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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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.
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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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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.
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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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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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DOI: https://doi.org/10.1038/s41596-021-00662-7
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