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89Zr-labeled PSMA ligands for pharmacokinetic PET imaging and dosimetry of PSMA-617 and PSMA-I&T: a preclinical evaluation and first in man

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Rationale

Prolonged in vivo evaluation of PSMA tracers could improve tumor imaging and patient selection for 177Lu-PSMA-617 and 177Lu-PSMA-I&T. In this study, we present the radiolabeling method of PSMA-617 and PSMA-I&T with the long-lived positron emitter 89Zr to enable PET imaging up to 7 days post-injection. We compared the biodistribution of 89Zr-PSMA-617 and 89Zr-PSMA-I&T to those of 177Lu-PSMA-617 and 177Lu-PSMA-I&T, respectively, in a PSMA+ xenograft model. Moreover, we provide the first human 89Zr-PSMA-617 images.

Materials and methods

PSMA ligands were labeled with 50-55 MBq [89Zr]ZrCl4 using a two-step labeling protocol. For biodistribution, BALB/c nude mice bearing PSMA+ and PSMA− xenografts received 0.6 µg (0.6–1 MBq) of 89Zr-PSMA-617, 89Zr-PSMA-I&T, 177Lu-PSMA-617, or 177Lu-PSMA-I&T intravenously. Ex vivo biodistribution and PET/SPECT imaging were performed up to 168 h post-injection. Dosimetry was performed from the biodistribution data. The patient received 90.5 MBq 89Zr-PSMA-617 followed by PET/CT imaging.

Results

89Zr-labeled PSMA ligands showed a comparable ex vivo biodistribution to its respective 177Lu-labeled counterparts with high tumor accumulation in the PSMA+ xenografts. However, using a dose estimation model for 177Lu, absorbed radiation dose in bone and kidneys differed among the 177Lu-PSMA and 89Zr-PSMA tracers. 89Zr-PSMA-617 PET in the first human patient showed high contrast of PSMA expressing tissues up to 48 h post-injection.

Conclusion

PSMA-617 and PSMA-I&T were successfully labeled with 89Zr and demonstrated high uptake in PSMA+ xenografts, which enabled PET up to 168 h post-injection. The biodistribution of 89Zr-PSMA-I&T and 89Zr-PSMA-617 resembled that of 177Lu-PSMA-I&T and 177Lu-PSMA-617, respectively. The first patient 89Zr-PSMA-617 PET images were of high quality warranting further clinical investigation.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

mPCa:

Metastasized prostate cancer

PCa:

Prostate cancer

PSMA:

Prostate-specific membrane antigen

PSMA-RLT:

Prostate-specific membrane antigen radioligand therapy

PET:

Positron emission tomography

44Sc:

Scandium-44

64Cu:

Copper-64

89Zr:

Zirconium-89

124I:

Iodine 124

177Lu:

Lutetium-177

DEM:

Dosimetry estimation model

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Acknowledgements

The authors thank Bianca Lemmers-van de Weem, Kitty Lemmens-Hermans, and Karin de Haas-Cremers for the technical assistance with the animal experiments.

Funding

This work was supported by the Else Kröner-Fresenius-Stiftung (2016-A64) and the Dutch Cancer Society (NKB-KWF 10443/2016–1).

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Authors and Affiliations

  1. Department of Medical Imaging, Nuclear Medicine, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

    Bastiaan M. Privé, Yvonne H. W. Derks, Gerben M. Franssen, Steffie M. B. Peters, Martin Gotthardt, Peter Laverman, Mark W. Konijnenberg, James Nagarajah & Sandra Heskamp

  2. Department of Nuclear Medicine, Saarland University Medical Center, Homburg, Germany

    Florian Rosar, Fadi Khreish, Mark Bartholomä, Stephan Maus & Samer Ezziddin

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  1. Bastiaan M. Privé
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Contributions

All authors were involved in the writing and reviewing of the manuscript. B. P. and Y. D. were involved in the study design, data analysis, and manuscript design. F. R. was involved in data collection and analysis. G. F. was involved in the data collection. S. P. and M. K. were involved in the data analysis. F. K., M. B., S. M., M. G., P. L., and S. E. were involved in the data collection and analysis. J. N. and S. H. were involved in the study design, data collection, and data analysis review.

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Correspondence to Bastiaan M. Privé.

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All experiments were approved by the institutional Animal Welfare Committee of the Radboud University Medical Center and were conducted in accordance to the guidelines of the Revised Dutch Act on Animal Experimentation. The patient was scanned in a compassionate access setting and provided informed consent before study entry.

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This article is part of the Topical Collection on Oncology - Genitourinary

Bastiaan M. Privé and Yvonne H. W. Derks are co-first authors

James Nagarajah and Sandra Heskamp are co-last authors

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Privé, B.M., Derks, Y.H.W., Rosar, F. et al. 89Zr-labeled PSMA ligands for pharmacokinetic PET imaging and dosimetry of PSMA-617 and PSMA-I&T: a preclinical evaluation and first in man. Eur J Nucl Med Mol Imaging 49, 2064–2076 (2022). https://doi.org/10.1007/s00259-021-05661-0

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