Skip to main content
SpringerLink
Log in

68Ga-labeled ODAP-Urea-based PSMA agents in prostate cancer: first-in-human imaging of an optimized agent

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Prostate-specific membrane antigen (PSMA) is a promising target for prostate cancer imaging and therapy. The most commonly used scaffold incorporates a glutamate-urea (Glu-Urea) function. We recently developed oxalyldiaminopropionic acid-urea (ODAP-Urea) PSMA ligands in an attempt to improve upon the pharmacokinetic properties of existing agents. Here, we report the synthesis of an optimized 68Ga-labeled ODAP-Urea-based ligand, [68Ga]Ga-P137, and first-in-human results.

Methods

Twelve ODAP-Urea-based ligands were synthesized and radiolabeled with 68Ga in high radiochemical yield and purity. Their PSMA inhibitory capacities were determined using the NAALADase assay. Radioligands were evaluated in mice-bearing 22Rv1 prostate tumors by microPET. Lead compound [68Ga]Ga-P137 was evaluated for stability, cell uptake, and biodistribution. PET imaging of [68Ga]Ga-P137 was performed in three patients head-to-head compared to [68Ga]Ga-PSMA-617.

Results

Ligands were synthesized in 11.1-44.4% yield and > 95% purity. They have high affinity to PSMA (Ki of 0.13 to 5.47 nM). [68Ga]Ga-P137 was stable and hydrophilic. [68Ga]Ga-P137 showed higher uptake than [68Ga]Ga-PSMA-617 in tumor-bearing mice at 6.43 ± 0.98%IA/g vs 3.41 ± 1.31%IA/g at 60-min post-injection. In human studies, the normal organ biodistribution of [68Ga]Ga-P137 was grossly equivalent to that of [68Ga]Ga-PSMA-617 except for within the urinary tract, in which [68Ga]Ga-P137 demonstrated lower uptake.

Conclusion

The optimized ODAP-Urea-based ligand [68Ga]Ga-P137 can image PSMA in xenograft models and humans, with lower bladder accumulation to the Glu-Urea-based agent, [68Ga]Ga-PSMA-617, in a preliminary, first-in-human study.

Trial registration

ClinicalTrials.gov Identifier: NCT04560725, Registered 23 September 2020. https://clinicaltrials.gov/ct2/show/NCT04560725

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

Not applicable.

Code availability

Not applicable.

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71:7–33.

    PubMed  Google Scholar 

  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    PubMed  Google Scholar 

  3. Ross JS, Sheehan CE, Fisher HA, et al. Correlation of primary tumor prostate-specific membrane antigen expression with disease recurrence in prostate cancer. Clin Cancer Res. 2003;9:6357–62.

    CAS  PubMed  Google Scholar 

  4. Rowe SP, Gorin MA, Pomper MG. Imaging of prostate-specific membrane antigen with small-molecule PET radiotracers: from the bench to advanced clinical applications. Annu Rev Med. 2019;70:461–77.

    Article  CAS  PubMed  Google Scholar 

  5. Sheikhbahaei S, Afshar-Oromieh A, Eiber M, et al. Pearls and pitfalls in clinical interpretation of prostate-specific membrane antigen (PSMA)-targeted PET imaging. Eur J Nucl Med Mol Imaging. 2017;44:2117–36.

    Article  PubMed  Google Scholar 

  6. Von Eyben FE, Picchio M, Von Eyben R, Rhee H, Bauman G. 68Ga-labeled prostate-specific membrane antigen ligand positron emission tomography/computed tomography for prostate cancer: a systematic review and meta-analysis. Eur Urol Focus. 2016;4:686–93.

    Article  Google Scholar 

  7. Wester HJ, Schottelius M. PSMA-targeted radiopharmaceuticals for imaging and therapy. Semin Nucl Med. 2019;49:302–12.

    Article  PubMed  Google Scholar 

  8. Mease RC, Dusich CL, Foss CA, et al. N-[N-[(S)-1,3-Dicarboxypropyl]carbamoyl]-4-[18F]fluorobenzyl-L-cysteine, [18F]DCFBC: a new imaging probe for prostate cancer. Clin Cancer Res. 2008;14:3036–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen Y, Pullambhatla M, Foss CA, et al. 2-(3-{1-Carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid, [18F]DCFPyL, a PSMA-based PET imaging agent for prostate cancer. Clin Cancer Res. 2011;17:7645–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cardinale J, Schäfer M, Beneˇsová M, et al. Preclinical evaluation of 18F-PSMA-1007, a new prostate-specific membrane antigen ligand for prostate cancer imaging. J Nucl Med. 2017;58:425–31.

    Article  CAS  PubMed  Google Scholar 

  11. Eder M, Schafer M, Bauder-Wust U, et al. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem. 2012;23:688–97.

    Article  CAS  PubMed  Google Scholar 

  12. Benešová M, Schäfer M, Bauder-Wüst U, et al. Preclinical evaluation of a tailor-made DOTA-conjugated PSMA inhibitor with optimized linker moiety for imaging and endoradiotherapy of prostate cancer. J Nucl Med. 2015;56:914–20.

    Article  PubMed  Google Scholar 

  13. Kabasakal L, AbuQbeitah M, Aygun A, et al. Pre-therapeutic dosimetry of normal organs and tissues of 177Lu-PSMA-617 prostate-specific membrane antigen (PSMA) inhibitor in patients with castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2015;42:1976–83.

    Article  CAS  PubMed  Google Scholar 

  14. Martina W, Margret S, Jakub S, et al. 68Ga- and 177Lu-labeled PSMA I&T: optimization of a PSMA-targeted theranostic concept and first proof-of-concept human studies. J Nucl Med. 2015;56:1169–76.

    Article  Google Scholar 

  15. Graham K, Lesche R, Gromov AV, et al. Radiofluorinated derivatives of 2-(phosphonomethyl)pentanedioic acid as inhibitors of prostate specific membrane antigen (PSMA) for the imaging of prostate cancer. J Med Chem. 2012;55:9510–20.

    Article  CAS  PubMed  Google Scholar 

  16. Yang X, Mease RC, Pullambhatla M, et al. [18F]Fluorobenzoyllysinepentanedioic acid carbamates: new scaffolds for positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA). J Med Chem. 2016;59:206–18.

    Article  CAS  PubMed  Google Scholar 

  17. Duan X, Liu F, Kwon H, et al. (S)-3-(Carboxyformamido)-2-(3-(carboxymethyl)ureido)propanoic acid as a novel PSMA targeting scaffold for prostate cancer imaging. J Med Chem. 2020;63:3563–76.

    Article  CAS  PubMed  Google Scholar 

  18. Thisgaard H, Kumlin J, Langkjaer N, et al. Multi-curie production of gallium-68 on a biomedical cyclotron and automated radiolabelling of PSMA-11 and DOTATATE. EJNMMI Radiopharm Chem. 2021;6:1–11.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Benešová M, Bauderwüst U, Schäfer M, et al. Linker modification strategies to control the prostate-specific membrane antigen (PSMA)-targeting and pharmacokinetic properties of DOTA-conjugated PSMA inhibitors. J Med Chem. 2016;59:1761–75.

    Article  PubMed  Google Scholar 

  20. Olszewski RT, Bukhari N, Zhou J, et al. NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. J Neurochem. 2004;89:876–85.

    Article  CAS  PubMed  Google Scholar 

  21. Liu T, Liu C, Xu X, et al. Preclinical evaluation and pilot clinical study of Al18F-PSMA-BCH for prostate cancer imaging. J Nucl Med. 2019;60:1284–92.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We gratefully appreciate all the chemists, nurses, and technicians from the Department of Nuclear Medicine, Peking University Cancer Hospital for their contributions to imaging studies.

Funding

This work was supported by the National Natural Science Foundation of China (21877004, 92059101), the Clinical Medicine Plus X—Young Scholars Project of Peking University (PKU2020LCXQ029), the Wu Jieping Medical Foundation (320.6750.2020–6-25), the Beijing Science and Technology Project (Z181100001618017), and the Science Foundation of Peking University First Hospital (2019SF08), the Found For Fostering Young Scholars of Peking University Health Science Center (BMU2021PYB024) .

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, Peking University First Hospital, Beijing, 100034, China

    Xiaojiang Duan, Zhen Cao, Xuekang Cai, Yan Fan & Xing Yang

  2. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China

    Hua Zhu, Chen Liu, Ya’nan Ren, Futao Liu, Xiaoyi Guo & Zhi Yang

  3. Department of Nuclear Medicine, the First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China

    Xiaojun Zhang & Jinming Zhang

  4. State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, National Pesticide Engineering Research Center, Nankai University, Tianjin, 300071, China

    Zhen Xi

  5. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, 21287, USA

    Martin G. Pomper

  6. Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, China

    Xing Yang

Authors
  1. Xiaojiang Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhen Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hua Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaojun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jinming Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ya’nan Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Futao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xuekang Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaoyi Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhen Xi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Martin G. Pomper
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Zhi Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yan Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Xing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Xing Yang, Yan Fan, and Zhi Yang conceived and designed the experiments. Xiaojiang Duan and Futao Liu performed the chemical synthesis of the PSMA-targeting ligands. Xiaojiang Duan, Hua Zhu, and Zhen Cao performed radiosynthesis, binding affinity, cellular experiments, and animal model preparation. Xiaojiang Duan, Xiaojun Zhang, Jinming Zhang, and Zhen Cao performed preclinical imaging experiments. Chen Liu, Hua Zhu, Ya'nan Ren, Xiaoyi Guo, and Xiaojiang Duan performed the clinical translation imaging preparation and experiments. Xing Yang, Xiaojiang Duan, and Xuekang Cai co-wrote the paper. Zhen Xi and Martin G. Pomper helped the data analysis with constructive discussions. All authors discussed the results and commented on manuscript.

Corresponding authors

Correspondence to Zhi Yang, Yan Fan or Xing Yang.

Ethics declarations

Ethics approval

All procedures involving human participants were carried out in accordance with the Ethics Committee of Peking University Cancer Hospital (2020KT107) and registered in NIH (NCT04560725). All animal studies were performed according to a protocol approved by the Peking University First Hospital Animal Care and Use Committee.

Informed consent

Written informed consents were obtained from all participants included in the study.

Consent to participate

Written informed consents were obtained from all participants included in the study.

Consent for publication

Not applicable.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xiaojiang Duan, Zhen Cao and Hua Zhu contribute equally to this work.

This article is part of the Topical Collection on Radiopharmacy

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 85.5 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Duan, X., Cao, Z., Zhu, H. et al. 68Ga-labeled ODAP-Urea-based PSMA agents in prostate cancer: first-in-human imaging of an optimized agent. Eur J Nucl Med Mol Imaging 49, 1030–1040 (2022). https://doi.org/10.1007/s00259-021-05486-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-021-05486-x

Keywords

Search

Navigation