Advertisement

Recent developments of prostate-specific membrane antigen (PSMA)-specific radiopharmaceuticals for precise imaging and therapy of prostate cancer: an overview

  • Subhani M. OkarviEmail author
Expert Review
  • 20 Downloads
Part of the following topical collections:
  1. Genitourinary

Abstract

Despite significant research activities and subsequent progress made in the fight against cancer over the last few decades, prostate cancer remains a major health-related problem and there is no effective option available for the treatment of advanced metastatic prostate cancer as yet. There is a high clinical demand for the development of new and efficacious tumor-targeting agents together with more efficient treatment methods that could improve the prostate patient outcome. Prostate-specific membrane antigen (PSMA) is highly expressed in all types of prostate carcinomas, making PSMA a potential molecular target for detecting localized and metastatic prostate cancer. The development of PSMA-targeting agents, radiolabeled with diagnostic and/or therapeutic radionuclides, holds great clinical potential for a new era of personalized management of metastatic prostate cancer. In the past few years, several PSMA-specific tumor-targeting agents, derived from the “glutamate–urea–lysine” pharmacophore (essential for PSMA receptor recognition), conjugated to different biologically relevant linker groups and radiometal chelating agents or prosthetic groups, have been prepared and evaluated preclinically and/or clinically. Some of these PSMA ligands have gone through a long journey all the way from basic research to human studies, which is a clear example of bench to bed clinical translation. The aim of this review is to provide an overview of some of the recent advances in radiolabeled PSMA-targeting agents, mainly in diagnostic nuclear imaging.

Keywords

Prostate-specific membrane antigen (PSMA) Prostate cancer Nuclear molecular imaging Peptides Radiopharmaceuticals 

Notes

Compliance with ethical standards

Conflict of interest

SM. Okarvi declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Pysz MA, Gambhir SS, Willmann JK (2010) Molecular imaging: current status and emerging strategies. Clin Radiol 65:500–516CrossRefGoogle Scholar
  2. 2.
    Mease RC, Foss CA, Pomper MG (2013) PET imaging in prostate cancer: focus on prostate-specific membrane antigen. Curr Top Med Chem 13:951–962CrossRefGoogle Scholar
  3. 3.
    James ML, Gambhir SS (2012) A molecular imaging primer: modalities, imaging agents, and applications. Physiol Rev 92:897–965CrossRefGoogle Scholar
  4. 4.
    Kircher MF, Hricak H, Larson SM (2012) Molecular imaging for personalized cancer care. Mol Oncol 6:182–195CrossRefGoogle Scholar
  5. 5.
    Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7–30CrossRefGoogle Scholar
  6. 6.
    Park BK, Park JW, Park SY, Kim CK, Lee HM, Jeon SS, Seo SI, Jeong BC, Choi HY (2011) Prospective evaluation of 3-T MRI performed before initial transrectal ultrasound-guided prostate biopsy in patients with high prostate-specific antigen and no previous biopsy. Am J Roentgenol 197:W876–W881CrossRefGoogle Scholar
  7. 7.
    Eder M, Eisenhut M, Babich J, Haberkorn U (2013) PSMA as a target for radiolabelled small molecules. Eur J Nucl Med Mol Imaging 40:819–823CrossRefGoogle Scholar
  8. 8.
    Lütje S, Heskamp S, Cornelissen AS, Poeppel TD, Sebastiaan A, Van den Broek SAMW, Rosenbaum-Krumme S, Bockisch A, Gotthardt M, Rijpkema M, Boerman OC (2015) PSMA ligands for radionuclide imaging and therapy of prostate cancer: clinical status. Theranostics 5:1388–1401CrossRefGoogle Scholar
  9. 9.
    Eder M, Schafer M, Haberkorn U, Eisenhut M (2012) 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjugate Chem 23:688–697CrossRefGoogle Scholar
  10. 10.
    Osborne JR, Akhtar NH, Vallabhajosula S, Anand A, Deh K, Tagawa ST (2013) Prostate-specific membrane antigen-based imaging. Urol Oncol 31:144–154CrossRefGoogle Scholar
  11. 11.
    Gourni E, Henriksen G (2017) Metal-based PSMA radioligands. Molecules 22:523CrossRefGoogle Scholar
  12. 12.
    Beer AJ, Eiber M, Souvatzoglou M, Schwaiger M, Krause BJ (2011) Radionuclide and hybrid imaging of recurrent prostate cancer. Lancet Oncol 12:181–191CrossRefGoogle Scholar
  13. 13.
    Evans JD, Jethwa KR, Ost P, Williams S, Kwon ED, Lowe VJ, Davis BJ (2018) Prostate cancer-specific PET radiotracers: a review on the clinical utility in recurrent disease. Pract Radiat Oncology 8:28–39CrossRefGoogle Scholar
  14. 14.
    Beer TM, Bubalo JS (2001) Complications of chemotherapy for prostate cancer. Semin Urol Oncol 19:222–230Google Scholar
  15. 15.
    Barve A, Jin W, Cheng K (2014) Prostate cancer relevant antigens and enzymes for targeted drug delivery. J Control Release 187:118–132CrossRefGoogle Scholar
  16. 16.
    Fani M, Maecke HR, Okarvi SM (2012) Radiolabeled peptides: valuable tools for the detection and treatment of cancer. Theranostics 2:481–501CrossRefGoogle Scholar
  17. 17.
    Ghosh A, Heston WD (2004) Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J Cell Biochem 91:528–539CrossRefGoogle Scholar
  18. 18.
    Maurer T, Eiber M, Schwaiger M, Gschwend JE (2016) Current use of PSMA–PET in prostate cancer management. Nat Rev Urol 4:226–235CrossRefGoogle Scholar
  19. 19.
    Silver DA, Pellicer I, Fair WR (1997) Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res 3:81–85Google Scholar
  20. 20.
    Hillier SM, Maresca KP, Lu G, Merkin RD, Marquis JC, Zimmerman CN, Eckelman WC, Joyal JL, Babich JW (2013) 99mTc-Labeled small-molecule inhibitors of prostate-specific membrane antigen for molecular imaging of prostate cancer. J Nucl Med 54:1369–1376CrossRefGoogle Scholar
  21. 21.
    Weineisen M, Schottelius M, Simecek J, Baum RP, Yildiz A, Beykan S, Kulkarni HR, Lassmann M, Klette I, Eiber M, Schwaiger M, Wester H-J (2015) 68Ga- and 177Lu-labeled PSMA I&T: optimization of a PSMA-targeted theranostic concept and first proof-of-concept human studies. J Nucl Med 56:1169–1176CrossRefGoogle Scholar
  22. 22.
    Wolf P (2011) Prostate specific membrane antigen as biomarker andtherapeutic target for prostate cancer. In: Spiess PE (ed) Prostate cancer—diagnostic and therapeutic advances. Intechweb.org, Rijeka, Croatia, pp 81–100Google Scholar
  23. 23.
    Baccala A, Sercia L, Li J, Heston W, Zhou M (2007) Expression of prostate-specific membrane antigen in tumor-associated neovasculature of renal neoplasms. Urology 70:385–390CrossRefGoogle Scholar
  24. 24.
    Conway RE, Petrovic N, Li Z, Heston W, Wu D, Shapiro LH (2006) Prostate specific membrane antigen regulates angiogenesis by modulating integrin signal transduction. Mol Cell Biol 26:5310–5324CrossRefGoogle Scholar
  25. 25.
    Weineisen M, Simecek J, Schottelius M, Schwaiger M, Wester H-J (2014) Synthesis and preclinical evaluation of DOTAGA conjugated PSMA ligands for functional imaging and endoradiotherapy of prostate cancer. EJNMMI Research 4:63CrossRefGoogle Scholar
  26. 26.
    Lenzo NP, Meyrick D, Turner JH (2018) Review of gallium-68 PSMA PET/CT imaging in the management of prostate cancer. Diagnostics 8:16CrossRefGoogle Scholar
  27. 27.
    Goffin KE, Joniau S, Tenke P, Slawin K, Klein EA, Stambler N, Strack T, Babich J, Armor T, Wong V (2017) Phase 2 study of 99mTc-trofolastat SPECT/CT to identify and localize prostate cancer in intermediate- and high-risk patients undergoing radical prostatectomy and extended pelvic LN dissection. J Nucl Med 58:1408–1413CrossRefGoogle Scholar
  28. 28.
    Kaittanis C, Andreou C, Hieronymus H, Mao N, Foss CA, Eiber M, Weirich G, Panchal P, Gopalan A, Zurita J, Achilefu S, Chiosis G, Ponomarev V, Schwaiger M, Carver BS, Pomper MG, Grimm J (2018) Prostate-specific membrane antigen cleavage of vitamin B9 stimulates ongogenic signaling through metabotropic glutamate receptors. J Expt Med 215:159–175CrossRefGoogle Scholar
  29. 29.
    Chakravarty R, Siamof CM, Dash A, Cai W (2018) Targeted α-therapy of prostate cancer using radiolabeled PSMA inhibitors: a game changer in nuclear medicine. Am J Nucl Med Mol Imaging 8:247–267Google Scholar
  30. 30.
    Navratil M, Ptacek J, Sacha P, Starkova J, Lubkowski J, Barinka C, Konvalinka J (2014) Structural and biochemical characterization of the folyl-poly-γ-l-glutamate hydrolyzing activity of human glutamate carboxypeptidase II. FEBS J 281:3228–3242CrossRefGoogle Scholar
  31. 31.
    Oliver AJ, Wiest O, Helquist P, Miller MJ, Tenniswood M (2003) Conformational and SAR analysis of NAALADase and PSMA inhibitors. Bioorg Med Chem 11:4455–4461CrossRefGoogle Scholar
  32. 32.
    Rowe SP, Gorin MA, Allaf ME, Pienta KJ, Tran PT, Pomper MG, Ross AE, Cho SY (2016) PET imaging of prostate-specific membrane antigen in prostate cancer: current state of the art and future challenges. Prostate Cancer Prostatic Dis 19:223–230CrossRefGoogle Scholar
  33. 33.
    Pillai MRA, Nanabala R, Joy A, Sasikumar A, Knapp FF (2016) Radiolabeled enzyme inhibitors and binding agents targeting PSMA: effective theranostic tools for imaging and therapy of prostate cancer. Nucl Med Biol 43:692–720CrossRefGoogle Scholar
  34. 34.
    Benesová M, Schäfer M, Bauder-Wüst U, Afshar-Oromieh A, Kratochwil C, Mier W, Haberkorn U, Kopka K, Eder M (2015) Preclinical evaluation of a tailor-made DOTA-conjugated PSMA inhibitor with optimized linker moiety for imaging and endoradiotherapy of prostate cancer. J Nucl Med 56:914–920CrossRefGoogle Scholar
  35. 35.
    Huang SS, Wang X, Zhang Y, Doke A, DiFilippo FP, Heston WD (2014) Improving the biodistribution of PSMA-targeting tracers with a highly negatively charged linker. Prostate 74:702–713CrossRefGoogle Scholar
  36. 36.
    Umbricht CA, Benešová M, Schmid RM, Türler A, Schibli R, Van der Meulen NP, Müller C (2017) 44Sc-PSMA-617 for radiotheragnostics in tandem with 177Lu-PSMA-617—preclinical investigations in comparison with 68Ga-PSMA-11 and 68Ga-PSMA-617. EJNMMI Res 7:9CrossRefGoogle Scholar
  37. 37.
    Tapas D, Guleria M, Parab A, Kale C, Shah H, Sarma HD, Lele VR, Banerjee S (2016) Clinical translation of 177Lu-labeled PSMA: initial experience in prostate cancer patients. Nuc Med Biol 43:296–302CrossRefGoogle Scholar
  38. 38.
    Bouchelouche K, Capala J (2010) “Image and treat”—an individualized approach to urological tumors. Curr Opin Oncol 22:274–280CrossRefGoogle Scholar
  39. 39.
    Robu S, Schmidt A, Eiber M, Schottelius M, Günther T, Yousefi BH, Schwaiger M, Wester H-J (2018) Synthesis and preclinical evaluation of novel 18F-labeled Glu-urea-Glu-based PSMA inhibitors for prostate cancer imaging: a comparison with 18F-DCFPyl and 18F-PSMA-1007. EJNMMI Res 8:30CrossRefGoogle Scholar
  40. 40.
    Cardinale J, Martin R, Remde Y, Schäfer M, Hienzsch A, Hübner S, Zerges A-M, Marx H, Hesse R, Weber K, Smits R, Hoepping A, Müller M, Neels OC, Kopka K (2017) Procedures for the GMP-compliant production and quality control of [18F]PSMA-1007: a next generation radiofluorinated tracer for the detection of prostate cancer. Pharmaceuticals 10:77CrossRefGoogle Scholar
  41. 41.
    Chen Y, Pullambhatla M, Foss CA, Byun Y, Nimmagadda S, Senthamizhchelvan S, Sgouros G, Mease RC, Pomper MG (2011) 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 17:7645–7653CrossRefGoogle Scholar
  42. 42.
    Bouchelouche K, Turkbey B, Choyke PL (2016) PSMA PET and radionuclide therapy in prostate cancer. Semin Nucl Med 46:522–535CrossRefGoogle Scholar
  43. 43.
    Robu S, Schottelius M, Eiber M, Maurer M, Gschwend J, Schwaiger M, Wester H-J (2017) Preclinical evaluation and first patient application of 99mTc-PSMA-I&S for SPECT imaging and radioguided surgery in prostate cancer. J Nucl Med 58:235–242CrossRefGoogle Scholar
  44. 44.
    Koerber SA, Will L, Kratochwil C, Haefner MF, Rathke H, Kremer C, Merkle J, Herfarth K, Kopka K, Choyke PL, Holland-Letz T, Haberkorn U, Debus J, Giesel FL (2019) 68Ga-PSMA-11 PET/CT in primary and recurrent prostate carcinoma: implications for radiotherapeutic management in 121 patients. J Nucl Med 60:234–240CrossRefGoogle Scholar
  45. 45.
    Hicks RM, Simko JP, Westphalen AC, Nguyen HG, Greene KL, Zhang L, Carroll PR, Hope TA (2018) Diagnostic accuracy of 68Ga-PSMA-11 PET/MRI compared with multiparametric MRI in the detection of prostate cancer. Radiology 289:730–737CrossRefGoogle Scholar
  46. 46.
    Schäfer M, Bauder-Wüst U, Leotta K, Zoller F, Mier W, Haberkorn U, Eisenhut M, Eder M (2012) A dimerized urea-based inhibitor of the prostate-specific membrane antigen for 68Ga-PET imaging of prostate cancer. EJNMMI Res 2:23CrossRefGoogle Scholar
  47. 47.
    Banerjee SR, Chen Z, Pullambhatla M, Lisok A, Chen J, Mease RC, Pomper MG (2016) Preclinical comparative study of 68Ga-labeled DOTA, NOTA, and HBED-CC chelated radiotracers for targeting PSMA. Bioconjug Chem 27:1447–1455CrossRefGoogle Scholar
  48. 48.
    Young JD, Abbate V, Imberti C, Meszaros LK, Ma MT, Terry SYA, Hider RC, Mullen GE, Blower PJ (2017) 68Ga-THP-PSMA: a PET imaging agent for prostate cancer offering rapid, room-temperature, 1-step kit-based radiolabeling. J Nucl Med 58:1270–1277CrossRefGoogle Scholar
  49. 49.
    Giesel FL, Will L, Lawal I, Lengana T, Kratochwil C, Vorster M, Neels O, Reyneke F, Haberkon U, Kopka K, Sathekge M (2018) Intraindividual comparison of 18F-PSMA-1007 and 18FDCFPyL PET/CT in the prospective evaluation of patients with newly diagnosed prostate carcinoma: a pilot study. J Nucl Med 59:1076–1080CrossRefGoogle Scholar
  50. 50.
    Rahbar K, Afshar-Oromieh A, Seifert R, Wagner S, Schäfers M, Bögemann M, Matthias Weckesser M (2018) Diagnostic performance of 18F-PSMA-1007 PET/CT in patients with biochemical recurrent prostate cancer. Eur J Nucl Med Mol Imaging 45:2055–2061CrossRefGoogle Scholar
  51. 51.
    Eppard E, de la Fuente A, Benešová M, Khawar A, Bundschuh RA, Gärtner FC, Kreppel B, Kopka K, Essler M, Rösch F (2017) Clinical translation and first in-human use of [44Sc]Sc-PSMA-617 for PET imaging of metastasized castrate-resistant prostate cancer. Theranostics 7:4359–4369CrossRefGoogle Scholar
  52. 52.
    Singh A, Baum RP, Klette I, van der Meulen Nicholas P, Muller C, Tuerler A, Schibli R (2015) Scandium-44 DOTATOC PET/CT: first in-human molecular imaging of neuroendocrine tumors and possible perspectives for theranostics. J Nucl Med 56(Supplement 3):267Google Scholar
  53. 53.
    Sterzing F, Kratochwil C, Fiedler H, Katayama S, Habl G, Kopka K, Afshar-Oromieh A, Debus J, Haberkorn U, Frederik L, Giesel FL (2016) 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 43:34–41CrossRefGoogle Scholar
  54. 54.
    Kesch C, Kratochwi C, Mier W, Kopka K, Frederik L, Giesel FL (2017) 68Ga or 18F for prostate cancer imaging? J Nucl Med 56:687–688CrossRefGoogle Scholar
  55. 55.
    Ebenhan T, Vorster M, Marjanovic-Painter B (2015) Development of a single vial kit solution for radiolabeling of 68Ga-DKFZ-PSMA-11 and its performance in prostate cancer patients. Molecules 20:14860–14878CrossRefGoogle Scholar
  56. 56.
    Satpati D, Shinto A, Kamaleshwaran KK, Sane S, Banerjee S (2016) Convenient preparation of [68Ga]DKFZ-PSMA-11 using a robust single-vial kit and demonstration of its clinical efficacy. Mol Imaging Biol 18:420–427CrossRefGoogle Scholar
  57. 57.
    Cardinale J, Schäfer M, Benesová M, Bauder-Wüst U, Leotta K, Eder M, Neels OC, Haberkorn U, Giesel FL, Kopka K (2017) Preclinical evaluation of 18F-PSMA-1007, a new prostate-specific membrane antigen ligand for prostate cancer imaging. J Nucl Med 58:425–431CrossRefGoogle Scholar
  58. 58.
    Rowe SP, Macura KJ, Mena E, Blackford AL, Nadal R, Antonarakis ES, Eisenberger M, Carducci M, Fan H, Dannals RF, Chen Y, Mease RC, Szabo Z, Pomper MG, Cho SY (2016) PSMA-Based [18F]DCFPyL PET/CT is superior to conventional imaging for lesion detection in patients with metastatic prostate cancer. Mol Imaging Biol 18:411–419CrossRefGoogle Scholar
  59. 59.
    Szabo Z, Mena E, Rowe SP, Plyku D, Nidal R, Eisenberger MA, Antonarakis ES, Fan Hong, Dannals RF, Chen Y, Mease RC, Vranesic M, Bhatnagar A, Sgouros G, Cho SY, Pomper MG (2015) Initial evaluation of [18F]DCFPyL for prostate-specific membrane antigen (PSMA)-targeted PET imaging of prostate cancer. Mol Imaging Biol 17:565–574CrossRefGoogle Scholar
  60. 60.
    Giesel FL, Cardinale J, Schäfer M, Neels O, Benešová M, Mier W, Haberkorn U, Kopka K, Kratochwil C (2016) 18F-Labelled PSMA-1007 shows similarity in structure, biodistribution and tumour uptake to the theragnostic compound PSMA-617. Eur J Nucl Med Mol Imaging 43:1929–1930CrossRefGoogle Scholar
  61. 61.
    Giesel FL, Hadaschik B, Cardinale J, Radtke J, Vinsensia M, Lehnert W, Kesch C, Tolstov Y, Singer S, Grabe N, Duensing S, Schäfer M, Neels OC, Mier W, Haberkorn U, Kopka K, Kratochwil C (2017) F-18 Labelled PSMA-1007: biodistribution, radiation dosimetry and histopathological validation of tumor lesions in prostate cancer patients. Eur J Nucl Med Mol Imaging 44:678–688CrossRefGoogle Scholar
  62. 62.
    Afshar-Oromieh A, Avtzi E, Giesel FL (2015) 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 42:197–209CrossRefGoogle Scholar
  63. 63.
    Gorin MA, Rowe SP (2017) PSMA: a potential therapeutic target in RCC. Nat Rev Urol 14:646–647CrossRefGoogle Scholar
  64. 64.
    Afriansyah A, Hamid A, Mochtar CA, Umbas R (2018) Prostate specific antigen (PSA) kinetic as a prognostic factor in metastatic prostate cancer receiving androgen deprivation therapy: systematic review and meta-analysis. F1000Res 7:246CrossRefGoogle Scholar
  65. 65.
    Mizokami A, Namiki M (2015) Reconsideration of progression to CRPC during androgen deprivation therapy. J Steroid Biochem Mol Biol 145:164–171CrossRefGoogle Scholar
  66. 66.
    Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, Mason M, Matveev V, Wiegel T, Zattoni F, Mottet N (2014) EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 65:467–479CrossRefGoogle Scholar
  67. 67.
    Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, Kopka K, Apostolidis C, Haberkorn U, Morgenstern A (2016) 225Ac-PSMA-617 for PSMA-targeted alpha radiation therapy of metastatic castration-resistant prostate cancer. J Nucl Med 57:1941–1944CrossRefGoogle Scholar
  68. 68.
    Kratochwil C, Bruchertseifer F, Rathke H, Bronzel M, Apostolidis C, Weichert W, Haberkorn U, Giesel FL, Morgenstern A (2017) Targeted alpha-therapy of metastatic castration-resistant prostate cancer with 225Ac-PSMA-617: dosimetry estimate and empiric dose finding. J Nucl Med 58:1624–1631CrossRefGoogle Scholar
  69. 69.
    Sathekge M, Knoesen O, Meckel M, Modiselle M, Vorster M, Marx S (2017) 213Bi-PSMA-617 targeted alpha-radionuclide therapy in metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging 44:1099–1100CrossRefGoogle Scholar
  70. 70.
    Gorin MA, Pomper MG (2016) PSMA-targeted imaging of prostate cancer: the best is yet to come. BJU Int 117:715–716CrossRefGoogle Scholar
  71. 71.
    Conti M, Eriksson L (2016) Physics of pure and non-pure positron emitters for PET: a review and a discussion. EJNMMI Phys 3:8CrossRefGoogle Scholar
  72. 72.
    Prenosil GA, Hentschel M, Furstner M, Krause T, Weitzel T, Klaeser B (2017) Technical note: transconvolution based equalization of positron energy effects for the use of 68Ge/68Ga phantoms in determining 18F PET recovery. Med Phys 44:3761–3766CrossRefGoogle Scholar
  73. 73.
    ClinicalTrials.gov [Internet] (2019). National Library of Medicine (US), Bethesda (MD)Google Scholar

Copyright information

© Italian Association of Nuclear Medicine and Molecular Imaging 2019

Authors and Affiliations

  1. 1.Cyclotron and Radiopharmaceuticals DepartmentKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia

Personalised recommendations