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A scalable protocol for the radiosynthesis of clinical grade lutetium-177-labeled theranostic agents

Nature Protocols volume 21, pages 60–78 (2026)Cite this article

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Abstract

Theranostics utilizes tandem targeted diagnostic and therapeutic agents that are molecularly analogous. In a theranostic approach, the diagnostic agent is a tracer typically radiolabeled with a positron emission tomography radionuclide such as fluorine-18 or gallium-68. Utilizing the selectivity of the tracer, the therapeutic agent is subsequently radiolabeled with an ablative radionuclide such as the β− emitting lanthanide lutetium-177 (177Lu). 177Lu is typically incorporated into theranostics using the chelators 2,2′,2′′,2′′′-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) and 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid (DOTAGA) that are used to prepare the 177Lu-radiopharmaceutical [177Lu]Lu-DOTA-TATE, [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T. Here we describe the scalable and validated production for these 177Lu-radiopharmaceuticals and further include the necessary quality control protocols. The procedures can be generalized and support both carrier added and noncarrier added 177Lu sources for use in a clinical setting. With robust procedures that accommodate 177Lu activity levels from 5 to 100 GBq, the procedures ensure stability for up to 8 h postproduction and achieve an average activity yield of 98%. As proven in over 1,000 patient cycles, this methodology is adaptable to both centralized production facilities and regional centers, enabling versatile application across small and large-scale production settings.

Key points

  • The procedure outlines a method for labeling DOTA- and DOTAGA-modified peptides with a scalable range of [177Lu]LuCl3 to create theranostics that target cancer-specific biomarkers, including prostate-specific antigen. The procedure also includes validated quality control procedures for the radiopharmaceuticals to ensure they meet clinical-grade standards before administration.

  • These radiotheranostic agents can be used to treat patients with neuroendocrine and prostate cancer.

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Fig. 1: [177Lu]-labeled theranostic structures.
Fig. 2: Diagram for the automated production of [177Lu]-labeled therapeutic radiopharmaceuticals.
Fig. 3: Chelation reaction schemes.
Fig. 4: Recommended generalized workflow for automated synthesis of 177Lu-radiopharmaceuticals.
Fig. 5: iPHASE user interface displaying the automated production cassette assembly.

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Acknowledgements

The authors acknowledge S. Poniger, the Co-Founder and Chief Engineer at iPHASE technologies, for his assistance and support while establishing this protocol. M.S.H. acknowledges philanthropic/government grant support from the Prostate Cancer Foundation including CANICA Oslo Norway, Peter MacCallum Foundation and a NHMRC Investigator Grant.

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Authors and Affiliations

  1. Department of Radiopharmaceutical Sciences, Cancer Imaging, The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    William W. Hunt, Mathew Long, Usama Kamil, Sunil Kellapatha, Wayne Noonan, Peter D. Roselt & Mohammad B. Haskali

  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia

    William W. Hunt, Peter D. Roselt, Michael S. Hofman & Mohammad B. Haskali

  3. Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Brittany Emmerson & Michael S. Hofman

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Contributions

M.B.H. and P.D.R. designed and carried out the technical development of this protocol related to the production of theranostics. M.B.H., S.K. and W.N. designed and carried out the QC aspects of this protocol. W.W.H., M.L. U.K., B.E. and M.S.H. assisted with the implementation and write up of this protocol. M.S.H. leads the clinical work using theranostics produced by this protocol.

Corresponding author

Correspondence to Mohammad B. Haskali.

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Competing interests

M.S.F. reports research grant support (to Peter MacCallum Cancer Centre) from Novartis (including AAA and Endocyte), ANSTO, Bayer, Isotopia and MIM. Consulting fees for lectures or advisory boards are from Astellas, AstraZeneca and MSD in the last 2 years and Janssen and Mundipharma in the last 5 years. The other authors declare no competing interests.

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

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Key references

Hofman, S. M. et al. Lancet 397, 797 (2021): https://doi.org/10.1016/S0140-6736(21)00237-3

Azad, A. A. et al. Lancet Oncol. 25, 1267 (2024): https://doi.org/10.1016/S1470-2045(24)00440-6

Hofman, S. M. et al. Lancet Oncol. 25, 99 (2024): https://doi.org/10.1016/S1470-2045(23)00529-6

Kostos, L. et al. Front. Med. 9, 1059122 (2022): https://doi.org/10.3389/fmed.2022.1059122

Eapen, R. S. et al. Eur. Urol. 85, 227 (2024): https://doi.org/10.1016/j.eururo.2023.08.026

Supplementary information

Supplementary Information

Supplementary methods: HPLC and TLC methods and representative chromatograms. Supplementary tutorial: precursor preparation and calculations. Automation Recipe: used in the protocol for preparation of the Lu-radiopharmaceuticals using the iPHASE MultiSyn radiosynthesizer.

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Hunt, W.W., Long, M., Kamil, U. et al. A scalable protocol for the radiosynthesis of clinical grade lutetium-177-labeled theranostic agents. Nat Protoc 21, 60–78 (2026). https://doi.org/10.1038/s41596-025-01176-2

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