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Role of Radiolabelled Small Molecules Binding to PSMA in Diagnosis and Therapy of Prostate Cancer

  • Uwe HaberkornEmail author
  • Matthias Eder
  • Klaus Kopka
  • John W. Babich
  • Michael Eisenhut
Chapter
Part of the Clinicians’ Guides to Radionuclide Hybrid Imaging book series (CGRHI)

Abstract

PET/CT with choline tracers has been used in the past for staging and detection of recurrent disease, but shows a low sensitivity and specificity, especially in patients with low PSA levels [1–3]. Therefore, novel tracers with improved imaging characteristics are needed. In this aspect the prostate-specific membrane antigen (PSMA) is a promising target. PSMA is a type II transmembrane protein with glutamate-carboxypeptidase and folate hydrolase activity, which shows overexpression on prostatic cancer including advanced stage prostate carcinomas [4, 5] and a low expression in normal tissues. After ligand binding to PSMA, the ligand-PSMA complex is internalized (Fig. 6.1), resulting in an effective accumulation of the bound molecule in the tumor cells. Together with a fast clearance of the tracer out of the circulation, this results in a high image quality for diagnosis and a high local dose for therapeutic applications. Several studies report that PSMA expression levels increase according to the stage and grade of the tumor [5–7]. Therefore, a variety of PSMA-targeted radioligands for diagnosis and therapy have been developed [8–23]. This chapter concentrates on small molecules binding to PSMA.

References

  1. 1.
    Igerc I, Kohlfurst S, Gallowitsch HJ, Matschnig S, Kresnik E, Gomez-Segovia I, et al. The value of 18F-choline PET/CT in patients with elevated PSA-level and negative prostate needle biopsy for localisation of prostate cancer. Eur J Nucl Med Mol Imaging. 2008;35:976–83.CrossRefPubMedGoogle Scholar
  2. 2.
    Husarik DB, Miralbell R, Dubs M, John H, Giger OT, Gelet A, et al. Evaluation of [18F]-choline PET/CT for staging and restaging of prostate cancer. Eur J Nucl Med Mol Imaging. 2008;35:253–63.CrossRefPubMedGoogle Scholar
  3. 3.
    Cimitan M, Bortolus R, Morassut S, Canzonieri V, Garbeglio A, Baresic T, et al. 18F-fluorocholine PET/CT imaging for the detection of recurrent prostate cancer at PSA relapse: experience in 100 consecutive patients. Eur J Nucl Med Mol Imaging. 2006;33:1387–98.CrossRefPubMedGoogle Scholar
  4. 4.
    Perner S, Hofer MD, Kim R, Shah RB, Li H, Moller P, et al. Prostate-specific membrane antigen expression as a predictor of prostate cancer progression. Hum Pathol. 2007;38:696–701.CrossRefPubMedGoogle Scholar
  5. 5.
    Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res. 1997;3:81–5.PubMedGoogle Scholar
  6. 6.
    Bostwick DG, Pacelli A, Blute M, Roche P, Murphy GP. Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 184 cases. Cancer. 1998;82:2256–61.CrossRefPubMedGoogle Scholar
  7. 7.
    Mannweiler S, Amersdorfer P, Trajanoski S, Terrett JA, King D, Mehes G. Heterogeneity of prostate-specific membrane antigen (PSMA) expression in prostate carcinoma with distant metastasis. Pathol Oncol Res. 2009;15:167–72.CrossRefPubMedGoogle Scholar
  8. 8.
    Maresca KP, Hillier SM, Femia FJ, Keith D, Barone C, Joyal JL, et al. A series of halogenated heterodimeric inhibitors of prostate specific membrane antigen (PSMA) as radiolabeled probes for targeting prostate cancer. J Med Chem. 2009;52:347–57.CrossRefPubMedGoogle Scholar
  9. 9.
    Hillier SM, Maresca KP, Femia FJ, Marquis JC, Foss CA, Nguyen N, et al. Preclinical evaluation of novel glutamate-urea-lysine analogues that target prostate-specific membrane antigen as molecular imaging pharmaceuticals for prostate cancer. Cancer Res. 2009;69:6932–40.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Hillier SM, Maresca KP, Lu G, Merkin RD, Marquis JC, Zimmerman CN, et al. 99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen for molecular imaging of prostate cancer. J Nucl Med. 2013;54:1369–76.CrossRefPubMedGoogle Scholar
  11. 11.
    Lu G, Maresca KP, Hillier SM, Zimmerman CN, Eckelman WC, Joyal JL, Babich JW. Synthesis and SAR of 99mTc/Re-labeled small molecule prostate specific membrane antigen inhibitors with novel polar chelates. Bioorg Med Chem Lett. 2013;23:1557–63.CrossRefPubMedGoogle Scholar
  12. 12.
    Eder M, Schafer M, Bauder-Wust U, Hull WE, Wangler 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.CrossRefPubMedGoogle Scholar
  13. 13.
    Barrett JA, Coleman RE, Goldsmith SJ, Vallabhajosula S, Petry NA, Cho S, et al. First-in-man evaluation of two high-affinity psma-avid small molecules for imaging prostate cancer. J Nucl Med. 2013;54:380–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Afshar-Oromieh A, Zechmann CM, Malcher A, Eder M, Eisenhut M, Linhart HG, et al. Comparison of PET imaging with a 68Ga-labelled PSMA-ligand and 18F-choline based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014;41:11–20.CrossRefPubMedGoogle Scholar
  15. 15.
    Afshar-Oromieh A, Avtzi E, Giesel FL, Holland-Letz T, Linhart HG, Eder M, et al. The diagnostic value of PET/CT imaging with the 68Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2015;42:197–209.CrossRefPubMedGoogle Scholar
  16. 16.
    Eder M, Eisenhut M, Babich J, Haberkorn U. PSMA as a target for radiolabelled small molecules. Eur J Nucl Med Mol Imaging. 2013;40:819–23.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Afshar-Oromieh A, Malcher A, Eder M, Eisenhut M, Linhart HG, Hadaschik BA, et al. PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions. Eur J Nucl Med Mol Imaging. 2013;40:486–95.CrossRefPubMedGoogle Scholar
  18. 18.
    Cho SY, Gage KL, Mease RC, Senthamizhchelvan S, Holt DP, Jeffrey-Kwanisai A, et al. Biodistribution, tumor detection, and radiation dosimetry of 18F-DCFBC, a low-molecular-weight inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer. J Nucl Med. 2012;53:1883–91.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Szabo Z, Mena E, Rowe SP, Plyku D, Nidal R, Eisenberger MA, Antonarakis ES, et al. Initial evaluation of 18F-DCFPyL for prostate-specific membrane antigen (PSMA)-targeted PET imaging of prostate cancer. Mol Imaging Biol. 2015;17(4):565–74. [Epub ahead of print].CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Banerjee SR, Pullambhatla M, Foss CA, Nimmagadda S, Ferdani R, Anderson CJ, et al. 64Cu-labeled inhibitors of prostate-specific membrane antigen for PET imaging of prostate cancer. J Med Chem. 2014;57:2657–69.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Herrmann K, Bluemel C, Weineisen M, Schottelius M, Wester HJ, Czernin J, et al. Biodistribution and radiation dosimetry for a probe targeting prostate-specific membrane antigen for imaging and therapy. J Nucl Med. 2015;56(6):855–61. epub.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Benešová M, Schäfer M, Bauder-Wüst 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.CrossRefPubMedGoogle Scholar
  23. 23.
    Chen Y, Pullambhatla M, Foss CA, Byun Y, Nimmagadda S, Senthamizhchelvan S, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B, et al. Evaluation of hybrid 68Ga-PSMA ligand PET/CT in 248 patients with biochemical recurrence after radical prostatectomy. J Nucl Med. 2015;56:668–74.CrossRefPubMedGoogle Scholar
  25. 25.
    Sterzing F, Clemens Kratochwil C, Fiedler H, Katayama S, Habl G, Klaus Kopka K, Afshar-Oromieh A, Debus J, Haberkorn U, Frederik L, Giesel FL. 68Ga-PSMA-11 PET/CT: a new technique with high potential for the radiotherapeutic management of prostate cancer patients. Eur J Nucl Med Mol Imaging. 2015;43(1):34–41. [Epub ahead of print].CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Morigi JJ, Stricker PD, van Leeuwen PJ, Tang R, Ho B, Nguyen Q, Hruby G, Fogarty G, Jagavkar R, Kneebone A, Hickey A, Fanti S, Tarlinton L, Emmett L. Prospective comparison of 18F-fluoromethylcholine versus 68Ga-PSMA PET/CT in prostate cancer patients who have rising PSA after curative treatment and are being considered for targeted therapy. J Nucl Med. 2015;56:1185–90.CrossRefPubMedGoogle Scholar
  27. 27.
    Zechmann CM, Afshar-Oromieh A, Armor T, Stubbs JB, Mier W, Hadaschik B, et al. Radiation dosimetry and first therapy results with a 124I/131I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy. Eur J Nucl Med Mol Imaging. 2014;41:1280–92.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kratochwil C, Giesel FL, Eder M, Afshar-Oromieh A, Benešová M, Mier W, et al. [177Lu]Lutetium-labelled PSMA ligand-induced remission in a patient with metastatic prostate cancer. Eur J Nucl Med Mol Imaging. 2015;42:987–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Uwe Haberkorn
    • 1
    • 2
    Email author
  • Matthias Eder
    • 3
  • Klaus Kopka
    • 3
  • John W. Babich
    • 4
  • Michael Eisenhut
    • 1
    • 2
    • 3
  1. 1.Department of Nuclear MedicineUniversity Hospital HeidelbergHeidelbergGermany
  2. 2.Clinical Cooperation Unit Nuclear MedicineGerman Cancer Research Center (dkfz)HeidelbergGermany
  3. 3.Division of Radiopharmaceutical ChemistryGerman Cancer Research Center (dkfz)HeidelbergGermany
  4. 4.Department of RadiopharmacyWeill Cornell Medical CollegeNew YorkUSA

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