Zirconium in PET studies
Monoclonal antibodies in immuno-PET and other large-molecule imaging agents have relatively slow pharmacokinetics; at least hours or even several days after injection are required to reach optimal biodistribution and image contrast. Radionuclides 89Zr and 124I have optimal half-lives, 3.27 and 4.18 days, respectively, for labelling these compounds.
89Zr has high fraction of non-positron decays, and 99% of decays result in non-prompt high-energy gamma ray emission. Because of the high-energy gamma rays extensive shielding during radiotracer transport and handling is required. On the other hand, the non-positron decay gamma rays do not interfere with the detection of the coincident photons, which have relatively low energy, resulting in high image resolution (Fischer et al., 2013). Quantitative accuracy can be achieved even in multi-centre studies (Makris et al., 2014). In addition to PET, 89Zr can also be used for Cerenkov luminescence imaging.
Zirconium exists primarily as oxophilic Zr4+ cation, or ZrO2+ in water, forming colloidal and polymeric structures, and it tends to precipitate as oxides and hydroxides except in very low pH. When administered as citrate or oxalate, zirconium binds to plasma proteins in humans (Mealey, 1957; Severin et al., 2015), accumulates in the bone (Holland et al., 2009), and in mice is slowly cleared into urine (Abou et al., 2011). Well-chelated Zr4+, such as Zr-DFO, is cleared very quickly via kidneys (Meijs et al., 1997). Zr4+ administered as chloride or phosphate forms colloids and precipitates that tend to be excreted to bile or accumulate in the liver and spleen (Holland et al., 2009; Abou et al., 2011; Deri et al., 2013; Severin et al., 2015). When Zr4+ is not tightly chelated, it has a strong tendency to accumulate in calcified tissue in the bone, from where it is released only very slowly (Abou et al., 2011; Deri et al., 2013; Severin et al., 2015). This leads to increased radiation dose to the bone marrow, but may also increase nonspecific uptake in tumours and infected regions (Severin et al., 2015). When protein-bound Zr-chelates are internalized, zirconium tends to stay in the cells, increasing the image contrast at late times (Zhang et al., 2011).
Proteins have been usually labelled with 89Zr4+ via conjugated tris-hydroxamate-based chelating agents, such as a natural siderophore desferrioxamine B (DFO). DFO provides reasonably good chelating stability in vivo, but the release of free 89Zr4+ is still seen as progressive bone uptake during PET studies. New chelators with better in vivo stability are under development (Guérard et al., 2014; Zhai et al., 2015; Vugts et al., 2017; Pandya et al., 2017), resulting in less bone uptake, radiation burden, and nonspecific uptake.
Abou DS, Ku T, Smith-Jones PM. In vivo biodistribution and accumulation of 89Zr in mice. Nucl Med Biol. 2011; 38: 675-681.
Conti M, Eriksson L. Physics of pure and non-pure positron emitters for PET: a review and a discussion. EJNMMI Phys. 2016; 3(1): 8.
Deri MA, Zeglis BM, Francesconi LC, Lewis JS. PET imaging with 89Zr: from radiochemistry to the clinic. Nucl Med Biol. 2013; 40(1): 3-14.
Fischer G, Seibold U, Schirrmacher R, Wängler B, Wängler C. 89Zr, a radiometal nuclide with high potential for molecular imaging with PET: chemistry, applications and remaining challenges. Molecules 2013; 18(6): 6469-6490.
Guérard F, Lee YS, Brechbiel MW. Rational design, synthesis, and evaluation of tetrahydroxamic acid chelators for stable complexation of ZrIV. Chemistry 2014; 20(19): 5584-5591.
Holland JP, Sheh Y, Lewis JS. Standardized methods for the production of high specific-activity zirconium-89. Nucl Med Biol. 2009; 36: 729-739.
Jauw YW, Menke-van der Houven van Oordt CW, Hoekstra OS, Hendrikse NH, Vugts DJ, Zijlstra JM, Huisman MC, van Dongen GA. Immuno-positron emission tomography with zirconium-89-labeled monoclonal antibodies in oncology: what can we learn from initial clinical trials? Front Pharmacol. 2016; 7: 131.
Jødal L, Le Loirec C, Champion C. Positron range in PET imaging: non-conventional isotopes. Phys Med Biol. 2014; 59(23): 7419-7434.
Kasbollah A, Eu P, Cowell S, Deb P. Review on production of 89Zr in a medical cyclotron for PET radiopharmaceuticals. J Nucl Med Technol. 2013; 41(1): 35-41.
Lee DB, Roberts M, Bluchel CG, Odell RA. Zirconium: biomedical and nephrological applications. ASAIO J. 2010; 56: 550-556.
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: 317-322.
Makris NE, Boellaard R, Visser EP, de Jong JR, Vanderlinden B, Wierts R, van der Veen BJ, Greuter HJ, Vugts DJ, van Dongen GA, Lammertsma AA, Huisman MC. Multicenter harmonization of 89Zr PET/CT performance. J Nucl Med. 2014; 55(2): 264-267.
Meijs WE, Haisma HJ, Klok RP, van Gog FB, Kievit E, Pinedo HM, Herscheid JDM. Zirconium-labeled monoclonal antibodies and their distribution in tumor-bearing nude mice. J Nucl Med. 1997; 38: 112-118.
Pandya DN, Bhatt N, Yuan H, Day CS, Ehrmann BM, Wright M, Bierbach U, Wadas TJ. Zirconium tetraazamacrocycle complexes display extraordinary stability and provide a new strategy for zirconium-89-based radiopharmaceutical development. Chem Sci. 2017; 8(3): 2309-2314.
Severin GW, Engle JW, Barnhart TE, Nickles RJ. 89Zr radiochemistry for positron emission tomography. Med Chem. 2011; 7(5): 389-394.
Severin GW, Jørgensen JT, Wiehr S, Rolle A-M, Hansen AE, Maurer A, Hasenberg M, Pichler B, Kjær A, Jensen AI. The impact of weakly bound 89Zr on preclinical studies: non-specific accumulation in solid tumors and aspergillus infection. Nucl Med Biol. 2015; 42: 360-368.
van de Watering FC, Rijpkema M, Perk L, Brinkmann U, Oyen WJ, Boerman OC. Zirconium-89 labeled antibodies: a new tool for molecular imaging in cancer patients. Biomed Res Int. 2014; 203601. doi: 10.1155/2014/203601.
Van Dongen GA, Huisman MC, Boellaard R, Harry Hendrikse N, Windhorst AD, Visser GW, Molthoff CF, Vugts DJ. 89Zr-immuno-PET for imaging of long circulating drugs and disease targets: why, how and when to be applied? Q J Nucl Med Mol Imaging 2015; 59(1): 18-38.
Verel I, Visser GW, Boerman OC, van Eerd JE, Finn R, Boellaard R, Vosjan MJ, Stigter-van Walsum M, Snow GB, van Dongen GA. Long-lived positron emitters zirconium-89 and iodine-124 for scouting of therapeutic radioimmunoconjugates with PET. Cancer Biother Radiopharm. 2003; 18(4): 655-661.
Vugts DJ, Visser GW, van Dongen GA. 89Zr-PET radiochemistry in the development and application of therapeutic monoclonal antibodies and other biologicals. Curr Top Med Chem. 2013; 13(4): 446-457.
Vugts DJ, Klaver C, Sewing C, Poot AJ, Adamzek K, Huegli S, Mari C, Visser GW, Valverde IE, Gasser G, Mindt TL, van Dongen GA. Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for 89Zr-immuno-PET. Eur J Nucl Med Mol Imaging 2017; 44(2): 286-295.
Zhai C, Summer D, Rangger C, Franssen GM, Laverman P, Haas H, Petrik M, Haubner R, Decristoforo C. Novel bifunctional cyclic chelator for 89Zr labeling . radiolabeling and targeting properties of RGD conjugates. Mol Pharmaceutics 2015; 12: 2142-2150.
Zhang Y, Hong H, Cai W. PET tracers based on Zirconium-89. Curr Radiopharm. 2011; 4(2): 131-139.
Created at: 2017-06-21
Updated at: 2018-09-16
Written by: Vesa Oikonen