alfred; Lebeda, Ondrej; Stursa, Jan Analytical Chemistry, Vol. 80, Issue 22 https://doi.org/10.1021/ac801304c	journal	November 2008
H ₄ octapa-Trastuzumab: Versatile Acyclic Chelate System for ¹¹¹ In and ¹⁷⁷ Lu Imaging and Therapy Price, Eric W.; Zeglis, Brian M.; Cawthray, Jacqueline F. Journal of the American Chemical Society, Vol. 135, Issue 34 https://doi.org/10.1021/ja4049493	journal	August 2013
Separation and preconcentration of actinides by extraction chromatography using a supported liquid anion exchanger: application to the characterization of high-level nuclear waste solutions Horwitz, E. Philip; Dietz, Mark L.; Chiarizia, Renato Analytica Chimica Acta, Vol. 310, Issue 1 https://doi.org/10.1016/0003-2670(95)00144-O	journal	June 1995
Alpha-Emitters and Targeted Alpha Therapy in Oncology: from Basic Science to Clinical Investigations Makvandi, Mehran; Dupis, Edouard; Engle, Jonathan W. Targeted Oncology, Vol. 13, Issue 2 https://doi.org/10.1007/s11523-018-0550-9	journal	February 2018
An Appendix of Radionuclides Used in Targeted Alpha Therapy Ferrier, Maryline G.; Radchenko, Valery Journal of Medical Imaging and Radiation Sciences, Vol. 50, Issue 4 https://doi.org/10.1016/j.jmir.2019.06.051	journal	December 2019
232Th(d,4n)230Pa cross-section measurements at ARRONAX facility for the production of 230U Duchemin, C.; Guertin, A.; Haddad, F. Nuclear Medicine and Biology, Vol. 41 https://doi.org/10.1016/j.nucmedbio.2013.12.011	journal	May 2014
Functionally Versatile and Highly Stable Chelator for ¹¹¹ In and ¹⁷⁷ Lu: Proof-of-Principle Prostate-Specific Membrane Antigen Targeting Li, Lily; Jaraquemada-Peláez, María de Guadalupe; Kuo, Hsiou-Ting Bioconjugate Chemistry, Vol. 30, Issue 5 https://doi.org/10.1021/acs.bioconjchem.9b00225	journal	April 2019
Engineered Recognition of Tetravalent Zirconium and Thorium by Chelator–Protein Systems: Toward Flexible Radiotherapy and Imaging Platforms Captain, Ilya; Deblonde, Gauthier J. -P.; Rupert, Peter B. Inorganic Chemistry, Vol. 55, Issue 22 https://doi.org/10.1021/acs.inorgchem.6b02041	journal	November 2016
Matching chelators to radiometals for radiopharmaceuticals Price, Eric W.; Orvig, Chris Chem. Soc. Rev., Vol. 43, Issue 1 https://doi.org/10.1039/C3CS60304K	journal	January 2014
Cross-sections of the reaction 232Th(p,3n)230Pa for production of 230U for targeted alpha therapy Morgenstern, Alfred; Apostolidis, Christos; Bruchertseifer, Frank Applied Radiation and Isotopes, Vol. 66, Issue 10 https://doi.org/10.1016/j.apradiso.2008.02.066	journal	October 2008
227Th-EDTMP: A potential therapeutic agent for bone metastasis Washiyama, Kohshin; Amano, Ryohei; Sasaki, Jun Nuclear Medicine and Biology, Vol. 31, Issue 7 https://doi.org/10.1016/j.nucmedbio.2004.05.001	journal	October 2004
Preparation of TH ²²⁷ -Labeled Radioimmunoconjugates, Assessment of Serum Stability and Antigen Binding Ability Larsen, Roy H.; Borrebaek, Jorgen; Dahle, Jostein Cancer Biotherapy and Radiopharmaceuticals, Vol. 22, Issue 3 https://doi.org/10.1089/cbr.2006.321	journal	June 2007
Fractionated Therapy of HER2-Expressing Breast and Ovarian Cancer Xenografts in Mice with Targeted Alpha Emitting 227Th-DOTA-p-benzyl-trastuzumab Heyerdahl, Helen; Abbas, Nasir; Brevik, Ellen Mengshoel PLoS ONE, Vol. 7, Issue 8 https://doi.org/10.1371/journal.pone.0042345	journal	August 2012
Radiochemical aspects of alpha emitting radionuclides for medical application Ferrier, Maryline G.; Radchenko, Valery; Wilbur, D. Scott Radiochimica Acta, Vol. 107, Issue 9-11 https://doi.org/10.1515/ract-2019-0005	journal	September 2019
Fission fragment yields in the fission of ${}^{232}{Th}$ by protons of energies 8 to 22 MeV Kudo, H.; Muramatsu, H.; Nakahara, H. Physical Review C, Vol. 25, Issue 6 https://doi.org/10.1103/PhysRevC.25.3011	journal	June 1982
Complexation of Thorium(IV) and Uranium(IV) by a Hexaacetic Hexaaza Macrocycle: Kinetic and Thermodynamic Topomers of Actinide Chelates with a Large Cavity Ligand Jacques, Vincent; Desreux, Jean F. Inorganic Chemistry, Vol. 35, Issue 25 https://doi.org/10.1021/ic9606439	journal	January 1996
A Dual Generator Concept to Yield 226Th: An Isotope of Interest for Targeted Alpha Therapy Fassbender, Michael; Mastren, Tara Journal of Medical Imaging and Radiation Sciences, Vol. 50, Issue 1 https://doi.org/10.1016/j.jmir.2019.03.009	journal	March 2019
p -NO ₂ –Bn–H ₄ neunpa and H ₄ neunpa–Trastuzumab: Bifunctional Chelator for Radiometalpharmaceuticals and ¹¹¹ In Immuno-Single Photon Emission Computed Tomography Imaging Spreckelmeyer, Sarah; Ramogida, Caterina F.; Rousseau, Julie Bioconjugate Chemistry, Vol. 28, Issue 8 https://doi.org/10.1021/acs.bioconjchem.7b00311	journal	August 2017
Hydroxypyridinonate Complex Stability of Group (IV) Metals and Tetravalent f-Block Elements: The Key to the Next Generation of Chelating Agents for Radiopharmaceuticals Sturzbecher-Hoehne, Manuel; Choi, Taylor A.; Abergel, Rebecca J. Inorganic Chemistry, Vol. 54, Issue 7 https://doi.org/10.1021/acs.inorgchem.5b00033	journal	March 2015
Targeted Alpha Therapy, an Emerging Class of Cancer Agents: A Review Parker, Christopher; Lewington, Valerie; Shore, Neal JAMA Oncology, Vol. 4, Issue 12 https://doi.org/10.1001/jamaoncol.2018.4044	journal	December 2018
Cross sections of the reaction ${}^{231}{Pa} (d, 3 n) {}^{230}U$ for the production of ${}^{230}U / {}^{226}{Th}$ for targeted $α$ therapy Morgenstern, A.; Lebeda, O.; Stursa, J. Physical Review C, Vol. 80, Issue 5 https://doi.org/10.1103/PhysRevC.80.054612	journal	November 2009
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
Production of medical isotopes from a thorium target irradiated by light charged particles up to 70 MeV Duchemin, C.; Guertin, A.; Haddad, F. Physics in Medicine and Biology, Vol. 60, Issue 3 https://doi.org/10.1088/0031-9155/60/3/931	journal	January 2015
Radioimmunotherapy for delivery of cytotoxic radioisotopes: current status and challenges Martins, Carlos Daniel; Kramer-Marek, Gabriela; Oyen, Wim J. G. Expert Opinion on Drug Delivery, Vol. 15, Issue 2 https://doi.org/10.1080/17425247.2018.1378180	journal	September 2017
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
Production of 230Pa by proton irradiation of 232Th at the LANL isotope production facility: Precursor of 230U for targeted alpha therapy Friend, Mitchell T.; Mastren, Tara; Parker, T. Gannon Applied Radiation and Isotopes, Vol. 156 https://doi.org/10.1016/j.apradiso.2019.108973	journal	February 2020
H ₆ phospa-trastuzumab: bifunctional methylenephosphonate-based chelator with ⁸⁹ Zr, ¹¹¹ In and ¹⁷⁷ Lu Price, Eric W.; Zeglis, Brian M.; Lewis, Jason S. Dalton Trans., Vol. 43, Issue 1 https://doi.org/10.1039/C3DT51940F	journal	January 2014
Chemical and Radiochemical Considerations in Radiolabeling with α-Emitting Radionuclides Scott Wilbur, D. Current Radiopharmaceuticalse, Vol. 4, Issue 3 https://doi.org/10.2174/1874471011104030214	journal	July 2011

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Title: Thorium chelators for targeted alpha therapy: Rapid chelation of thorium-226

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