• Ferdinando CalabriaEmail author
  • Antonio Bagnato
  • Vincenzo Gangemi
  • Rosina Paonessa
  • Mario Leporace
  • Nicoletta Urbano
  • Giuseppe Lucio Cascini


Copper (Cu) is a transition metal with atomic number 29, involved in several physiological processes, being cofactor for numerous enzymes, such as the “Cu/Zn superoxide dismutase,” “cytochrome-C-oxidase,” “tyrosinase,” “ceruloplasmin,” and other proteins. Moreover, the Cu is essential for respiration, iron transport and metabolism, cell growth, and hemostasis [1, 2]. It may also play a role in cancer development and progression, acting as neo-angiogenetic promoter [3, 4].













64Cu-prostate-specific membrane antigen






Human copper transporter 1




Deoxyribonucleic acid


Tetraazacyclododecane-tetraacetic acid


Good manufacture practice


Linear energy transfer


Neuroendocrine tumors


Positron emission tomography/computed tomography


Prostate-specific membrane antigen


Receptors radiation therapy


Single photon emission computed tomography/computed tomography


Somatostatin receptor


  1. 1.
    Niccoli Asabella A, Cascini GL, Altini C, et al. The copper radioisotopes: a systematic review with special interest to 64Cu. Biomed Res Int. 2014;2014:786463.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Puig S, Thiele DJ. Molecular mechanisms of copper uptake and distribution. Curr Opin Chem Biol. 2002;6:171–80.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Reilly W, McAuslan BR. Matrix control of tumor angiogenesis. Adv Exp Med Biol. 1988;242:221–7.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Finney L, Vogt S, Fukai T, et al. Copper and angiogenesis: unravelling a relationship key to cancer progression. Clin Exp Pharmacol Physiol. 2009;36:88–94.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Blower PJ, Lewis JS, Zweit J. Copper radionuclides and radiopharmaceuticals in nuclear medicine. Nucl Med Biol. 1996;23:957–80.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Szymański P, Frączek T, Markowicz M, et al. Development of copper based drugs, radiopharmaceuticals and medical materials. Biometals. 2012;25:1089–112.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Evangelista L, Luigi M, Cascini GL. New issues for copper-64: from precursor to innovative PET tracers in clinical oncology. Curr Radiopharm. 2013;6:117–23.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Kassis AI, Adelstein SJ. Radiobiologic principles in radionuclide therapy. J Nucl Med. 2005;46:4s–12s.PubMedPubMedCentralGoogle Scholar
  9. 9.
    George AM, Sabovljev SA, Hart LE, et al. DNA quaternary structure in the radiation sensitivity of human lymphocytes—a proposed role of copper. Br J Cancer Suppl. 1987;8:141–4.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Frindel M, Camus N, Rauscher A, et al. Radiolabeling of HTE1PA: a new monopicolinate cyclam derivative for Cu-64 phenotypic imaging. In vitro and in vivo stability studies in mice. Nucl Med Biol. 2014;41:e49–57.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Banerjee SR, Pullambhatla M, Foss CA, et al. 64Cu-labeled inhibitors of prostate-specific membrane antigen for PET imaging of prostate cancer. J Med Chem. 2014;27:6.Google Scholar
  12. 12.
    Cai Z, Anderson CJ. Chelators for copper radionuclides in positron emission tomography radiopharmaceuticals. J Labelled Comp Radiopharm. 2014;57:224–30.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Anderson CJ, Ferdani R. Copper-64 radiopharmaceuticals for PET imaging of cancer: advances in preclinical and clinical research. Cancer Biother Radiopharm. 2009;24:379–93.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Sweat SD, Pacelli A, Murphy GP, et al. Prostate-specific membrane antigen expression is greatest in prostate adenocarcinoma and lymph node metastases. Urology. 1998;52:637–40.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Zhou Y, Li J, Xu X, et al. 64Cu-based Radiopharmaceuticals in Molecular Imaging. Technol Cancer Res Treat. 2019;1:1533033819830758.Google Scholar
  16. 16.
    Eder M, Eisenhut M, Babich J, et al. PSMA as a target for radiolabelled small molecules. Eur J Nucl Med Mol Imaging. 2013;40:819–23.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Cui C, Hanyu M, Hatori A, et al. Synthesis and evaluation of [64Cu]PSMA-617 targeted for prostate-specific membrane antigen in prostate cancer. Am J Nucl Med Mol Imaging. 2017;7:40–52.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Berliner C, Tienken M, Frenzel T, et al. Detection rate of PET/CT in patients with biochemical relapse of prostate cancer using 68Ga-PSMA;T and comparison with published data of 68Ga PSMA HBED-CC. Eur J Nucl Med Mol Imaging. 2017;44:670–7.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Buemel C, Krebs M, Polat B, et al. 68Ga-PSMA-PET/CT in patients with biochemical prostate cancer recurrence and negative 18F-choline-PET/CT. Clin Nucl Med. 2016;41:515–21.CrossRefGoogle Scholar
  20. 20.
    Grubmüller B, Baum RP, Capasso E, et al. 64Cu-PSMA-617 PET/CT imaging of prostate adenocarcinoma: first in-human studies. Cancer Biother Radiopharm. 2016;31:277–86.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Calabria F, Gallo G, Schillaci O, et al. Bio-distribution, imaging protocols and diagnostic accuracy of PET with tracers of lipogenesis in imaging prostate cancer: a comparison between 11C-choline, 18F-fluoroethylcholine and 18F-methylcholine. Curr Pharm Des. 2015;21:4738–47.CrossRefGoogle Scholar
  22. 22.
    Cantiello F, Crocerossa F, Russo GI, et al. Comparison between 64Cu-PSMA-617 PET/CT and 18F-choline PET/CT imaging in early diagnosis of prostate cancer biochemical recurrence. Clin Genitourin Cancer. 2018;16:385–91.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Huang YT, Fong W, Thomas P. Rectal carcinoma on 68Ga-PSMA PET/CT. Clin Nucl Med. 2016;41:167–8.CrossRefGoogle Scholar
  24. 24.
    Krohn T, Verburg FA, Pufe T, 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.CrossRefGoogle Scholar
  25. 25.
    Calabria F, Gangemi V, Gullà D, et al. 64Cu-PSMA uptake in meningioma: a potential pitfall of a promising radiotracer. Rev Esp Med Nucl Imagen Mol. 2017;36:335–6.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Bilgin R, Ergül N, Çermik TF. Incidental meningioma mimicking metastasis of prostate adenocarcinoma in 68Ga-Labeled PSMA Ligand PET/CT. Clin Nucl Med. 2016;41:956–8.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Calabria F. Fifty shades of meningioma: challenges and perspectives of different PET molecular probes. Clin Transl Imaging. 2017;5:403–5.CrossRefGoogle Scholar
  28. 28.
    Calabria F, Pichler R, Leporace M et al. 68Ga/64Cu PSMA bio-distribution in prostate cancer patients: potential pitfalls for different tracers. Curr Radiopharm. 2019 [Epub ahead of print].Google Scholar
  29. 29.
    Fallanca F, Giovacchini G, Picchio M, et al. Incidental detection by [11C]choline PET/CT of meningiomas in prostate cancer patients. Q J Nucl Med Mol Imaging. 2009;53:417–21.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Strele-Trieb P, Dunzinger A, Sonnberger M, et al. Uptake of 68Ga-prostate-specific membrane antigen PET in Adrenal Gland: a potential pitfall. Clin Nucl Med. 2017;43:50–1.CrossRefGoogle Scholar
  31. 31.
    Keidar Z, Gill R, Goshen E, et al. 68Ga-PSMA PET/CT in prostate cancer patients - patterns of disease, benign findings and pitfalls. Cancer Imaging. 2018;18:39.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Jochumsen MR, Bouchelouche K. Intense 68Ga-PSMA uptake in diverticulum of the sigmoid colon. Clin Nucl Med. 2018;43:110–1.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Calabria FF, Chiaravalloti A, Jaffrain-Rea ML, et al. 18F-DOPA PET/CT physiological distribution and pitfalls: experience in 215 patients. Clin Nucl Med. 2016;41:753–60.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Calabria F, Chiaravalloti A, Cicciò C, et al. PET/CT with 18F-choline: physiological whole bio-distribution in male and female subjects and diagnostic pitfalls on 1000 prostate cancer patients: 18F-choline PET/CT bio-distribution and pitfalls. A southern Italian experience. Nucl Med Biol. 2017;51:40–54.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Fujibayashi Y, Taniuchi H, Yonekura Y, et al. Copper-62-ATSM: a new hypoxia imaging agent with high membrane permeability and low redox potential. J Nucl Med. 1997;38:1155–60.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Padhani AR, Krohn KA, Lewis JS, et al. Imaging oxygenation of human tumours. Eur Radiol. 2007;17:861–72.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Yuan H, Schroeder T, Bowsher JE, et al. Intertumoral differences in hypoxia selectivity of the PET imaging agent 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone). J Nucl Med. 2006;47:989–98.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Liu J, Hajibeigi A, Ren G, et al. Retention of the radiotracers 64Cu-ATSM and 64Cu-PTSM in human and murine tumors is influenced by MDR1 protein expression. J Nucl Med. 2009;50:1332–9.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Yoshii Y, Furukawa T, Kiyono Y, et al. Internal radiotherapy with copper-64-diacetyl-bis (N4-methylthiosemicarbazone) reduces CD133+ highly tumorigenic cells and metastatic ability of mouse colon carcinoma. Nucl Med Biol. 2011;38:151–7.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Yoshii Y, Yoneda M, Ikawa M, et al. Radiolabeled Cu-ATSM as a novel indicator of overreduced intracellular state due to mitochondrial dysfunction: studies with mitochondrial DNA-less ρ0 cells and cybrids carrying MELAS mitochondrial DNA mutation. Nucl Med Biol. 2012;39:177–85.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Nehmeh SA, Lee NY, Schröder H, et al. Reproducibility of intratumor distribution of (18)F-fluoromisonidazole in head and neck cancer. Int J Radiat Oncol Biol Phys. 2008;70:235–42.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    McCall KC, Humm JL, Bartlett R, et al. Copper-64-diacetyl-bis(N(4)-methylthiosemicarbazone) pharmacokinetics in FaDu xenograft tumors and correlation with microscopic markers of hypoxia. Int J Radiat Oncol Biol Phys. 2012;84:e393–9.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Carlin S, Zhang H, Reese M, et al. A comparison of the imaging characteristics and microregional distribution of 4 hypoxia PET tracers. J Nucl Med. 2014;55:515–21.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Tateishi K, Tateishi U, Sato M, et al. Application of 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) PET imaging to predict highly malignant tumor grades and hypoxia-inducible factor-1α expression in patients with glioma. AJNR Am J Neuroradiol. 2013;34:98–9.CrossRefGoogle Scholar
  45. 45.
    Minagawa Y, Shizukuishi K, Koike I, et al. Assessment of tumor hypoxia by 62Cu-ATSM PET/CT as a predictor of response in head and neck cancer: a pilot study. Ann Nucl Med. 2011;25:339–45.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Dehdashti F, Mintun MA, Lewis JS, et al. In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM. Eur J Nucl Med Mol Imaging. 2003;30:844–50.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Lopci E, Grassi I, Rubello D, et al. Prognostic evaluation of disease outcome in solid tumors investigated with 64Cu-ATSM PET/CT. Clin Nucl Med. 2016;41:e87–92.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Barrio M, Czernin J, Fanti S, et al. The impact of SSTR-directed PET/CT on the management of patients with neuroendocrine tumor: A systematic review and meta-analysis. J Nucl Med. 2017;58:756–61.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Hanaoka H, Tominaga H, Yamada K, et al. Evaluation of (64)Cu-labeled DOTA-D-Phe(1)-Tyr (3)-octreotide ((64)Cu-DOTA-TOC) for imaging somatostatin receptor-expressing tumors. Ann Nucl Med. 2009;23:559–667.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Anderson CJ, Pajeau TS, Edwards WB, et al. In vitro and in vivo evaluation of copper-64-octreotide conjugates. J Nucl Med. 1995;36:2315–25.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Pfeifer A, Knigge U, Mortensen J, et al. Clinical PET of neuroendocrine tumors using 64Cu-DOTATATE: first-in-humans study. J Nucl Med. 2012;53:1207–15.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Pfeifer A, Knigge U, Binderup T, et al. 64Cu-DOTATATE PET for neuroendocrine tumors: a prospective head-to-head comparison with 111In-DTPA-octreotide in 112 patients. J Nucl Med. 2015;56:847–54.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Johnbeck CB, Knigge U, Loft A, et al. Head-to-head comparison of 64Cu-DOTATATE and 68Ga-DOTATOC PET/CT: a prospective study of 59 patients with neuroendocrine tumors. J Nucl Med. 2017;58:451–7.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Bahri H, Laurence L, Edeline J, et al. High prognostic value of 18F-FDG PET for metastatic gastroenteropancreatic neuroendocrine tumors: a long-term evaluation. J Nucl Med. 2014;55:1786–90.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Bhatkar D, Utpat K, Basu S, et al. Dual tracer PET imaging (68Ga-DOTATATE and 18F-FDG) features in pulmonary carcinoid: correlation with tumor proliferation index. Indian J Nucl Med. 2017;32:39–41.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Pedersen SF, Sandholt BV, Keller SH, et al. 64Cu-DOTATATE PET/MRI for detection of activated macrophages in carotid atherosclerotic plaques: studies in patients undergoing endarterectomy. Arterioscler Thromb Vasc Biol. 2015;35:1696–703.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Ferdinando Calabria
    • 1
    Email author
  • Antonio Bagnato
    • 1
  • Vincenzo Gangemi
    • 2
  • Rosina Paonessa
    • 2
  • Mario Leporace
    • 1
  • Nicoletta Urbano
    • 3
  • Giuseppe Lucio Cascini
    • 2
  1. 1.Department of Nuclear Medicine and Theranostics“Mariano Santo” HospitalCosenzaItaly
  2. 2.Nuclear Medicine Unit, Department of Diagnostic Imaging“Magna Graecia” UniversityCatanzaroItaly
  3. 3.Nuclear Medicine UnitUniversity Hospital “Tor Vergata”RomeItaly

Personalised recommendations