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Synthesis of 68Ga-radiopharmaceuticals using both generator-derived and cyclotron-produced 68Ga as exemplified by [68Ga]Ga-PSMA-11 for prostate cancer PET imaging

Nature Protocols volume 17, pages 980–1003 (2022)Cite this article

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Abstract

[68Ga]Ga-PSMA-11, a urea-based peptidomimetic, is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that targets the prostate-specific membrane antigen (PSMA). The recent Food and Drug Administration approval of [68Ga]Ga-PSMA-11 for PET imaging of patients with prostate cancer, expected follow-up approval of companion radiotherapeutics (e.g., [177Lu]Lu-PSMA-617, [225Ac]Ac-PSMA-617) and large prostate cancer patient volumes requiring access are poised to create an unprecedented demand for [68Ga]Ga-PSMA-11 in nuclear medicine clinics around the world. Meeting this global demand is going to require a variety of synthesis methods compatible with 68Ga eluted from a generator or produced on a cyclotron. To address this urgent need in the PET radiochemistry community, herein we report detailed protocols for the synthesis of [68Ga]Ga-PSMA-11, (also known as HBED-CC, Glu-urea-Lys(Ahx)-HBED-CC and PSMA-HBED-CC) using both generator-eluted and cyclotron-produced 68Ga and contrast the pros and cons of each method. The radiosyntheses are automated and have been validated for human use at two sites (University of Michigan (UM), United States; Royal Prince Alfred Hospital (RPA), Australia) and used to produce [68Ga]Ga-PSMA-11 for patient use in good activity yields (single generator, 0.52 GBq (14 mCi); dual generators, 1.04–1.57 GBq (28–42 mCi); cyclotron method (single target), 1.47–1.89 GBq (40–51 mCi); cyclotron method (dual target), 3.63 GBq (98 mCi)) and high radiochemical purity (99%) (UM, n = 645; RPA, n > 600). Both methods are appropriate for clinical production but, in the long term, the method employing cyclotron-produced 68Ga is the most promising for meeting high patient volumes. Quality control testing (visual inspection, pH, radiochemical purity and identity, radionuclidic purity and identity, sterile filter integrity, bacterial endotoxin content, sterility, stability) confirmed doses are suitable for clinical use, and there is no difference in clinical prostate cancer PET imaging using [68Ga]Ga-PSMA-11 prepared using the two production methods.

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Fig. 1: Theranostic agents for nuclear medicine.
Fig. 2: Synthesis of [68Ga]Ga-PSMA-11.
Fig. 3: Generator-based production of [68Ga]Ga-PSMA-11.
Fig. 4: Cyclotron-based production of [68Ga]Ga-PSMA-11.
Fig. 5: Activity receiving vial for collection of the irradiated 68Zn solution.
Fig. 6: Two-column approach for 68Ga chemical separation.
Fig. 7: Analytical HPLC traces.
Fig. 8: Radio-TLC traces.
Fig. 9: Prostate cancer PET–CT scans obtained using [68Ga]Ga-PSMA-11.

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Data availability

Data generated during this study are included in this published article and the supporting primary research articles. Raw data for recent representative production batches of [68Ga]Ga-PSMA-11 prepared using generator-derived and cyclotron-produced 68Ga, according to the procedures reported in this article, have also been deposited at https://doi.org/10.6084/m9.figshare.16628914. Additional information is available on request to the authors.

References

  1. Hermann, K. et al. Radiotheranostics: a roadmap for future development. Lancet Oncol. 21, e146–e156 (2020).

    Article  Google Scholar 

  2. Qaim, S. M. Theranostic radionuclides: recent advances in production methodologies. J. Radioanal. Nucl. Chem. 322, 1257–1266 (2019).

    Article  CAS  Google Scholar 

  3. Kopka, K. A short history of transforming the diagnostic tracer PSMA-11 into the theranostic variant PSMA-617. Endocr. Abstr. 47, OC29 (2016).

    Google Scholar 

  4. Al-Nahas, A. et al. Gallium-68 PET: a new frontier in receptor cancer imaging. Anticancer Res 27, 4087–4094 (2007).

    Google Scholar 

  5. Decristoforo, C. Gallium-68—a new opportunity for PET available from a long shelf-life generator—automation and applications. Curr. Radiopharm. 5, 212–220 (2012).

    Article  CAS  Google Scholar 

  6. Filippi, L. et al. Theranostic approaches in nuclear medicine: current status and future prospects. Expert Rev. Med. Dev. 17, 331–343 (2020).

    Article  CAS  Google Scholar 

  7. Pencharz, D. et al. Theranostics in neuroendocrine tumours: somatostatin receptor imaging and therapy. Br. J. Radiol. 91, 20180108 (2018).

    Article  Google Scholar 

  8. Werner, R. A. et al. The theranostic promise for neuroendocrine tumors in the late 2010s—where do we stand, where do we go? Theranostics 8, 6088–6100 (2018).

    Article  CAS  Google Scholar 

  9. CancerNet. Prostate Cancer: Statistics https://www.cancer.net/cancer-types/prostate-cancer/statistics (accessed 27 April 2021).

  10. Afshar-Oromieh, A. et al. PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions. Eur. J. Nucl. Med. Mol. Imaging 40, 486–495 (2013).

    Article  CAS  Google Scholar 

  11. Abghari-Gerst, M. A comprehensive assessment of 68Ga-PSMA-11 PET in biochemically recurrent prostate cancer: results from a prospective multi-center study in 2005 patients. J. Nucl. Med. https://doi.org/10.2967/jnumed.121.262412 (2021).

  12. Carlucci, G. 68Ga-PSMA-11 NDA approval: a novel and successful academic partnership. J. Nucl. Med. 62, 149–155 (2021).

    Article  CAS  Google Scholar 

  13. Telix. FDA approves Telix’s prostate cancer imaging product, Illuccix® [press release]. https://telixpharma.com/news-media/fda-approves-telixs-prostate-cancer-imaging-product-illuccix/ (20 December 2021).

  14. Stephens, K. FDA approves first commercially available PSMA PET imaging agent for prostate cancer. AXIS Imaging News https://www.proquest.com/docview/2533524558 (2021).

  15. Lee, C. H. et al. The feasibility of 64Cu-PSMA I&T PET for prostate cancer. Cancer Biother. Radiopharm. https://doi.org/10.1089/cbr.2020.4189 (2021).

  16. Jones, W. PSMA theranostics: review of the current status of PSMA-targeted imaging and radioligand therapy. Cancers 12, 1367 (2020).

    Article  CAS  Google Scholar 

  17. Lenzo, N. et al. Review of gallium-68 PSMA PET/CT imaging in the management of prostate cancer. Diagnostics 8, 16 (2018).

    Article  Google Scholar 

  18. Massat, M. B. Nuclear medicine prepares for greater 68Ga demand. Appl. Radiol. 50, 30–31 (2021).

    Article  Google Scholar 

  19. Jackson, I. M. et al. Use of 55 PET radiotracers under approval of a Radioactive Drug Research Committee (RDRC). EJNMMI Radiopharm. Chem. 5, 24 (2020).

    Article  Google Scholar 

  20. Rodnick, M. E. et al. Cyclotron-based production of 68Ga, [68Ga]GaCl3, and [68Ga]Ga-PSMA-11 from a liquid target. EJNMMI Radiopharm. Chem. 5, 25 (2020).

    Article  Google Scholar 

  21. Becker, K. V. et al. A review of accelerator-produced Ga-68 with solid targets. Curr. Radiopharm. https://doi.org/10.2174/1874471013666201224113651 (2020).

  22. Svedjehed, J., Pärnaste, M. & Gagnon, K. Demystifying solid targets: simple and rapid distribution-scale production of [68Ga]GaCl3 and [68Ga]Ga-PSMA-11. Nucl. Med. Biol. https://doi.org/10.1016/j.nucmedbio.2021.10.002 (2022).

  23. Do Carmon, S. J. C., Scott, P. J. H. & Alves, F. Production of radiometals in liquid targets. EJNMMI Radiopharm. Chem. 5, 2 (2020).

    Article  Google Scholar 

  24. Gallium (68Ga) PSMA-11 injection. European Pharmacopoeia. 10, 5397–5398 (2021).

  25. Cutler, C. S. & Minoshima S. Shortage of Germanium68/gallium68 generators in the United States https://s3.amazonaws.com/rdcms-snmmi/files/production/public/Ga68%20shortage%20letter.pdf (Society of Nuclear Medicine and Molecular Imaging, 2018).

  26. Soto-Montenegro, M. L. et al. Meningiomas: a comparative study of 68Ga-DOTATOC, 68Ga-DOTANOC and 68Ga-DOTATATE for molecular imaging in mice. PLoS ONE 9, e111624 (2014).

    Article  Google Scholar 

  27. Martin, R. et al. Cationic eluate pretreatment for automated synthesis of [68Ga]CPCR4.2. Nucl. Med. Biol. 41, 84–89 (2014).

    Article  CAS  Google Scholar 

  28. Society of Nuclear Medicine and Molecular Imaging. FDA approves cyclotron-produced Ga-68 DOTATOC for neuroendocrine tumors [press release]. www.snmmi.org/NewsPublications/NewsDetail.aspx?ItemNumber=34801 (2020).

  29. Gallium (68Ga) Chloride (accelerator produced) solution for radiolabelling. European Pharmacopoeia. 10, 4864–4865 (2020).

Download references

Acknowledgements

The authors thank A. Afshar-Oromieh, K. Kopka and their colleagues at the University Hospital of Heidelberg and the German Cancer Research Center (DKFZ) Heidelberg for the valuable assistance in qualifying UM for clinical production of [68Ga]Ga-PSMA-11. In addition, the authors thank S. Happel at Triskem for valuable suggestions, feedback and initial resin samples. P.J.H.S. thanks the University of Michigan Department of Radiology for financial support.

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Authors and Affiliations

  1. University of Michigan, Department of Radiology, Division of Nuclear Medicine, Ann Arbor, MI, USA

    Melissa E. Rodnick, Mara Clark, Brian G. Hockley, Bradford D. Henderson, Laura Bruton, Sean Preshlock, Monica Abghari-Gerst, Morand R. Piert & Peter J. H. Scott

  2. GE Healthcare, GEMS PET Systems, Uppsala, Sweden

    Carina Sollert, D. Christian Parr, Jens Frigell & Katherine Gagnon

  3. Department of Molecular Imaging, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

    Daniela Stark, Andrew Katsifis, Michael J. Fulham & Stefan Eberl

  4. Faculty of Engineering School of Computer Science, The University of Sydney, Sydney, New South Wales, Australia

    Michael J. Fulham & Stefan Eberl

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Contributions

K.G. and P.J.H.S. conceived and developed the project, and provided supervision and funding. C.S., D.C.P., J.F. and K.G. developed the target and initial chemistry sequences at GE. M.E.R., M.C., L.B. and S.P. conducted radiosyntheses at UM. B.D.H. and B.G.H. provided QC and quality assurance at UM. M.R.P. and M.A.-G. are nuclear medicine physicians at UM. D.S. and A.K. conducted radiosyntheses and QC at RPA. S.E. assisted with project development and target and cyclotron aspects at RPA. M.J.F. is PET physician, provided funding for the RPA contribution and contributed to the manuscript.

Corresponding authors

Correspondence to Stefan Eberl, Katherine Gagnon or Peter J. H. Scott.

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Competing interests

K.G., J.F., D.C.P. and C.S. are employees of GE Healthcare. S.E., A.K., D.S., M.J.F., M.E.R., M.C., B.G.H., B.D.H., M.A.-G., S.P., L.B., M.R.P. and P.J.H.S. declare no conflict of interest.

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Nature Protocols thanks Leonardo L. Fuscaldi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Key references using this protocol

Jackson, I. M. et al. EJNMMI Radiopharm. Chem. 5, 24 (2020): https://doi.org/10.1186/s41181-020-00110-z

Rodnick, M. et al. EJNMMI Radiopharm. Chem. 5, 25 (2020): https://doi.org/10.1186/s41181-020-00106-9

Abhari-Gerst, M. et al. J. Nucl. Med. 62, jnumed.121.262412 (2021): https://doi.org/10.2967/jnumed.121.262412

Key data used in this protocol

Jackson, I. M. et al. EJNMMI Radiopharm. Chem. 5, 24 (2020): https://doi.org/10.1186/s41181-020-00110-z

Rodnick, M. et al. EJNMMI Radiopharm. Chem. 5, 25 (2020): https://doi.org/10.1186/s41181-020-00106-9

Abhari-Gerst, M. et al. J. Nucl. Med. 62, jnumed.121.262412 (2021): https://doi.org/10.2967/jnumed.121.262412

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Rodnick, M.E., Sollert, C., Stark, D. et al. Synthesis of 68Ga-radiopharmaceuticals using both generator-derived and cyclotron-produced 68Ga as exemplified by [68Ga]Ga-PSMA-11 for prostate cancer PET imaging. Nat Protoc 17, 980–1003 (2022). https://doi.org/10.1038/s41596-021-00662-7

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