Production of radioimmunoPET grade zirconium-89

Document Type : Original Article

Authors

Radiation Application Research School, Nuclear Science and Technology Research Institute, Tehran, Iran

Abstract

Introduction: Particular characteristics of 89Zr to produce various labeled compounds are crucial for developing radioimmunopharmaceuticals for clinical trials. This study aimed to produce 89Zr for radiolabeling purposes as radioimmunoPET grade precursor.
 Methods: The computational calculations for 89Zr production via 89Y(p,n)89Zr reaction were performed using TALYS-1.8 and ALICE-91. 89Zr was produced by the proton bombardment of the yttrium pellet using a 30 MeV cyclotron. ZR resin was used for the separation of 89Zr from the target. The radionuclidic purity was assessed by a high purity germanium detector. The inductively coupled plasma spectrometry and instant thin layer chromatography methods were considered for chemical and radiochemical purity assessments, respectively. The biodistribution of [89Zr]Zr-oxalate was studied in Wistar rats by both sacrification and imaging. [89Zr]Zr-DFO-trastuzumab was produced as a proof of concept for a radioimmunoPET labeling.
Results: Considering the cross-section of 89Y(p,n)89Zr reaction, 14 MeV proton energy was selected for 89Zr production, while the yttrium pellet target was irradiated at least for 125 µAh,. 89Zr was finally prepared with a yield of 25.9±1.48 MBq/µAh, a specific activity of 344.1 MBq/µg, the radionuclidic and radiochemical purity higher than 99.99% and 99%, respectively. Total amount of the metal ions in the final solution was less than 0.1 ppm. Biodistribution of [89Zr]Zr-oxalate demonstrated high accumulation in the bone, lungs, and heart. [89Zr]Zr-DFO-trastuzumab was produced with a radiochemical purity higher than 99% and specific activity of 74 GBq/g in about 2 hours.
Conclusion: [89Zr]Zr-oxalate was produced with suitable activity and high purity for the preparation of the radioimmunopharmaceuticals.

Keywords

Main Subjects


  1. Burkhardt C, Bühler L, Viertl D, Stora T. New isotopes for the treatment of pancreatic cancer in collaboration with CERN: a mini review. Front Med (Lausanne). 2021 Aug 2;8:674656.
  2. Klaassen NJM, Arntz MJ, Gil Arranja A, Roosen J, Nijsen JFW. The various therapeutic applications of the medical isotope holmium-166: a narrative review. EJNMMI Radiopharm Chem. 2019 Aug 5;4(1):19.
  3. Marengo M, Lodi F, Magi S, Cicoria G, Pancaldi D, Boschi S. Assessment of radionuclidic impurities in 2-[18F] fluoro-2-deoxy-D-glucose ([18F] FDG) routine production. Appl Radiat Isot. 2008 Mar 1;66(3):295-302.
  4. Lodi F, Rizzello A, Trespidi S, Di Pierro D, Marengo M, Farsad M, Fanti S, Al-Nahhas A, Rubello D, Boschi S. Reliability and reproducibility of N-[11C] methyl-choline and L-(S-methyl-[11C]) methionine solid-phase synthesis: a useful and suitable method in clinical practice. Nucl Med Commun. 2008 Aug 1;29(8):736-40.
  5. Jalilian AR. An overview on Ga-68 radiopharmaceuticals for positron emission tomography applications. Iran J Nucl Med. 2016;24(1):1.
  6. Chomet M, van Dongen GAMS, Vugts DJ. State of the art in radiolabeling of antibodies with common and uncommon radiometals for preclinical and clinical immuno-PET. Bioconjug Chem. 2021 Jul 21;32(7):1315-1330.
  7. Dammes N, Peer D. Monoclonal antibody-based molecular imaging strategies and theranostic opportunities. Theranostics. 2020 Jan 1;10(2):938-955.
  8. Chu SYF, Ekström LP,  Firestone RB. Table of radioactive isotopes. Accessed September 9, 2022. Available from: http://nucleardata.nuclear.lu.se/toi/nuclide.asp?iZA=400089 
  9. Sadeghi M, Enferadi M, Bakhtiari M. Accelerator production of the positron emitter zirconium-89. Ann Nucl Energy. 2012 Mar 1;41:97-103.
  10. Deri MA, Zeglis BM, Francesconi LC, Lewis JS. PET imaging with ⁸⁹Zr: from radiochemistry to the clinic. Nucl Med Biol. 2013 Jan;40(1):3-14.
  11. Severin GW, Engle JW, Barnhart TE, Nickles RJ. 89Zr radiochemistry for positron emission tomography. Med Chem. 2011 Sep;7(5):389-94.
  12. Zakaly HMH, Mostafa MYA, Zhukovsky M. Biokinetic modelling of 89Zr-labelled monoclonal antibodies for dosimetry assessment in humans. Int J Radiat Res. 2020 Oct;18(4):825-833.
  13. van de Watering FC, Rijpkema M, Perk L, Brinkmann U, Oyen WJ, Boerman OC. Zirconium-89 labeled antibodies: a new tool for molecular imaging in cancer patients. Biomed Res Int. 2014;2014:203601.
  14. Jauw YW, Menke-van der Houven van Oordt CW, Hoekstra OS, Hendrikse NH, Vugts DJ, Zijlstra JM, Huisman MC, van Dongen GA. Immuno-positron emission tomography with zirconium-89-labeled monoclonal antibodies in oncology: what can we learn from initial clinical trials? Front Pharmacol. 2016 May 24;7:131.
  15. Sharifian M, Sadeghi M, Alirezapour B, Yarmohammadi M, Ardaneh K. Modeling and experimental data of zirconium-89 production yield. Appl Radiat Isot. 2017 Dec;130:206-210.
  16. Kasbollah A, Eu P, Cowell S, Deb P. Review on production of 89Zr in a medical cyclotron for PET radiopharmaceuticals. J Nucl Med Technol. 2013 Mar;41(1):35-41.
  17. Currie, L. Quantifying uncertainty in nuclear analytical measurements. IAEA-TECDOC-1401. Accessed September 9, 2022. Available from: https://www.nist.gov/publications/quantifying-uncertainty-nuclear-analytical-measurements 
  18. Chang AJ, Desilva R, Jain S, Lears K, Rogers B, Lapi S. 89Zr-radiolabeled trastuzumab imaging in orthotopic and metastatic breast tumors. Pharmaceuticals (Basel). 2012 Jan 5;5(1):79-93.
  19. Wooten AL, Madrid E, Schweitzer GD, Lawrence LA, Mebrahtu E, Lewis BC, Lapi SE. Routine production of 89Zr using an automated module.
    Appl Sci.. 2013 Jul 12;3(3):593-613.
  20. Mansel A, Franke K. Production of no-carrier-added 89Zr at an 18 MeV cyclotron, its purification and use in investigations in solvent extraction. J Radioanal Nucl Chem. 2021 Apr;328(1):419-23.
  21. Uddin MS, Hagiwara M, Baba M, Tarkanyi F, Ditroi F. Experimental studies on excitation functions of the proton-induced activation reactions on yttrium. Appl Radiat Isot. 2005 Sep;63(3):367-74.
  22. Omara HM, Hassan KF, Kandil SA, Hegazy FE, Saleh ZA. Proton induced reactions on 89Y with particular reference to the production of the medically interesting radionuclide 89Zr. Radiochim Acta. 2009 Aug 1;97(9):467-71.
  23. Hohn A, Zimmermann K, Schaub E, Hirzel W, Schubiger PA, Schibli R. Production and separation of ''non-standard'' PET nuclides at a large cyclotron facility: the experiences at the Paul Scherrer Institute in Switzerland. Q J Nucl Med Mol Imaging. 2008 Jun;52(2):145-50. Epub 2008 Jan 5.
  24. Holland JP, Sheh Y, Lewis JS. Standardized methods for the production of high specific-activity zirconium-89. Nucl Med Biol. 2009 Oct;36(7):729-39.
  25. Kandil SA, Scholten B, Saleh ZA, Youssef AM, Qaim SM, Coenen HH. A comparative study on the separation of radiozirconium via ion-exchange and solvent extraction techniques, with particular reference to the production of 88Zr and 89Zr in proton induced reactions on yttrium. J Radioanal Nucl Chem. 2007 Oct;274(1):45-52.
  26. Dabkowski AM, Probst K, Marshall C. Cyclotron production for the radiometal Zirconium-89 with an IBA cyclone 18/9 and COSTIS solid target system (STS). AIP Conf Proc. 2012 Dec 19; 1509(1): 108-113.
  27. Larenkov A, Bubenschikov V, Makichyan A, Zhukova M, Krasnoperova A, Kodina G. Preparation of Zirconium-89 solutions for radiopharmaceutical purposes: interrelation between formulation, radiochemical purity, stability and biodistribution. Molecules. 2019 Apr 18;24(8):1534.
  28. Baroncelli F, Grossi G. The complexing power of hydroxamic acids and its effect on the behaviour of organic extractants in the reprocessing of irradiated fuels—I the complexes between benzohydroxamic acid and zirconium, iron (III) and uranium (VI). J inorg nucl chem. 1965 May 1;27(5):1085-92.
  29. Abou DS, Ku T, Smith-Jones PM. In vivo biodistribution and accumulation of 89Zr in mice. Nucl Med Biol. 2011 Jul;38(5):675-81. doi: 10.1016/j.nucmedbio.2010.12.011. Epub 2011 Mar 3.
  30. Heskamp S, Raavé R, Boerman O, Rijpkema M, Goncalves V, Denat F. 89Zr-Immuno-positron emission tomography in oncology: state-of-the-art 89Zr radiochemistry. Bioconjug Chem. 2017 Sep 20;28(9):2211-2223.
  31. Holland JP, Divilov V, Bander NH, Smith-Jones PM, Larson SM, Lewis JS. 89Zr-DFO-J591 for immunoPET of prostate-specific membrane antigen expression in vivo. J Nucl Med. 2010 Aug;51(8):1293-300.
  32. Laverman P, van der Geest T, Terry SY, Gerrits D, Walgreen B, Helsen MM, Nayak TK, Freimoser-Grundschober A, Waldhauer I, Hosse RJ, Moessner E, Umana P, Klein C, Oyen WJ, Koenders MI, Boerman OC. Immuno-PET and immuno-SPECT of rheumatoid arthritis with radiolabeled anti-fibroblast activation protein antibody correlates with severity of arthritis. J Nucl Med. 2015 May;56(5):778-83.