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 radiopharmaceutical 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; Bhatt et al., 2018), resulting in less bone uptake, radiation burden, and nonspecific uptake.

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Updated at: 2022-01-18
Created at: 2017-06-21
Written by: Vesa Oikonen