Skip to main content

Advertisement

SpringerLink
Log in

Development and first-in-human study of PSMA-targeted PET tracers with improved pharmacokinetic properties

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

Abstract

Purpose

A series of new 68Ga-labeled tracers based on [68Ga]Ga-PSMA-617 were developed to augment the tumor-to-kidney ratio and reduce the activity accumulation in bladder, ultimately minimize radiation toxicity to the urinary system.

Methods

We introduced quinoline group, phenylalanine and decanoic acid into different tracers to enhance their lipophilicity, strategically limiting their metabolic pathway through the urinary system. Their binding affinity onto LNCaP cells was determined through in vitro saturation assays and competition binding assays. In vivo metabolic study, PET imaging and biodistribution experiment were performed in LNCaP tumor-bearing B-NSG male mice. The most promising tracer was selected for first-in-human study.

Results

Four radiotracers were synthesized with radiochemical purity (RCP) > 95% and molar activity in a range of 20.0-25.5 GBq/μmol. The binding affinities (Ki) of TWS01, TWS02 to PSMA were in the low nanomolar range (< 10 nM), while TWS03 and TWS04 exhibited binding affinities with Ki > 20 nM (59.42 nM for TWS03 and 37.14 nM for TWS04). All radiotracers exhibited high stability in vivo except [68Ga]Ga-TWS03. Micro PET/CT imaging and biodistribution analysis revealed that [68Ga]Ga-TWS02 enabled clear tumor visualization in PET images at 1.5 h post-injection, with higher tumor-to-kidney ratio (T/K, 0.93) and tumor-to-muscle ratio (T/M, 107.62) compared with [68Ga]Ga-PSMA-617 (T/K: 0.39, T/M: 15.01) and [68Ga]Ga-PSMA-11 (T/K: 0.15, T/M: 24.00). In first-in-human study, [68Ga]Ga-TWS02 effectively detected PCa-associated lesions including primary and metastatic lesions, with lower accumulation in urinary system, suggesting that [68Ga]Ga-TWS02 might be applied in the detection of bladder invasion, with minimized radiation toxicity to the urinary system.

Conclusion

Introduction of quinoline group, phenylalanine and decanoic acid into different tracers can modulate the binding affinity and pharmacokinetics of PSMA in vivo. [68Ga]Ga-TWS02 showed high binding affinity to PSMA, excellent pharmacokinetic properties and clear imaging of PCa-associated lesions, making it a promising radiotracer for the clinical diagnosis of PCa. Moreover, TWS02 with a chelator DOTA could also label 177Lu and 225Ac, which could be used for PCa treatment without significant side effects.

Trial registration

The clinical evaluation of this study was registered On October 30, 2021 at https://www.chictr.org.cn/ (No: ChiCTR2100052545).

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

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

References

  1. Bergengren O, Pekala KR, Matsoukas K, Fainberg J, Mungovan SF, Bratt O, et al. 2022 update on prostate cancer epidemiology and risk factors-a systematic review. Eur Urol. 2023;84:191–206. https://doi.org/10.1016/j.eururo.2023.04.021.

    Article  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA: a cancer journal for clinicians. 2021;71:7–33. https://doi.org/10.3322/caac.21654.

  3. Sekhoacha M, Riet K, Motloung P, Gumenku L, Adegoke A, Mashele S. Prostate cancer review: genetics, diagnosis, treatment options, and alternative approaches. Molecules. 2022;27. https://doi.org/10.3390/molecules27175730.

  4. Rebello RJ, Oing C, Knudsen KE, Loeb S, Johnson DC, Reiter RE, et al. Prostate cancer. Nat Rev Dis Primers. 2021;7:9.https://doi.org/10.1038/s41572-020-00243-0

  5. Daryanani A, Turkbey B. Recent advancements in CT and MR imaging of prostate cancer. Semin Nucl Med. 2022;52:365–73. https://doi.org/10.1053/j.semnuclmed.2021.11.013.

    Article  PubMed  Google Scholar 

  6. Fischer BM, Siegel BA, Weber WA, von Bremen K, Beyer T, Kalemis A. PET/CT is a cost-effective tool against cancer: synergy supersedes singularity. Eur J Nucl Med Mol Imaging. 2016;43:1749–52. https://doi.org/10.1007/s00259-016-3414-5.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Catana C, Guimaraes AR, Rosen BR. PET and MR imaging: the odd couple or a match made in heaven? J Nucl Med. 2013;54:815–24. https://doi.org/10.2967/jnumed.112.112771.

    Article  CAS  PubMed  Google Scholar 

  8. Basu S. The scope and potentials of functional radionuclide imaging towards advancing personalized medicine in oncology: emphasis on PET-CT. Discov Med. 2012;13:65–73.

    PubMed  Google Scholar 

  9. Cermik TF, Ergul N, Yilmaz B, Mercanoglu G. Tumor imaging with 68Ga-DOTA-FAPI-04 PET/CT: comparison with 18F-FDG PET/CT in 22 different cancer types. Clin Nucl Med. 2022;47:e333–9. https://doi.org/10.1097/RLU.0000000000004073.

    Article  PubMed  Google Scholar 

  10. Cornford P, van den Bergh RCN, Briers E, Van den Broeck T, Cumberbatch MG, De Santis M, et al. EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate cancer. Part II-2020 update: treatment of relapsing and metastatic prostate cancer. Eur Urol. 2021;79:263–82. https://doi.org/10.1016/j.eururo.2020.09.046.

  11. Carter RE, Feldman AR, Coyle JT. Prostate-specific membrane antigen is a hydrolase with substrate and pharmacologic characteristics of a neuropeptidase. Proc Natl Acad Sci USA. 1996;93:749–53. https://doi.org/10.1073/pnas.93.2.749.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Farolfi A, Calderoni L, Mattana F, Mei R, Telo S, Fanti S, et al. Current and emerging clinical applications of PSMA PET diagnostic imaging for prostate cancer. J Nucl Med. 2021;62:596–604. https://doi.org/10.2967/jnumed.120.257238.

    Article  CAS  PubMed  Google Scholar 

  13. Wester HJ, Schottelius M. PSMA-targeted radiopharmaceuticals for imaging and therapy. Semin Nucl Med. 2019;49:302–12. https://doi.org/10.1053/j.semnuclmed.2019.02.008.

    Article  PubMed  Google Scholar 

  14. Souvatzoglou M, Eiber M, Martinez-Moeller A, Fürst S, Holzapfel K, Maurer T, et al. PET/MR in prostate cancer: technical aspects and potential diagnostic value. Eur J Nucl Med Mol Imaging. 2013;40(Suppl 1):S79-88. https://doi.org/10.1007/s00259-013-2445-4.

    Article  PubMed  Google Scholar 

  15. Krohn T, Verburg FA, Pufe T, Neuhuber W, Vogg A, Heinzel A, et al. [(68)Ga]PSMA-HBED uptake mimicking lymph node metastasis in coeliac ganglia: an important pitfall in clinical practice. Eur J Nucl Med Mol Imaging. 2015;42:210–4. https://doi.org/10.1007/s00259-014-2915-3.

    Article  PubMed  Google Scholar 

  16. Iravani A, Hofman MS, Mulcahy T, Williams S, Murphy D, Parameswaran BK, et al. (68)Ga PSMA-11 PET with CT urography protocol in the initial staging and biochemical relapse of prostate cancer. Cancer Imaging. 2017;17:31. https://doi.org/10.1186/s40644-017-0133-5.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Hofman MS, Lawrentschuk N, Francis RJ, Tang C, Vela I, Thomas P, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet. 2020;395:1208–16. https://doi.org/10.1016/s0140-6736(20)30314-7.

    Article  CAS  PubMed  Google Scholar 

  18. Afshar-Oromieh A, Babich JW, Kratochwil C, Giesel FL, Eisenhut M, Kopka K, et al. The rise of PSMA ligands for diagnosis and therapy of prostate cancer. J Nucl Med. 2016;57:79s–89s. https://doi.org/10.2967/jnumed.115.170720.

    Article  CAS  PubMed  Google Scholar 

  19. Lütje S, Heskamp S, Cornelissen AS, Poeppel TD, van den Broek SA, Rosenbaum-Krumme S, et al. PSMA ligands for radionuclide imaging and therapy of prostate cancer: clinical status. Theranostics. 2015;5:1388–401. https://doi.org/10.7150/thno.13348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Eder M, Schäfer M, Bauder-Wüst U, Hull WE, Wängler C, Mier W, et al. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem. 2012;23:688–97. https://doi.org/10.1021/bc200279b.

    Article  CAS  PubMed  Google Scholar 

  21. Sachpekidis C, Afshar-Oromieh A, Kopka K, Strauss DS, Pan L, Haberkorn U, et al. (18)F-PSMA-1007 multiparametric, dynamic PET/CT in biochemical relapse and progression of prostate cancer. Eur J Nucl Med Mol Imaging. 2020;47:592–602. https://doi.org/10.1007/s00259-019-04569-0.

    Article  PubMed  Google Scholar 

  22. Hong JJ, Liu BL, Wang ZQ, Tang K, Ji XW, Yin WW, et al. The value of (18)F-PSMA-1007 PET/CT in identifying non-metastatic high-risk prostate cancer. EJNMMI Res. 2020;10:138. https://doi.org/10.1186/s13550-020-00730-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mease RC, Kang CM, Kumar V, Banerjee SR, Minn I, Brummet M, et al. An improved (211)At-labeled agent for PSMA-targeted alpha-therapy. J Nucl Med. 2022;63:259–67. https://doi.org/10.2967/jnumed.121.262098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Benesova M, Umbricht CA, Schibli R, Muller C. Albumin-binding PSMA ligands: optimization of the tissue distribution profile. Mol Pharm. 2018;15:934–46. https://doi.org/10.1021/acs.molpharmaceut.7b00877.

    Article  CAS  PubMed  Google Scholar 

  25. Potemkin R, Strauch B, Kuwert T, Prante O, Maschauer S. Development of (18)F-Fluoroglycosylated PSMA-ligands with improved renal clearance behavior. Mol Pharm. 2020;17:933–43. https://doi.org/10.1021/acs.molpharmaceut.9b01179.

    Article  CAS  PubMed  Google Scholar 

  26. Siebinga H, Hendrikx J, Huitema ADR, de Wit-van der Veen BJ. Predicting the effect of different folate doses on [(68)Ga]Ga-PSMA-11 organ and tumor uptake using physiologically based pharmacokinetic modeling. EJNMMI Res. 2023;13:60. https://doi.org/10.1186/s13550-023-01008-y

  27. Benešová M, Bauder-Wüst U, Schäfer M, Klika KD, Mier W, Haberkorn U, 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. https://doi.org/10.1021/acs.jmedchem.5b01210.

    Article  CAS  PubMed  Google Scholar 

  28. Kopka K, Benešová M, Bařinka C, Haberkorn U, Babich J. Glu-ureido-based inhibitors of prostate-specific membrane antigen: lessons learned during the development of a novel class of low-molecular-weight theranostic radiotracers. J Nucl Med. 2017;58:17s–26s. https://doi.org/10.2967/jnumed.116.186775.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang X, Wu Y, Zeng Q, Xie T, Yao S, Zhang J, et al. Synthesis, preclinical evaluation, and first-in-human PET study of quinoline-containing PSMA tracers with decreased renal excretion. J Med Chem. 2021;64:4179–95. https://doi.org/10.1021/acs.jmedchem.1c00117.

    Article  CAS  PubMed  Google Scholar 

  30. Hennrich U, Eder M. [(68)Ga]Ga-PSMA-11: The first FDA-approved (68)Ga-Radiopharmaceutical for PET imaging of prostate cancer. Pharmaceuticals (Basel). 2021;14. https://doi.org/10.3390/ph14080713.

  31. Chen Y, Zhang X, Ni M, Gao X, Wang X, Xie Q, et al. Synthesis, preclinical evaluation, and first-in-human pet study of [(68)Ga]-labeled biphenyl-containing PSMA tracers. J Med Chem. 2023;66:13332–45. https://doi.org/10.1021/acs.jmedchem.3c01475.

    Article  CAS  PubMed  Google Scholar 

  32. Gao F, Sihver W, Jurischka C, Bergmann R, Haase-Kohn C, Mosch B, et al. Radiopharmacological characterization of (6)(4)Cu-labeled alpha-MSH analogs for potential use in imaging of malignant melanoma. Amino Acids. 2016;48:833–47. https://doi.org/10.1007/s00726-015-2131-x.

    Article  CAS  PubMed  Google Scholar 

  33. Gao F, Sihver W, Bergmann R, Belter B, Bolzati C, Salvarese N, et al. Synthesis, characterization, and initial biological evaluation of [(99m) Tc]Tc-Tricarbonyl-labeled DPA-alpha-MSH peptide derivatives for potential melanoma imaging. ChemMedChem. 2018;13:1146–58. https://doi.org/10.1002/cmdc.201800110.

    Article  CAS  PubMed  Google Scholar 

  34. Yang H, Zhang C, Yuan Z, Rodriguez-Rodriguez C, Robertson A, Radchenko V, et al. Synthesis and evaluation of a macrocyclic actinium-225 chelator, quality control and in vivo evaluation of (225) Ac-crown-alphaMSH peptide. Chemistry. 2020;26:11435–40. https://doi.org/10.1002/chem.202002999.

    Article  CAS  PubMed  Google Scholar 

  35. Benesova M, Schafer M, Bauder-Wust U, Afshar-Oromieh A, Kratochwil C, Mier W, 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. https://doi.org/10.2967/jnumed.114.147413.

    Article  CAS  PubMed  Google Scholar 

  36. Ceci F, Rovera G, Iorio GC, Guarneri A, Chiofalo V, Passera R, et al. Event-free survival after (68) Ga-PSMA-11 PET/CT in recurrent Hormone-Sensitive Prostate Cancer (HSPC) patients eligible for salvage therapy. Eur J Nucl Med Mol Imaging. 2022;49:3257–68. https://doi.org/10.1007/s00259-022-05741-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Aboagye EO, Barwick TD, Haberkorn U. Radiotheranostics in oncology: Making precision medicine possible. CA: a cancer journal for clinicians. 2023;73:255–74. https://doi.org/10.3322/caac.21768.

  38. Lisney AR, Leitsmann C, Strauss A, Meller B, Bucerius JA, Sahlmann CO. The role of PSMA PET/CT in the primary diagnosis and follow-up of prostate cancer-a practical clinical review. Cancers. 2022;14. https://doi.org/10.3390/cancers14153638.

  39. Giesel FL, Hadaschik B, Cardinale J, Radtke J, Vinsensia M, Lehnert W, et al. F-18 labelled PSMA-1007: biodistribution, radiation dosimetry and histopathological validation of tumor lesions in prostate cancer patients. Eur J Nucl Med Mol Imaging. 2017;44:678–88. https://doi.org/10.1007/s00259-016-3573-4.

    Article  CAS  PubMed  Google Scholar 

  40. Piron S, Verhoeven J, Vanhove C, De Vos F. Recent advancements in (18)F-labeled PSMA targeting PET radiopharmaceuticals. Nucl Med Biol. 2022;106–107:29–51. https://doi.org/10.1016/j.nucmedbio.2021.12.005.

    Article  CAS  PubMed  Google Scholar 

  41. Georgakopoulos A, Bamias A, Chatziioannou S. Current role of PSMA-PET imaging in the clinical management of prostate cancer. Ther Adv Med Oncol. 2023;15:17588359231208960. https://doi.org/10.1177/17588359231208960.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Sheikhbahaei S, Afshar-Oromieh A, Eiber M, Solnes LB, Javadi MS, Ross AE, 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. https://doi.org/10.1007/s00259-017-3780-7.

    Article  PubMed  Google Scholar 

  43. Hofman MS, Hicks RJ, Maurer T, Eiber M. Prostate-specific membrane antigen PET: clinical utility in prostate cancer, normal patterns, pearls, and pitfalls. Radiographics. 2018;38:200–17. https://doi.org/10.1148/rg.2018170108.

    Article  PubMed  Google Scholar 

  44. Kuo HT, Pan J, Zhang Z, Lau J, Merkens H, Zhang C, et al. Effects of linker modification on tumor-to-kidney contrast of (68)Ga-labeled PSMA-targeted imaging probes. Mol Pharm. 2018;15:3502–11. https://doi.org/10.1021/acs.molpharmaceut.8b00499.

    Article  CAS  PubMed  Google Scholar 

  45. Benesova M, Bauder-Wust U, Schafer M, Klika KD, Mier W, Haberkorn U, 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. https://doi.org/10.1021/acs.jmedchem.5b01210.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Translational Medicine Core Facility of Shandong University for consultation and instrument availability that supported this work. We would like to thank the School of Basic Medical Science Core Facility, Shandong University for technician support. We would like to thank the School of Pharmaceutical sciences, Shandong University for technician support.

Funding

This study was financially supported by the National Natural Science Foundation of China (22376125), and the Natural Science Foundation of Shandong Province (ZR2019BA015, ZR2023MH004).

Author information

Author notes

  1. Haodong Hou and Yuan Pan contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory for Experimental Teratology of the Ministry of Education and Research Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Shandong University, No. 44 Wenhua Xi Road, Jinan, 250012, Shandong, China

    Haodong Hou, Yuan Pan, Yanzhi Wang, Yuze Ma, Guihua Hou & Feng Gao

  2. Department of Urology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, No. 1 Huanghe West Road, Huai’an, 223300, Jiangsu, China

    Xiaobing Niu

  3. Department of Pathology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, No. 1 Huanghe West Road, Huai’an, 223300, Jiangsu, China

    Suan Sun

  4. Department of Nuclear Medicine, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, No. 1 Huanghe West Road, Huai’an, 223300, Jiangsu, China

    Weijing Tao

Authors
  1. Haodong Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuan Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanzhi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuze Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaobing Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Suan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guihua Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Weijing Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Feng Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Haodong Hou, Yanzhi Wang, Yuze Ma, Xiaobing Niu, and Suan Sun. The first draft of the manuscript was written by Haodong Hou, Yuan Pan, Guihua Hou, Weijing Tao, and Feng Gao. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Guihua Hou, Weijing Tao or Feng Gao.

Ethics declarations

Ethics approval

Animal experiments were conducted following the regulations approved by the Animal Ethics Committee of Shandong University (ECSBMSSDU2021-2–67). Human studies were approved by the Ethics Committee of Huai’an First People’s Hospital (Approval No.: YX-2020–168-01).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent to publish

The authors affirm that human research participants provided informed consent for publication of the images in Fig. 5a and b.

Competing interests

All authors declare they have no relevant financial or non-financial interests that are directly or indirectly related to the work submitted for publication.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 5961 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hou, H., Pan, Y., Wang, Y. et al. Development and first-in-human study of PSMA-targeted PET tracers with improved pharmacokinetic properties. Eur J Nucl Med Mol Imaging (2024). https://doi.org/10.1007/s00259-024-06726-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00259-024-06726-6

Keywords

Search

Navigation