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      • Record: found
      • Abstract: found
      • Article: found
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      Automated synthesis of [ 89Zr]ZrCl 4, [ 89Zr]ZrDFOSquaramide-bisPh(PSMA) and [ 89Zr]ZrDFOSquaramide-TATE

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          Abstract

          Background

          Automated [ 89Zr]Zr-radiolabeling processes have the potential to streamline the production of [ 89Zr]Zr-labelled PET imaging agents. Most radiolabeling protocols use [ 89Zr][Zr(ox) 4] 4− as the starting material and oxalate is removed after radiolabeling. In some instances, radiolabeling with [ 89Zr]ZrCl 4 as starting material gives better radiochemical yields at lower reaction temperatures. In this work, a fully-automated process for production of [ 89Zr]ZrCl 4 is reported and its use for the synthesis of [ 89Zr]ZrDFOSq-bisPhPSMA and [ 89Zr]ZrDFOSq-TATE.

          Results

          A simple automated process for the isolation of [ 89Zr]ZrCl 4 by trapping [ 89Zr][Zr(ox) 4] 4− on a bicarbonate-activated strong anion exchange cartridge followed by elution with 0.1 M HCl in 1 M NaCl was developed. [ 89Zr]ZrCl 4 was routinely recovered from [ 89Zr][Zr(ox) 4] 4− in > 95% yield in mildly acidic solution of 0.1 M HCl in 1 M NaCl using a fully-automated process. The [ 89Zr]ZrCl 4 was neutralized with sodium acetate buffer (0.25 M) removing the requirement for cumbersome manual neutralization with strong base. The mixture of [ 89Zr]ZrCl 4 was used for direct automated radiolabeling reactions to produce [ 89Zr]Zr-DFOSquaramide-bisPhPSMA and [ 89Zr]ZrDFOSquaramide-TATE in 80–90% over all RCY in > 95% RCP.

          Conclusions

          This method for the production of [ 89Zr]ZrCl 4 does not require removal of HCl by evaporation making this process relatively fast and efficient. The fully automated procedures for the production of [ 89Zr]ZrCl 4 and its use in radiolabeling are well suited to support the centralized and standardized manufacture of multiple dose preparations of zirconium-89 based radiopharmaceuticals.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s41181-024-00270-2.

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          Most cited references21

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          Perspective on Solvent Use in the Pharmaceutical Industry

          David J. C. Constable, Conchita Jimenez-Gonzalez, Richard Henderson (2007)
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            Standardized methods for the production of high specific-activity zirconium-89.

            Jason P Holland, Yiauchung Sheh, Jason Lewis (2009)
            Zirconium-89 is an attractive metallo-radionuclide for use in immuno-PET due to favorable decay characteristics. Standardized methods for the routine production and isolation of high-purity and high-specific-activity (89)Zr using a small cyclotron are reported. Optimized cyclotron conditions reveal high average yields of 1.52+/-0.11 mCi/muA.h at a proton beam energy of 15 MeV and current of 15 muA using a solid, commercially available (89)Y-foil target (0.1 mm, 100% natural abundance). (89)Zr was isolated in high radionuclidic and radiochemical purity (>99.99%) as [(89)Zr]Zr-oxalate by using a solid-phase hydroxamate resin with >99.5% recovery of the radioactivity. The effective specific-activity of (89)Zr was found to be in the range 5.28-13.43 mCi/microg (470-1195 Ci/mmol) of zirconium. New methods for the facile production of [(89)Zr]Zr-chloride are reported. Radiolabeling studies using the trihydroxamate ligand desferrioxamine B (DFO) gave 100% radiochemical yields in 7 days. Small-animal positron emission tomography (PET) imaging studies have demonstrated that free (89)Zr(IV) ions administered as [(89)Zr]Zr-chloride accumulate in the liver, whilst [(89)Zr]Zr-DFO is excreted rapidly via the kidneys within <20 min. These results have important implication for the analysis of immuno-PET imaging of (89)Zr-labeled monoclonal antibodies. The detailed methods described can be easily translated to other radiochemistry facilities and will facilitate the use of (89)Zr in both basic science and clinical investigations.
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              89Zr immuno-PET: comprehensive procedures for the production of 89Zr-labeled monoclonal antibodies.

              Matthew Snow, Gerard Visser, Iris Verel … (2003)
              The use of immuno-PET, the combination of PET with monoclonal antibodies (mAbs), is an attractive option to improve tumor detection and mAb quantification. The long-lived positron emitter (89)Zr has ideal physical characteristics for immuno-PET, such as a half-life of 3.27 d, which is compatible with the time needed for intact mAbs to achieve optimal tumor-to-nontumor ratios. Thus far, a major limitation in the use of (89)Zr has been the lack of suitable methods for its stable coupling to mAbs. In this article, practical protocols for reproducible isolation of highly pure (89)Zr and the production of optimal-quality mAb-(89)Zr conjugates are provided. (89)Zr was produced by a (p,n) reaction on natural yttrium ((89)Y), isolated with a hydroxamate column, and used for labeling of premodified mAbs. mAbs were premodified with a novel bifunctional derivative of the chelate desferrioxamine B (Df) via a new linker chemistry. To this end, Df was initially succinylated (N-sucDf), temporarily filled with Fe(III), esterified by use of tetrafluorophenol, and then directly coupled to mAbs. Chimeric mAb (cmAb) U36, directed against head and neck cancer, was used for in vitro and in vivo evaluation. The in vitro stability of cmAb U36-N-sucDf-(89)Zr was assessed in human serum, and its in vivo behavior was evaluated by biodistribution and PET imaging studies in tumor-bearing nude mice. A cmAb U36-Df-(89)Zr conjugate containing a previously described succinimide ring-thioether unit in the linker was used as a reference. (89)Zr was produced in large batches (6.5-13.5 GBq) and isolated with improved radionuclidic purity (>99.99%) and high yield (>94%). The Df-premodified mAbs gave (89)Zr-labeling efficiencies of 80% within 30 min, resulting in conjugates with preserved integrity and immunoreactivity. With respect to stability, the novel cmAb U36-N-sucDf-(89)Zr conjugate appeared to be superior to the reference conjugate. In vivo, the novel conjugate demonstrated selective tumor targeting, and on PET images obtained at 24, 48, and 72 h after injection of this conjugate, small tumors in the range of 19-154 mg were readily visualized. Methods were developed for improved purification of the long-lived positron emitter (89)Zr. Moreover, a novel bifunctional Df chelate was synthesized for the reproducible coupling of (89)Zr to mAbs. The suitability of such conjugates to detect millimeter-sized tumors in xenograft-bearing nude mice was demonstrated.
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                Author and article information

                Contributors
                Asif Noor: asif.noor@unimelb.edu.au
                Paul S. Donnelly:
                ORCID: http://orcid.org/0000-0001-5373-0080
                pauld@unimelb.edu.au
                Journal
                Journal ID (nlm-ta): EJNMMI Radiopharm Chem
                Journal ID (iso-abbrev): EJNMMI Radiopharm Chem
                Title: EJNMMI Radiopharmacy and Chemistry
                Publisher: Springer International Publishing (Cham )
                ISSN (Electronic): 2365-421X
                Publication date (Electronic): 8 May 2024
                Publication date PMC-release: 8 May 2024
                Publication date Collection: December 2024
                Volume: 9
                Electronic Location Identifier: 39
                Affiliations
                [1 ]School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, ( https://ror.org/01ej9dk98) Parkville, VIC 3010 Australia
                [2 ]Department of Radiopharmaceutical Sciences, Cancer Imaging, The Peter MacCallum Cancer Centre, ( https://ror.org/02a8bt934) Melbourne, VIC 3000 Australia
                [3 ]Sir Peter MacCallum Department of Oncology, The University of Melbourne, ( https://ror.org/01ej9dk98) Melbourne, VIC 3010 Australia
                [4 ]iPHASE Technologies Pty Ltd., Rowville, VIC 3178 Australia
                [5 ]Telix Pharmaceuticals Limited, Suite 401, 55 Flemington Road, North Melbourne, VIC 3051 Australia
                Author information
                http://orcid.org/0000-0001-5373-0080
                Article
                Publisher ID: 270
                DOI: 10.1186/s41181-024-00270-2
                PMC ID: 11078908
                PubMed ID: 38717578
                SO-VID: 945bd57e-1d16-40ff-9e0e-eaf1e8891b07
                Copyright © © The Author(s) 2024
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 24 March 2024
                Date accepted : 26 April 2024
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100019996, Innovative Manufacturing CRC;
                Categories
                Subject: Research Article
                Custom metadata
                issue-copyright-statement © Springer Nature Switzerland AG 2024

                Keywords: zirconium-89,radiopharmaceuticals,automated synthesis,[89zr]zrcl4
                Data availability:
                Keywords: zirconium-89, radiopharmaceuticals, automated synthesis, [89zr]zrcl4

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