The Radiopharmaceutical Chemistry of the Radioisotopes of Copper

  • Xiaoxi Ling
  • Cathy S. Cutler
  • Carolyn J. AndersonEmail author


There are five radioisotopes of copper that are suitable for use in nuclear imaging or targeted radionuclide therapy: copper-67, copper-64, copper-62, copper-61, and copper-60. The diverse nuclear properties of these radionuclides include half-lives ranging from 10 min to 62 h and decay pathways via positron (β+) and beta-minus (β) emission. Single-photon emission computed tomography (SPECT) as well as radionuclide therapy can be performed using copper-67, while the quartet of other radioisotopes decays via positron emission for positron emission tomography (PET). Two current foci of research into the radiopharmaceutical chemistry of copper are the creation of new coordination architectures for the radiometal and the development of relatively simple radiolabeling techniques that will lead to agents that remain stable in vivo. This chapter will discuss the production of the various radionuclides, the development of chelators for copper(II), and the applications of copper radiopharmaceuticals in both imaging and therapy.


Copper radionuclides (production) Copper radiopharmaceuticals Macrocyclic chelators Copper bis(thiosemicarbazones) Copper-64 PET imaging Hypoxia imaging 



Alzheimer’s disease


Amyotrophic lateral sclerosis


4-((8-Amino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosan-1-yl)amino)benzoic acid





Brookhaven Linac Isotope Producer


Brookhaven National Laboratory








1,4,8,11-Tetraazabicyclo[6.6.2]hexadecane-4-acetic acid-11-methylphosphonic acid


1,4,8,11-Tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid


Computed tomography


1,8-Diamino-3,6,10,13,16,19- hexaazabicyclo[6,6,6]-eicosane


1,4,7,10-Tetraazacyclododecane-1,4-7,10-tetraacetic acid


Standard reduction potentials


Ethylenediaminetetraacetic acid


Ethylglyoxal bis(thiosemicarbazone)


1-(5-Fluoro-5-deoxy-α-D- arabinofuranosyl)-2-nitroimidazole




Facility for Rare Isotope Beams








Kilo-electron volts (103)


Los Alamos National Lab


Monoclonal antibody


5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid


Mega-electron volts (106)


Miniaturized positron emission tomography




Michigan State University


1-(1,3-Carboxypropyl)-4,7- dicarboxymethyl-1,4,7-triazacyclononane


1,4,7-Tricarboxymethyl-1,4,7- triazacyclononane


National Superconducting Cyclotron Laboratory


1-[(1,4,7,10,13-Pentaazacyclopentaadec-1-yl)methyl]benzoic acid


1,4,8,11-Tetraazabicyclo[6.6.3]heptadecane-4,11-diacetic acid


Polyethylene glycol


Positron emission tomography


Potential of hydrogen


Pyruvaldehyde-bis(N4- methylthiosemicarbazone)






Superoxide dismutase 1


Single-photon emission computed tomography


Somatostatin receptor




1,4,8,11-Tetraazacyclotetradecane-1,4-biacetic acid


1,4,8,11-Tetraazacyclotetradecane-1,8-biacetic acid


1,4,8,11-Tetraazacyclotetradecane-1,4,8,11-tetraacetic acid




  1. 1.
    Bases R, Brodie SS, Rubenfeld S. Attempts at tumor localization using Cu 64-labeled copper porphyrins. Cancer. 1958;11(2):259–63.PubMedCrossRefGoogle Scholar
  2. 2.
    Raynaud C, Comar D, Dutheil M, Blanchon P, Monod O, Parrot R, Rymer M. Lung cancer diagnosis with 67Cu: preliminary results. J Nucl Med. 1973;14(12):947–50.PubMedGoogle Scholar
  3. 3.
    Kilian K, Pegier M, Pyrzynska K. The fast method of Cu-porphyrin complex synthesis for potential use in positron emission tomography imaging. Spectrochim Acta A Mol Biomol Spectrosc. 2016;159:123–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Shi J, Liu TW, Chen J, Green D, Jaffray D, Wilson BC, Wang F, Zheng G. Transforming a targeted porphyrin theranostic agent into a PET imaging probe for cancer. Theranostics. 2011;1:363–70.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Chakravarty R, Chakraborty S, Dash A. (64)Cu(2+) Ions as PET Probe: An emerging paradigm in molecular imaging of cancer. Mol Pharm. 2016;13(11):3601–12.PubMedCrossRefGoogle Scholar
  6. 6.
    Piccardo A, Paparo F, Puntoni M, Righi S, Bottoni G, Bacigalupo L, et al. (64)CuCl2 PET/CT in prostate cancer relapse. J Nucl Med. 2018;59(3):444–51.PubMedCrossRefGoogle Scholar
  7. 7.
    Hordyjewska A, Popiolek L, Kocot J. The many “faces” of copper in medicine and treatment. Biometals. 2014;27(4):611–21.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Uriu-Adams JY, Keen CL. Copper, oxidative stress, and human health. Mol Asp Med. 2005;26(4–5):268–98.CrossRefGoogle Scholar
  9. 9.
    Owen CA. Wilson’s disease: The etiology, clinical aspects, and treatment of inherited copper toxicosis (Coppyer in biology and medicine series). Noyes: Park Ridge; 1981.Google Scholar
  10. 10.
    Owen CA. Biochemical aspects of copper: Copper proteins, ceruloplasmin, and copper protein binding. Noyes: Park Ridge; 1982.Google Scholar
  11. 11.
    Osborn SB, Walshe JM. Studies with radioactive copper (64Cu and 67Cu) in relation to the natural history of Wilson’s disease. Lancet. 1967;1(7486):346–50.PubMedCrossRefGoogle Scholar
  12. 12.
    Delhez H, Prins HW, Prinsen L, van den Hamer CJ. Autoradiographic demonstration of the copper-accumulating tissues in mice with a defect homologous to Menkes’ Kinky Hair disease. Pathol Res Pract. 1983;178(1):48–50.PubMedCrossRefGoogle Scholar
  13. 13.
    Dasgupta AK, Mausner LF, Srivastava SC. A new separation for 67Cu from proton irradiated Zn. Appl Radiat Isot. 1991;42:371–6.CrossRefGoogle Scholar
  14. 14.
    Mirzadeh S, Mausner LF, Srivastava SC. Production of no-carrier added 67Cu. Int J Rad Appl Instrum A. 1986;37(1):29–36.PubMedCrossRefGoogle Scholar
  15. 15.
    Novak-Hofer I, Schubiger AP. Copper-67 as a therapeutic nuclide for radioimmunotherapy. Eur J Nucl Med Mol Imaging. 2002;29(6):821–30.PubMedCrossRefGoogle Scholar
  16. 16.
    Mausner LF, Kolsky KL, Joshi V, Srivastava SC. Radionuclide development at BNL for nuclear medicine therapy. Appl Radiat Isot. 1998;49(4):285–94.PubMedCrossRefGoogle Scholar
  17. 17.
    Mastren T, Pen A, Loveless S, Marquez BV, Bollinger E, Marois B, et al. Harvesting (67)Cu from the collection of a secondary beam cocktail at the National Superconducting Cyclotron Laboratory. Anal Chem. 2015;87(20):10323–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Mastren T, Pen A, Peaslee GF, Wozniak N, Loveless S, Essenmacher S, et al. Feasibility of isotope harvesting at a projectile fragmentation facility: (6)(7)Cu. Sci Rep. 2014;4:6706.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Zinn KR, Chaudhuri TR, Cheng TP, Morris JS, Meyer WA. Production of no-carrier-added Cu-64 from zinc metal irradiated under boron shielding. Cancer. 1994;73(3):774–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Smith SV, Waters DJ, Di Bartolo N. Separation of 64Cu from 67Ga waste products using anion exchange and low acid aqueous/organic mixtures. Radiochim Acta. 1997;75:65–8.Google Scholar
  21. 21.
    McCarthy DW, Shefer RE, Klinkowstein RE, Bass LA, Margeneau WH, Cutler CS, et al. Efficient production of high specific activity 64Cu using a biomedical cyclotron. Nucl Med Biol. 1997;24(1):35–43.PubMedCrossRefGoogle Scholar
  22. 22.
    Szelecsenyi F, Blessing G, Qaim SM. Excitation function of proton induced nuclear reactions on enriched 61Ni and 64Ni: possibility of production of no-carrier-added 61Cu and 64Cu at a small cyclotron. Appl Radiat Isot. 1993;44:575–80.CrossRefGoogle Scholar
  23. 23.
    McCarthy DW, Bass LA, Cutler PD, Shefer RE, Klinkowstein RE, Herrero P, et al. High purity production and potential applications of copper-60 and copper-61. Nucl Med Biol. 1999;26(4):351–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Obata A, Kasamatsu S, McCarthy DW, Welch MJ, Saji H, Yonekura Y, Fujibayashi Y. Production of therapeutic quantities of 64Cu using a 12 MeV cyclotron. Nucl Med Biol. 2003;30:535–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Zeissler SK, Pavan RA, Orzechowski J, Langlois R, Rodrigue S, van Lier JE. Production of 64Cu on the sherbrooke TR-PET cyclotron. J Radioanal Nucl Chem. 2003;257:175–7.CrossRefGoogle Scholar
  26. 26.
    Avila-Rodriguez MA, Nye JA, Nickles RJ. Simultaneous production of high specific activity 64Cu and 61Co with 11.4 MeV protons on enriched 64Ni nuclei. Appl Radiat Isot. 2007;65(10):1115–20.PubMedCrossRefGoogle Scholar
  27. 27.
    Lewis JS, Welch MJ, Tang L. Workshop on the production, application and clinical translation of “non-standard” PET nuclides: a meeting report. Q J Nucl Med Mol Imaging. 2008;52(2):101–6.PubMedGoogle Scholar
  28. 28.
    Szajek LP, Meyer W, Plascjak P, Eckleman WC. Semi-remote production of [64Cu]CuCl2 and preparation of high specific activity [64Cu]Cu-ATSM for PET studies. Radiochim Acta. 2005;93(4):239–44.CrossRefGoogle Scholar
  29. 29.
    Dehdashti F, Grigsby PW, Mintun MA, Lewis JS, Siegel BA, Welch MJ. Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: relationship to therapeutic response-a preliminary report. Int J Radiat Oncol Biol Phys. 2003;55(5):1233–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Lewis JS, Laforest R, Dehdashti F, Grigsby PW, Welch MJ, Siegel BA. An imaging comparison of 64Cu-ATSM and 60Cu-ATSM in cancer of the uterine cervix. J Nucl Med. 2008;49(7):1177–82.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Robinson GD, Zielinski FW, Lee AW. The zinc-62/copper-62 generator: A convenient source of copper-62 for radiopharmaceuticals. Int J Appl Radiat Isot. 1980;31:111–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Green MA, Mathias CJ, Welch MJ, McGuire AH, Perry D, Fernandez-Rubio F, et al. Copper-62-labeled pyruvaldehyde bis(N4-methylthiosemicarbazonato)copper(II): Synthesis and evaluation as a positron emission tomography tracer for cerebral and myocardial perfusion. J Nucl Med. 1990;31(12):1989–96.PubMedGoogle Scholar
  33. 33.
    Ng Y, Lacy JL, Fletcher JW, Green MA. Performance of a (6)(2)Zn/(6)(2)Cu microgenerator in kit-based synthesis and delivery of [(6)(2)Cu]Cu-ETS for PET perfusion imaging. Appl Radiat Isot. 2014;91:38–43.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Fujibayashi Y, Matsumoto K, Yonekura Y, Konishi J, Yokayama A. A new zinc-62/copper-62 generator as a copper-62 source for PET radiopharmaceuticals. J Nucl Med. 1989;30(11):1838–42.PubMedGoogle Scholar
  35. 35.
    Fukumura T, Okada K, Suzuki H, Nakao R, Mukai K, Szelecsenyi F, et al. Improved 62Zn/62Cu generator based on a cation exchanger and its fully remote-controlled preparation for clinical use. Nucl Med Biol. 2006;33(6):821–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Zhao Y, Sultan D, Detering L, Luehmann H, Liu Y. Facile synthesis, pharmacokinetic and systemic clearance evaluation, and positron emission tomography cancer imaging of 64Cu–Au alloy nanoclusters. Nanoscale. 2041;6(22):13501–9.CrossRefGoogle Scholar
  37. 37.
    Linder MC. Biochemistry of copper, Vol 10. Biochemistry of the elements. New York: Plenum Press; 1991.CrossRefGoogle Scholar
  38. 38.
    Linder MC, Hazegh-Azam M. Copper biochemistry and molecular biology. Am J Clin Nutr. 1996;63(Suppl):797s–811s.PubMedGoogle Scholar
  39. 39.
    Frieden E. Perspectives on copper biochemistry. Clin Physiol Biochem. 1986;4(1):11–9.PubMedGoogle Scholar
  40. 40.
    Levitzki A, Anbar M. Formation of the bis(biuretat0)-complex of tervalent copper and its redox potential. Chem Commun (London). 1968;403a.Google Scholar
  41. 41.
    Price EW, Orvig C. Matching chelators to radiometals for radiopharmaceuticals. Chem Soc Rev. 2014;43(1):260–90.PubMedCrossRefGoogle Scholar
  42. 42.
    Panichelli P, Villano C, Cistaro A, Bruno A, Barbato F, Piccardo A, Duatti A. Imaging of brain tumors with copper-64 chloride: early experience and results. Cancer Biother Radiopharm. 2016;31(5):159–67.PubMedCrossRefGoogle Scholar
  43. 43.
    Guo W, Sun X, Jacobson O, Yan X, Min K, Srivatsan A, et al. Radioactive [64Cu]CuInS/ZnS quantum dots for PET and optical imaging: improved radiochemical stability and controllable cerenkov luminescence. ACS Nano. 2015;9(1):488–95.PubMedCrossRefGoogle Scholar
  44. 44.
    Beaino W, Anderson CJ. PET imaging of very late antigen-4 in melanoma: comparison of 68Ga- and 64Cu-labeled NODAGA and CB-TE1A1P-LLP2A conjugates. J Nucl Med. 2014;55(11):1856–63.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Paterson BM, Donnelly PS. Copper complexes of bis(thiosemicarbazones): from chemotherapeutics to diagnostic and therapeutic radiopharmaceuticals. Chem Soc Rev. 2011;40(5):3005–18.PubMedCrossRefGoogle Scholar
  46. 46.
    Vāvere AL, Lewis JS. Cu–ATSM: a radiopharmaceutical for the PET imaging of hypoxia. Dalton Trans. 2007;(43):4893–902.CrossRefGoogle Scholar
  47. 47.
    Petering HG, Buskirk HH, Underwood GE. The anti-tumor activity of 2-keto-3-ethoxybutyraldehyde bis(thiosemicarbazone) and related compounds. Cancer Res. 1964;24:367–72.PubMedGoogle Scholar
  48. 48.
    Mathias CJ, Welch MJ, Raichle ME, Mintun MA, Lich LL, McGuire AH, et al. Evaluation of a potential generator-produced PET tracer for cerebral perfusion imaging: single-pass cerebral extraction measurements and imaging with radiolabeled Cu-PTSM. J Nucl Med. 1990;31(3):352–9.Google Scholar
  49. 49.
    Okazawa H, Fujibayashi Y, Yonekura Y, Tamaki N, Nishizawa S, Magata Y, et al. Clinical application of 62Zn/62Cu positron generator: perfusion and plasma pool images in normal subjects. Ann Nucl Med. 1995;9(2):81–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Taniuchi H, Fujibayashi Y, Okazawa H, Yonekura Y, Konishi J, Yokoyama A. Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM), a metal complex with selective NADH-dependent reduction by complex I in brain mitochondria: a potential radiopharmaceutical for mitochondria-functional imaging with positron emission tomography (PET). Biol Pharm Bull. 1995;18(8):1126–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Okazawa H, Yonekura Y, Fujibayashi Y, Mukai T, Nishizawa S, Magata Y, et al. Measurement of regional cerebral blood flow with copper-62-PTSM and a three-compartment model. J Nucl Med. 1996;37(7):1089–93.PubMedGoogle Scholar
  52. 52.
    Okazawa H, Yonekura Y, Fujibayashi Y, Nishizawa S, Magata Y, Ishizu K, et al. Clinical application and quantitative evaluation of generator-produced copper-62-PTSM as a brain perfusion tracer for PET. J Nucl Med. 1994;35(12):1910–5.PubMedGoogle Scholar
  53. 53.
    Green MA. A potential copper radiopharmaceutical for imaging the heart and brain: copper-labeled pyruvaldehyde bis(N4-methylthiosemicarbazone). Nucl Med Biol. 1987;14:59–61.Google Scholar
  54. 54.
    Beanlands RS, Muzik O, Mintun M, Mangner T, Lee K, Petry N, et al. The kinetics of copper-62-PTSM in the normal human heart. J Nucl Med. 1992;33(5):684–90.PubMedGoogle Scholar
  55. 55.
    Tadamura E, Tamaki N, Okazawa H, Fujibayashi Y, Kudoh T, Yonekura Y, et al. Generator-produced copper-62-PTSM as a myocardial PET perfusion tracer compared with nitrogen-13-ammonia. J Nucl Med. 1996;37(5):729–35.PubMedGoogle Scholar
  56. 56.
    Mathias CJ, Welch MJ, Perry DJ, McGuire AH, Zhu X, Connett JM, Green MA. Investigation of copper-PTSM as a PET tracer for tumor blood flow. Nucl Med Biol. 1991;18:807–11.Google Scholar
  57. 57.
    Acevedo KM, Hayne DJ, McInnes LE, Noor A, Duncan C, Moujalled D, et al. Effect of structural modifications to glyoxal-bis(thiosemicarbazonato)copper(II) complexes on cellular copper uptake, copper-mediated ATP7A Trafficking, and P-glycoprotein mediated efflux. J Med Chem. 2018;61(3):711–23.PubMedCrossRefGoogle Scholar
  58. 58.
    Fodero-Tavoletti MT, Villemagne VL, Paterson BM, White AR, Li Q-X, Camakaris J, et al. Bis (thiosemicarbazonato) Cu-64 complexes for positron emission tomography imaging of Alzheimer’s disease. J Alzheimers Dis. 2010;20(1):49–55.PubMedCrossRefGoogle Scholar
  59. 59.
    Torres JB, Andreozzi EM, Dunn JT, Siddique M, Szanda I, Howlett DR, et al. PET imaging of copper trafficking in a mouse model of Alzheimer disease. J Nucl Med. 2016;57(1):109–14.PubMedCrossRefGoogle Scholar
  60. 60.
    Cowley AR, Dilworth JR, Donnelly PS, Labisbal E, Sousa A. An unusual dimeric structure of a cu(i) bis(thiosemicarbazone) complex: implications for the mechanism of hypoxic selectivity of the Cu(II) derivatives. J Am Chem Soc. 2002;124(19):5270–1.PubMedCrossRefGoogle Scholar
  61. 61.
    Fujibayashi Y, Cutler CS, Anderson CJ, McCarthy DW, Jones LA, Sharp T, et al. Comparative studies of Cu-64-ATSM and C-11-acetate in an acute myocardial infarction model: ex vivo imaging of hypoxia in rats. Nucl Med Biol. 1999;26(1):117–21.PubMedCrossRefGoogle Scholar
  62. 62.
    Lim S, Paterson BM, Fodero-Tavoletti MT, O’Keefe GJ, Cappai R, Barnham KJ, et al. A copper radiopharmaceutical for diagnostic imaging of Alzheimer’s disease: a bis(thiosemicarbazonato)copper(ii) complex that binds to amyloid-β plaques. Chem Commun. 2010;46(30):5437–9.Google Scholar
  63. 63.
    Hickey JL, Lim S, Hayne DJ, Paterson BM, White JM, Villemagne VL, et al. Diagnostic imaging agents for Alzheimer’s disease: copper radiopharmaceuticals that target Aβ plaques. J Am Chem Soc. 2013;135(43):16120–32.PubMedCrossRefGoogle Scholar
  64. 64.
    Cowley AR, Dilworth JR, Donnelly PS, Heslop JM, Ratcliffe SJ. Bifunctional chelators for copper radiopharmaceuticals: the synthesis of [Cu(ATSM)–amino acid] and [Cu(ATSM)–octreotide] conjugates. Dalton Trans. 2007;(2):209–17.CrossRefGoogle Scholar
  65. 65.
    Hueting R, Christlieb M, Dilworth JR, Garayoa EG, Gouverneur V, Jones MW, et al. Bis(thiosemicarbazones) as bifunctional chelators for the room temperature 64-copper labeling of peptides. Dalton Trans. 2010;39(15):3620–32.PubMedCrossRefGoogle Scholar
  66. 66.
    Bormans G, Janssen A, Adriaens P, Crombez D, Witsenboer A, De Goeij J, et al. A 62Zn/62Cu generator for the routine production of 62Cu-PTSM. Appl Radiat Isot. 1992;43:1437–41.CrossRefGoogle Scholar
  67. 67.
    Haynes NG, Lacy JL, Nayak N, Martin CS, Dai D, Mathias CJ, Green MA. Performance of a 62Zn/62Cu generator in clinical trials of PET perfusion agent 62Cu-PTSM. J Nucl Med. 2000;41(2):309–14.PubMedGoogle Scholar
  68. 68.
    Herrero P, Markham J, Weinheimer CJ, Anderson CJ, Welch MJ, Green MA, Bergmann SR. Quantification of regional myocardial perfusion with generator-produced 62Cu-PTSM and positron emission tomography. Circulation. 1993;87:173–83.PubMedCrossRefGoogle Scholar
  69. 69.
    Wallhaus TR, Lacy J, Whang J, Green MA, Nickles RJ, Stone CK. Human biodistribution and dosimetry of the PET perfusion agent 62Cu-PTSM from a compact modular 62Zn/62Cu generator. J Nucl Med. 1998;39(11):1958–64.PubMedGoogle Scholar
  70. 70.
    Herrero P, Hartman JJ, Green MA, Anderson CJ, Welch MJ, Markham J, Bergmann SR. Regional myocardial perfusion assessed with generator-produced copper-62-PTSM and PET. J Nucl Med. 1996;37(8):1294–300.PubMedGoogle Scholar
  71. 71.
    Mathias CJ, Bergmann SR, Green MA. Development and validation of a solvent extraction technique for determination of Cu-PTSM in blood. Nucl Med Biol. 1993;20(3):343–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Mathias CJ, Bergmann SR, Green MA. Species-dependent binding of copper(II) bis(thiosemicarbazone) radiopharmaceuticals to serum albumin. J Nucl Med. 1995;36(8):1451–5.PubMedGoogle Scholar
  73. 73.
    Green MA, Mathias CJ, Willis LR, Handa RK, Lacy JL, Miller MA, Hutchins GD. Assessment of Cu-ETS as a PET radiopharmaceutical for evaluation of regional renal perfusion. Nucl Med Biol. 2007;34(3):247–55.PubMedCrossRefGoogle Scholar
  74. 74.
    Basken NE, Mathias CJ, Lipka AE, Green MA. Species dependence of [64Cu]Cu-Bis(thiosemicarbazone) radiopharmaceutical binding to serum albumins. Nucl Med Biol. 2008;35(3):281–6.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Harris AL. Hypoxia – a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38–47.PubMedCrossRefGoogle Scholar
  76. 76.
    Rajendran JG, Krohn KA. F-18 fluoromisonidazole for imaging tumor hypoxia: imaging the microenvironment for personalized cancer therapy. Semin Nucl Med. 2015;45(2):151–62.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Bell C, Dowson N, Fay M, Thomas P, Puttick S, Gal Y, Rose S. Hypoxia imaging in gliomas with 18F-fluoromisonidazole PET: toward clinical translation. Semin Nucl Med. 2015;45(2):136–50.PubMedCrossRefGoogle Scholar
  78. 78.
    Tran LB, Bol A, Labar D, Jordan B, Magat J, Mignion L, et al. Hypoxia imaging with the nitroimidazole 18F-FAZA PET tracer: a comparison with OxyLite, EPR oximetry and 19F-MRI relaxometry. Radiother Oncol. 2012;105(1):29–35.PubMedCrossRefGoogle Scholar
  79. 79.
    Maurer RI, Blower PJ, Dilworth JR, Reynolds CA, Zheng Y, Mullen GE. Studies on the mechanism of hypoxic selectivity in copper bis(thiosemicarbazone) radiopharmaceuticals. J Med Chem. 2002;45(7):1420–31.PubMedCrossRefGoogle Scholar
  80. 80.
    Blower PJ, Castle TC, Cowley AR, Dilworth JR, Donnelly PS, Labisbal E, Sowrey FE, Teat SJ, Went MJ. Structural trends in copper(ii) bis(thiosemicarbazone) radiopharmaceuticals. Dalton Trans. 2003;(23):4416–25.Google Scholar
  81. 81.
    Xiao Z, Donnelly PS, Zimmermann M, Wedd AG. Transfer of copper between bis(thiosemicarbazone) ligands and intracellular copper-binding proteins. insights into mechanisms of copper uptake and hypoxia selectivity. Inorg Chem. 2008;47(10):4338–47.PubMedCrossRefGoogle Scholar
  82. 82.
    Waghorn PA, Jones MW, Theobald MB, Arrowsmith RL, Pascu SI, Botchway SW. Shining light on the stability of metal thiosemicarbazonate complexes in living cells by FLIM. Chem Sci. 2013;4(4):1430.CrossRefGoogle Scholar
  83. 83.
    Grigsby PW, Malyapa RS, Higashikubo R, Schwarz JK, Welch MJ, Huettner PC, Dehdashti F. Comparison of molecular markers of hypoxia and imaging with (60)Cu-ATSM in cancer of the uterine cervix. Mol Imaging Biol. 2007;9(5):278–83.PubMedCrossRefGoogle Scholar
  84. 84.
    Tateishi K, Tateishi U, Sato M, Yamanaka S, Kanno H, Murata H, et al. Application of 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) PET imaging to predict highly malignant tumor grades and hypoxia-inducible factor-1alpha expression in patients with glioma. AJNR Am J Neuroradiol. 2013;34(1):92–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Nie X, Laforest R, Elvington A, Randolph GJ, Zheng J, Voller T, et al. PET/MRI of hypoxic atherosclerosis using 64Cu-ATSM in a Rabbit model. J Nucl Med. 2015;57(12):2006–11.CrossRefGoogle Scholar
  86. 86.
    Nie X, Randolph GJ, Elvington A, Bandara N, Zheleznyak A, Gropler RJ, et al. Imaging of hypoxia in mouse atherosclerotic plaques with (64)Cu-ATSM. Nucl Med Biol. 2016;43(9):534–42.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Bourgeois M, Rajerison H, Guerard F, Mougin-Degraef M, Barbet J, Michel N, et al. Contribution of [64Cu]-ATSM PET in molecular imaging of tumour hypoxia compared to classical [18F]-MISO—a selected review. Nucl Med Rev. 2011;14(2):90–5.CrossRefGoogle Scholar
  88. 88.
    Moi MK, Meares CF, McCall MJ, Cole WC, DeNardo SJ. Copper chelates as probes of biological systems: stable copper complexes with a macrocyclic bifunctional chelating agent. Anal Biochem. 1985;148(1):249–53.PubMedCrossRefGoogle Scholar
  89. 89.
    Wadas TJ, Wong EH, Weisman GR, Anderson CJ. Coordinating radiometals of copper, gallium, indium, yttrium, and zirconium for PET and SPECT imaging of disease. Chem Rev. 2010;110(5):2858–902.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Wadas TJ, Anderson CJ. Radiolabeling of TETA- and CB-TE2A-conjugated peptides with copper-64. Nat Protoc. 2006;1(6):3062–8.PubMedCrossRefGoogle Scholar
  91. 91.
    Sprague JE, Li WP, Liang K, Achilefu S, Anderson CJ. In vitro and in vivo investigation of matrix metalloproteinase expression in metastatic tumor models. Nucl Med Biol. 2006;33(2):227–37.PubMedCrossRefGoogle Scholar
  92. 92.
    Chen X, Sievers E, Hou Y, Park R, Tohme M, Bart R, et al. Integrin alpha v beta 3-targeted imaging of lung cancer. Neoplasia. 2005;7(3):271–9.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Boswell CA, Sun X, Niu W, Weisman GR, Wong EH, Rheingold AL, Anderson CJ. Comparative in vivo stability of copper-64-labeled cross-bridged and conventional tetraazamacrocyclic complexes. J Med Chem. 2004;47(6):1465–74.PubMedCrossRefGoogle Scholar
  94. 94.
    Riesen A, Zehnder M, Kaden TA. Metal complexes of macrocyclic ligands. Part XXIII. Synthesis, properties, and structures of mononuclear complexes with 12- and 14-membered tetraazamacrocycle-N,N′,N″,N‴-tetraacetic acids. Helv Chim Acta. 1986;69(8):2067–73.CrossRefGoogle Scholar
  95. 95.
    Tonei DM, Ware DC, Brothers PJ, Plieger PG, Clark GR. Coordination chemistry of 1,4-bis-carboxymethylcyclam, H2(1,4-bcc). Dalton Trans. 2006;(1):152–8.CrossRefGoogle Scholar
  96. 96.
    Chapman J, Ferguson G, Gallagher JF, Jennings MC, Parker D. Copper and nickel complexes of 1,8-disubstituted derivatives of 1,4,8,11-tetraazacyclotetradecane. Dalton Trans. 1992;(3):345–53.CrossRefGoogle Scholar
  97. 97.
    Pandya DN, Kim JY, Park JC, Lee H, Phapale PB, Kwak W, et al. Revival of TE2A; a better chelate for Cu(II) ions than TETA? Chem Commun. 2010;46(20):3517–9.Google Scholar
  98. 98.
    Bailly C, Gouard S, Lacombe M, Remaud-Le Saec P, Chalopin B, Bourgeois M, et al. Comparison of immuno-PET of CD138 and PET imaging with (64)CuCl2 and (18)F-FDG in a preclinical syngeneic model of multiple myeloma. Oncotarget. 2018;9(10):9061–72.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Watanabe H, Kawasaki A, Sano K, Ono M, Saji H. Synthesis and evaluation of copper-64 labeled benzofuran derivatives targeting β-amyloid aggregates. Bioorg Med Chem. 2016;24(16):3618–23.PubMedCrossRefGoogle Scholar
  100. 100.
    Sargeson AM. The potential for the cage complexes in biology. Coord Chem Rev. 1996;151:89–114.CrossRefGoogle Scholar
  101. 101.
    Di Bartolo NM, Sargeson AM, Donlevy TM, Smith SV. Synthesis of a new cage ligand, SarAR, and its complexation with selected transition metal ions for potential use in radioimaging. J Chem Soc Dalton Trans. 2001;(15):2303–9.Google Scholar
  102. 102.
    Wei L, Ye Y, Wadas TJ, Lewis JS, Welch MJ, Achilefu S, Anderson CJ. (64)Cu-labeled CB-TE2A and diamsar-conjugated RGD peptide analogs for targeting angiogenesis: comparison of their biological activity. Nucl Med Biol. 2009;36(3):277–85.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Cai H, Fissekis J, Conti PS. Synthesis of a novel bifunctional chelator AmBaSar based on sarcophagine for peptide conjugation and (64)Cu radiolabelling. Dalton Trans. 2009;(27):5395–400.Google Scholar
  104. 104.
    Cai H, Li Z, Huang CW, Shahinian AH, Wang H, Park R, Conti PS. Evaluation of copper-64 labeled AmBaSar conjugated cyclic RGD peptide for improved microPET imaging of integrin alphavbeta3 expression. Bioconjug Chem. 2010;21(8):1417–24.PubMedCrossRefGoogle Scholar
  105. 105.
    Bernhardt PV, Bramley R, Engelhardt LM, Harrowfield JM, Hockless DCR, Korybut-Daszkiewicz BR, et al. Copper(II) Complexes of substituted macrobicyclic hexaamines: Combined trigonal and tetragonal distortions. Inorg Chem. 1995;34(14):3589–99.CrossRefGoogle Scholar
  106. 106.
    Paterson BM, Roselt P, Denoyer D, Cullinane C, Binns D, Noonan W, et al. PET imaging of tumours with a 64Cu labeled macrobicyclic cage amine ligand tethered to Tyr3-octreotate. Dalton Trans. 2014;43(3):1386–96.PubMedCrossRefGoogle Scholar
  107. 107.
    Paterson BM, Buncic G, McInnes LE, Roselt P, Cullinane C, Binns DS, et al. Bifunctional (64)Cu-labelled macrobicyclic cage amine isothiocyanates for immuno-positron emission tomography. Dalton Trans. 2015;44(11):4901–9.PubMedCrossRefGoogle Scholar
  108. 108.
    Dearling JL, Paterson BM, Akurathi V, Betanzos-Lara S, Treves ST, Voss SD, et al. The ionic charge of copper-64 complexes conjugated to an engineered antibody affects biodistribution. Bioconjug Chem. 2015;26(4):707–17.PubMedCrossRefGoogle Scholar
  109. 109.
    Sun X, Wuest M, Weisman GR, Wong EH, Reed DP, Boswell CA, et al. Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands. J Med Chem. 2002;45(2):469–77.PubMedCrossRefGoogle Scholar
  110. 110.
    Sprague JE, Peng Y, Sun X, Weisman GR, Wong EH, Achilefu S, Anderson CJ. Preparation and biological evaluation of copper-64-labeled tyr3-octreotate using a cross-bridged macrocyclic chelator. Clin Cancer Res. 2004;10(24):8674–82.PubMedCrossRefGoogle Scholar
  111. 111.
    Sprague JE, Kitaura H, Zou W, Ye Y, Achilefu S, Weilbaecher KN, et al. Noninvasive imaging of osteoclasts in parathyroid hormone-induced osteolysis using a 64Cu-labeled RGD peptide. J Nucl Med. 2007;48(2):311–8.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Hausner SH, Kukis DL, Gagnon MK, Stanecki CE, Ferdani R, Marshall JF, et al. Evaluation of [64Cu]Cu-DOTA and [64Cu]Cu-CB-TE2A chelates for targeted positron emission tomography with an alphavbeta6-specific peptide. Mol Imaging. 2009;8(2):111–21.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Dumont RA, Deininger F, Haubner R, Maecke HR, Weber WA, Fani M. Novel (64)Cu- and (68)Ga-labeled RGD conjugates show improved PET imaging of alpha(nu)beta(3) integrin expression and facile radiosynthesis. J Nucl Med. 2011;52(8):1276–84.PubMedCrossRefGoogle Scholar
  114. 114.
    Fani M, Del Pozzo L, Abiraj K, Mansi R, Tamma ML, Cescato R, et al. PET of somatostatin receptor-positive tumors using 64Cu- and 68Ga-somatostatin antagonists: the chelate makes the difference. J Nucl Med. 2011;52(7):1110–8.PubMedCrossRefGoogle Scholar
  115. 115.
    Shokeen M, Zheleznyak A, Wilson JM, Jiang M, Liu R, Ferdani R, et al. Molecular imaging of very late antigen-4 (alpha4beta1 integrin) in the premetastatic niche. J Nucl Med. 2012;53(5):779–86.PubMedCrossRefGoogle Scholar
  116. 116.
    Wong EH, Weisman GR, Hill DC, Reed DP, Rogers ME, Condon JS, et al. Synthesis and characterization of cross-bridged cyclams and pendant-armed derivatives and structural studies of their copper(II) complexes. J Am Chem Soc. 2000;122(43):10561–72.CrossRefGoogle Scholar
  117. 117.
    Woodin KS, Heroux KJ, Boswell CA, Wong EH, Weisman GR, Niu W, et al. Kinetic inertness and electrochemical behavior of copper(II) tetraazamacrocyclic complexes: Possible implications for in vivo stability. Eur J Inorg Chem. 2005;(23):4829–33.CrossRefGoogle Scholar
  118. 118.
    Ferdani R, Stigers DJ, Fiamengo AL, Wei L, Li BT, Golen JA, Rheingold AL, et al. Synthesis, Cu(II) complexation, 64Cu-labeling and biological evaluation of cross-bridged cyclam chelators with phosphonate pendant arms. Dalton Trans. 2012;41(7):1938–50.PubMedCrossRefGoogle Scholar
  119. 119.
    Guo Y, Ferdani R, Anderson CJ. Preparation and biological evaluation of (64)cu labeled tyr(3)-octreotate using a phosphonic Acid-based cross-bridged macrocyclic chelator. Bioconjug Chem. 2012;23(7):1470–7.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Hu LY, Bauer N, Knight LM, Li Z, Liu S, Anderson CJ, et al. Characterization and evaluation of (64)Cu-labeled A20FMDV2 conjugates for imaging the integrin αvβ 6. Mol Imaging Biol. 2014;16(4):567–77.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Cai Z, Ouyang Q, Zeng D, Nguyen K, Modi J, Wang L, et al. 64Cu-labeled somatostatin analogs conjugated with cross-bridged phosphonate-based chelators via strain-promoted click chemistry for PET imaging: in silico through in vivo studies. J Med Chem. 2014;57(14):6019–29.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Ocak M, Beaino W, White A, Zeng D, Cai Z, Anderson CJ. (64)Cu-labeled phosphonate cross-bridged chelator conjugates of c(RGDyK) for PET/CT imaging of osteolytic bone metastases. Cancer Biother Radiopharm. 2018;33(2):74–83.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Pandya DN, Dale AV, Kim JY, Lee H, Ha YS, An GI, Yoo J. New macrobicyclic chelator for the development of ultrastable 64Cu-radiolabeled bioconjugate. Bioconjug Chem. 2012;23(3):330–5.PubMedCrossRefGoogle Scholar
  124. 124.
    Dale AV, An GI, Pandya DN, Ha YS, Bhatt N, Soni N, et al. Synthesis and evaluation of new generation cross-bridged bifunctional chelator for (64)Cu radiotracers. Inorg Chem. 2015;54(17):8177–86.PubMedCrossRefGoogle Scholar
  125. 125.
    Sarkar S, Bhatt N, Ha YS, Huynh PT, Soni N, Lee W, et al. High in vivo stability of (64)Cu-labeled cross-bridged chelators is a crucial factor in improved tumor imaging of RGD peptide conjugates. J Med Chem. 2018;61(1):385–95.PubMedCrossRefGoogle Scholar
  126. 126.
    Pandya DN, Bhatt N, An GI, Ha YS, Soni N, Lee H, et al. Propylene cross-bridged macrocyclic bifunctional chelator: a new design for facile bioconjugation and robust (64)Cu complex stability. J Med Chem. 2014;57(17):7234–43.PubMedCrossRefGoogle Scholar
  127. 127.
    Burgman P, O’Donoghue JA, Lewis JS, Welch MJ, Humm JL, Ling CC. Cell line-dependent differences in uptake and retention of the hypoxia-selective nuclear imaging agent Cu-ATSM. Nucl Med Biol. 2005;32(6):623–30.PubMedCrossRefGoogle Scholar
  128. 128.
    Vāvere AL, Lewis JS. Examining the relationship between Cu-ATSM hypoxia selectivity and fatty acid synthase expression in human prostate cancer cell lines. Nucl Med Biol. 2008;35(3):273–9.PubMedCrossRefGoogle Scholar
  129. 129.
    Hueting R, Kersemans V, Cornelissen B, Tredwell M, Hussien K, Christlieb M, et al. A comparison of the behavior of (64)Cu-acetate and (64)Cu-ATSM in vitro and in vivo. J Nucl Med. 2014;55(1):128–34.PubMedCrossRefGoogle Scholar
  130. 130.
    Boschi A, Martini P, Janevik-Ivanovska E, Duatti A. The emerging role of copper-64 radiopharmaceuticals as cancer theranostics. Drug Discov Today. 2018; 23(8):1489–501.Google Scholar
  131. 131.
    Chatterjee S, Lesniak WG, Miller MS, Lisok A, Sikorska E, Wharram B, et al. Rapid PD-L1 detection in tumors with PET using a highly specific peptide. Biochem Biophys Res Commun. 2017;483(1):258–63.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Xiaoxi Ling
    • 1
  • Cathy S. Cutler
    • 2
  • Carolyn J. Anderson
    • 1
    Email author
  1. 1.Department of MedicineUniversity of PittsburghPittsburghUSA
  2. 2.Medical Isotope Research & Production (MIRP) Program, Collider Accelerator DepartmentBrookhaven National LaboratoryUptonUSA

Personalised recommendations