The Radiopharmaceutical Chemistry of Zirconium-89

  • Bernadette V. Marquez-Nostra
  • Nerissa ViolaEmail author


Over the past decade, the increasing availability of zirconium-89 has fueled a rise in the development and use of targeted positron emission tomography (PET) probes with relatively long serum half-lives, particularly radiolabeled antibodies. The stable coordination of 89Zr in radiopharmaceuticals is of critical importance to prevent its in vivo release and subsequent non-specific accumulation in nontarget organs, especially the bone. To date, the only chelator for 89Zr to be used in the clinic is the siderophore-derived desferrioxamine (DFO), though concerns persist regarding the in vivo stability of the [89Zr]Zr-DFO complex. In recent years, research into the development of alternative, more stable chelators for 89Zr has flourished. This chapter provides a general overview of zirconium-89, specifically its chemical properties, production, radiochemistry, and biomedical applications. Several examples of new chelators for 89Zr are discussed along with their strengths and weaknesses compared to DFO. Finally, a brief exploration of the future of 89Zr radiochemistry is included to provide the reader with awareness of the most recent progress in the field as well as what this relatively new positron-emitting radionuclide can offer going forward.


Zirconium-89 Desferrioxamine Antibody imaging ImmunoPET Bifunctional chelators 


  1. 1.
    Deri MA, Zeglis BM, Francesconi LC, Lewis JS. PET imaging with (8)(9)Zr: from radiochemistry to the clinic. Nucl Med Biol. 2013;40(1):3–14.PubMedCrossRefGoogle Scholar
  2. 2.
    Abou DS, Ku T, Smith-Jones PM. In vivo biodistribution and accumulation of 89Zr in mice. Nucl Med Biol. 2011;38(5):675–81.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Ulaner GA, Hyman DM, Ross DS, Corben A, Chandarlapaty S, Goldfarb S, et al. Detection of HER2-positive metastases in patients with HER2-negative primary breast cancer using 89Zr-trastuzumab PET/CT. J Nucl Med. 2016;57(10):1523–8.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Greenwood NN, Earnshaw A. Chemistry of the elements. 2nd ed. Oxford: Elsevier Butterworth-Heinemann; 1997.Google Scholar
  5. 5.
    Kozak CM, Mountford P. Zirconium & hafnium. Inorganic & coordination chemistry. In: King RB, editor. Encyclopedia of inorganic chemistry. 2nd ed. Chichester/West Sussex: Wiley; 2006.Google Scholar
  6. 6.
    Intorre BI, Martell AE. Zirconium complexes in aqueous solution. I. Reaction with multidentate ligands1. J Am Chem Soc. 1960;82(2):358–64.CrossRefGoogle Scholar
  7. 7.
    Intorre BJ, Martell AE. Aqueous zirconium complexes. II. Mixed chelates. J Am Chem Soc. 1961;83(17):3618–23.CrossRefGoogle Scholar
  8. 8.
    Ekberg C, Kallvenius G, Albinsson Y, Brown PL. Studies on the hydrolytic behavior of Zr(IV). J Solution Chem. 2004;33(1):47–79.CrossRefGoogle Scholar
  9. 9.
    Conti M, Eriksson L. Physics of pure and non-pure positron emitters for PET: a review and a discussion. EJNMMI Physics. 2016;3:8.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Moses WW. Fundamental limits of spatial resolution in PET. Nucl Instr Methods Phys Res A. 2011;648(Suppl 1):S236–S40.CrossRefGoogle Scholar
  11. 11.
    Disselhorst JA, Brom M, Laverman P, Slump CH, Boerman OC, Oyen WJ, et al. Image-quality assessment for several positron emitters using the NEMA NU 4-2008 standards in the Siemens Inveon small-animal PET scanner. J Nucl Med. 2010;51(4):610–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Link JM, Krohn KA, Eary JF, Kishore R, Lewellen TK, Johnson MW, et al. Zr-89 for antibody labeling and positron emission tomography. J Labelled Compd Radiopharm. 1986;23(10–12):1297–8.Google Scholar
  13. 13.
    Eary JF, Link JM, Kishore R, Johnson MW, Badger CC, Richter KY, et al. Production of positron emitting Zr89 for antibody imaging by PET. J Nucl Med. 1986;27(6):983.Google Scholar
  14. 14.
    Dejesus OT, Nickles RJ. Production and purification of Zr-89, a potential PET antibody label. Appl Radiat Isot. 1990;41(8):789–90.CrossRefGoogle Scholar
  15. 15.
    Meijs WE, Herscheid JDM, Haisma HJ, Wijbrandts R, Vanlangevelde F, Vanleuffen PJ, et al. Production of highly pure no-carrier added Zr-89 for the labeling of antibodies with a positron emitter. Appl Radiat Isot. 1994;45(12):1143–7.CrossRefGoogle Scholar
  16. 16.
    Holland JP, Sheh Y, Lewis JS. Standardized methods for the production of high specific-activity zirconium-89. Nucl Med Biol. 2009;36(7):729–39.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Wooten A, Madrid E, Schweitzer G, Lawrence L, Mebrahtu E, Lewis B, et al. Routine production of 89Zr using an automated module. Appl Sci. 2013;3(3):593.CrossRefGoogle Scholar
  18. 18.
    Queern SL, Aweda TA, Massicano AVF, Clanton NA, El Sayed R, Sader JA, et al. Production of Zr-89 using sputtered yttrium coin targets 89Zr using sputtered yttrium coin targets. Nucl Med Biol. 2017;50:11–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Pandey MK, Engelbrecht HP, Byrne JP, Packard AB, DeGrado TR. Production of 89Zr via the 89Y(p,n)89Zr reaction in aqueous solution: effect of solution composition on in-target chemistry. Nucl Med Biol. 2014;41(4):309–16.PubMedCrossRefGoogle Scholar
  20. 20.
    Verel I, Visser GW, Boellaard R, Stigter-van Walsum M, Snow GB, van Dongen GA. 89Zr immuno-PET: comprehensive procedures for the production of 89Zr-labeled monoclonal antibodies. J Nucl Med. 2003;44(8):1271–81.PubMedGoogle Scholar
  21. 21.
    Guerard F, Lee YS, Tripier R, Szajek LP, Deschamps JR, Brechbiel MW. Investigation of Zr(IV) and 89Zr(IV) complexation with hydroxamates: progress towards designing a better chelator than desferrioxamine B for immuno-PET imaging. Chem Commun (Camb). 2013;49(10):1002–4.CrossRefGoogle Scholar
  22. 22.
    Hoard JL, Glen GL, Silverton JV. The configuration of Zr(C2O4)4-4 and the stereochemistry of discrete eight-coordination. J Am Chem Soc. 1961;83(20):4293–5.CrossRefGoogle Scholar
  23. 23.
    Lin M, Mukhopadhyay U, Waligorski GJ, Balatoni JA, González-Lepera C. Semi-automated production of 89Zr-oxalate/89Zr-chloride and the potential of 89Zr-chloride in radiopharmaceutical compounding. Appl Radiat Isot. 2016;107(Supplement C):317–22.PubMedCrossRefGoogle Scholar
  24. 24.
    Bickel H, Gaeumann E, Keller-Schierlein W, Prelog V, Vischer E, Wettstein A, Zaehner H. On iron-containing growth factors, sideramines, and their antagonists, the iron-containing antibiotics, sideromycins. Experientia. 1960;16:129–33. [Article in German]PubMedCrossRefGoogle Scholar
  25. 25.
    Bergeron RJ, McManis JS. Reagents for the stepwise functionalization of spermine. J Org Chem. 1988;53(13):3108–11.CrossRefGoogle Scholar
  26. 26.
    Perk LR, Vosjan MJ, Visser GW, Budde M, Jurek P, Kiefer GE, et al. P-Isothiocyanatobenzyl-desferrioxamine: a new bifunctional chelate for facile radiolabeling of monoclonal antibodies with zirconium-89 for immuno-PET imaging. Eur J Nucl Med Mol Imaging. 2010;37(2):250–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Vosjan MJ, Perk LR, Visser GW, Budde M, Jurek P, Kiefer GE, et al. Conjugation and radiolabeling of monoclonal antibodies with zirconium-89 for PET imaging using the bifunctional chelate p-isothiocyanatobenzyl-desferrioxamine. Nat Protoc. 2010;5(4):739–43.PubMedCrossRefGoogle Scholar
  28. 28.
    Marquez BV, Ikotun OF, Zheleznyak A, Wright B, Hari-Raj A, Pierce RA, et al. Evaluation of 89Zr-pertuzumab in breast cancer xenografts. Mol Pharm. 2014;11(11):3988–95.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Meijs WE, Haisma HJ, Klok RP, van Gog FB, Kievit E, Pinedo HM, et al. Zirconium-labeled monoclonal antibodies and their distribution in tumor-bearing nude mice. J Nucl Med. 1997;38(1):112–8.PubMedGoogle Scholar
  30. 30.
    Tinianow JN, Gill HS, Ogasawara A, Flores JE, Vanderbilt AN, Luis E, et al. Site-specifically 89Zr-labeled monoclonal antibodies for ImmunoPET. Nucl Med Biol. 2010;37(3):289–97.PubMedCrossRefGoogle Scholar
  31. 31.
    Houghton JL, Zeglis BM, Abdel-Atti D, Aggeler R, Sawada R, Agnew BJ, et al. Site-specifically labeled CA19.9-targeted immunoconjugates for the PET, NIRF, and multimodal PET/NIRF imaging of pancreatic cancer. Proc Natl Acad Sci U S A. 2015;112(52):15850–5.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Tavare R, McCracken MN, Zettlitz KA, Salazar FB, Olafsen T, Witte ON, et al. Immuno-PET of murine T cell reconstitution postadoptive stem cell transplantation using anti-CD4 and anti-CD8 cys-diabodies. J Nucl Med. 2015;56(8):1258–64.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Meijs WE, Herscheid JDM, Haisma HJ, Pinedo HM. Evaluation of desferal as a bifunctional chelating agent for labeling antibodies with Zr-89. Int J Rad Appl Instrum A. 1992;43(12):1443–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Zeglis BM, Lewis JS. The bioconjugation and radiosynthesis of 89Zr-DFO-labeled antibodies. J Vis Exp. 2015;96.Google Scholar
  35. 35.
    Kuda-Wedagedara ANW, Workinger JL, Nexo E, Doyle RP, Viola-Villegas N. (89)Zr-cobalamin PET tracer: synthesis, cellular uptake, and use for tumor imaging. ACS Omega. 2017;2(10):6314–20.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Bauman A, Valverde IE, Fischer CA, Vomstein S, Mindt TL. Development of 68Ga- and 89Zr-labeled exendin-4 as potential radiotracers for the imaging of insulinomas by PET. J Nucl Med. 2015;56(10):1569–74.PubMedCrossRefGoogle Scholar
  37. 37.
    Ferris TJ, Charoenphun P, Meszaros LK, Mullen GE, Blower PJ, Went MJ. Synthesis and characterisation of zirconium complexes for cell tracking with Zr-89 by positron emission tomography. Dalton Trans. 2014;43(39):14851–7.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Charoenphun P, Meszaros LK, Chuamsaamarkkee K, Sharif-Paghaleh E, Ballinger JR, Ferris TJ, et al. [(89)Zr]oxinate4 for long-term in vivo cell tracking by positron emission tomography. Eur J Nucl Med Mol Imaging. 2015;42(2):278–87.PubMedCrossRefGoogle Scholar
  39. 39.
    Asiedu KO, Koyasu S, Szajek LP, Choyke PL, Sato N. Bone marrow cell trafficking analyzed by (89)Zr-oxine positron emission tomography in a murine transplantation model. Clin Cancer Res. 2017;23(11):2759–68.PubMedCrossRefGoogle Scholar
  40. 40.
    Bansal A, Pandey MK, Demirhan YE, Nesbitt JJ, Crespo-Diaz RJ, Terzic A, et al. Novel (89)Zr cell labeling approach for PET-based cell trafficking studies. EJNMMI Res. 2015;5:19.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Zhang P, Yue Y, Pan D, Yang R, Xu Y, Wang L, et al. Pharmacokinetics study of Zr-89-labeled melanin nanoparticle in iron-overload mice. Nucl Med Biol. 2016;43(9):529–33.PubMedCrossRefGoogle Scholar
  42. 42.
    Boros E, Bowen AM, Josephson L, Vasdev N, Holland JP. Chelate-free metal ion binding and heat-induced radiolabeling of iron oxide nanoparticles. Chem Sci. 2015;6(1):225–36.PubMedCrossRefGoogle Scholar
  43. 43.
    Abou DS, Thorek DL, Ramos NN, Pinkse MW, Wolterbeek HT, Carlin SD, et al. (89)Zr-labeled paramagnetic octreotide-liposomes for PET-MR imaging of cancer. Pharm Res. 2013;30(3):878–88.PubMedCrossRefGoogle Scholar
  44. 44.
    Cheng L, Kamkaew A, Shen S, Valdovinos HF, Sun H, Hernandez R, et al. Facile preparation of multifunctional WS2 /WOx nanodots for chelator-free (89) Zr-labeling and in vivo PET imaging. Small. 2016;12(41):5750–8.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Chen F, Goel S, Valdovinos HF, Luo H, Hernandez R, Barnhart TE, et al. In vivo integrity and biological fate of chelator-free zirconium-89-labeled mesoporous silica nanoparticles. ACS Nano. 2015;9(8):7950–9.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Holland JP, Divilov V, Bander NH, Smith-Jones PM, Larson SM, Lewis JS. 89Zr-DFO-J591 for immunoPET of prostate-specific membrane antigen expression in vivo. J Nucl Med. 2010;51(8):1293–300.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Vugts DJ, Klaver C, Sewing C, Poot AJ, Adamzek K, Huegli S, et al. Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for (89)Zr-immuno-PET. Eur J Nucl Med Mol Imaging. 2017;44(2):286–95.PubMedCrossRefGoogle Scholar
  48. 48.
    Patra M, Bauman A, Mari C, Fischer CA, Blacque O, Haussinger D, Gasser G, Mindt TL. An octadentate bifunctional chelating agent for the development of stable zirconium-89 based molecular imaging probes. Chem Commun (Camb). 2014;50:11523–5.CrossRefGoogle Scholar
  49. 49.
    White DL, Durbin PW, Jeung N, Raymond KN. Specific sequestering agents for the actinides. 16. Synthesis and initial biological testing of polydentate oxohydroxypyridinecarboxylate ligands. J Med Chem. 1988;31(1):11–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Allott L, Da Pieve C, Meyers J, Spinks T, Ciobota DM, Kramer-Marek G, et al. Evaluation of DFO-HOPO as an octadentate chelator for zirconium-89. Chem Commun (Camb). 2017;53(61):8529–32.CrossRefGoogle Scholar
  51. 51.
    Deri MA, Ponnala S, Zeglis BM, Pohl G, Dannenberg JJ, Lewis JS, et al. Alternative chelator for (8)(9)Zr radiopharmaceuticals: radiolabeling and evaluation of 3,4,3-(LI-1,2-HOPO). J Med Chem. 2014;57(11):4849–60.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Deri MA, Ponnala S, Kozlowski P, Burton-Pye BP, Cicek HT, Hu C, et al. P-SCN-Bn-HOPO: a superior bifunctional chelator for (89)Zr immunoPET. Bioconjug Chem. 2015;26(12):2579–91.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Tinianow JN, Pandya DN, Pailloux SL, Ogasawara A, Vanderbilt AN, Gill HS, et al. Evaluation of a 3-hydroxypyridin-2-one (2,3-HOPO) based macrocyclic chelator for (89)Zr(4+) and its use for immunopet imaging of HER2 positive model of ovarian carcinoma in mice. Theranostics. 2016;6(4):511–21.CrossRefGoogle Scholar
  54. 54.
    Rousseau J, Zhang Z, Dias GM, Zhang C, Colpo N, Benard F, et al. Design, synthesis and evaluation of novel bifunctional tetrahydroxamate chelators for PET imaging of (89)Zr-labeled antibodies. Bioorg Med Chem Lett. 2017;27(4):708–12.PubMedCrossRefGoogle Scholar
  55. 55.
    Ma MT, Cullinane C, Imberti C, Baguna Torres J, Terry SY, Roselt P, et al. New tris(hydroxypyridinone) bifunctional chelators containing isothiocyanate groups provide a versatile platform for rapid one-step labeling and PET imaging with (68)Ga(3.). Bioconjug Chem. 2016;27(2):309–18.PubMedCrossRefGoogle Scholar
  56. 56.
    Ma MT, Meszaros LK, Paterson BM, Berry DJ, Cooper MS, Ma Y, et al. Tripodal tris(hydroxypyridinone) ligands for immunoconjugate PET imaging with (89)Zr(4+): comparison with desferrioxamine-B. Dalton Trans. 2015;44(11):4884–900.PubMedCrossRefGoogle Scholar
  57. 57.
    Knetsch PA, Zhai C, Rangger C, Blatzer M, Haas H, Kaeopookum P, et al. [(68)Ga]FSC-(RGD)3 a trimeric RGD peptide for imaging alphavbeta3 integrin expression based on a novel siderophore derived chelating scaffold-synthesis and evaluation. Nucl Med Biol. 2015;42(2):115–22.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Zhai C, Summer D, Rangger C, Franssen GM, Laverman P, Haas H, et al. Novel bifunctional cyclic chelator for (89)Zr labeling-radiolabeling and targeting properties of RGD conjugates. Mol Pharm. 2015;12(6):2142–50.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Boros E, Holland JP, Kenton N, Rotile N, Caravan P. Macrocycle-based hydroxamate ligands for complexation and immunoconjugation of (89)zirconium for positron emission tomography (PET) imaging. ChemPlusChem. 2016;81(3):274–81.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Pandya DN, Bhatt N, Yuan H, Day CS, Ehrmann BM, Wright M, et al. Zirconium tetraazamacrocycle complexes display extraordinary stability and provide a new strategy for zirconium-89-based radiopharmaceutical development. Chem Sci. 2017;8(3):2309–14.PubMedCrossRefGoogle Scholar
  61. 61.
    Bhatt NB, Pandya DN, Xu J, Tatum D, Magda D, Wadas TJ. Evaluation of macrocyclic hydroxyisophthalamide ligands as chelators for zirconium-89. PLoS One. 2017;12(6):e0178767.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Radiology and Biomedical ImagingPET Center, Yale UniversityNew HavenUSA
  2. 2.Department of OncologyKarmanos Cancer Institute, Wayne State UniversityDetroitUSA

Personalised recommendations