Salts of gallium isotopes 68 and 67 can be used for inflammation and cancer imaging with PET and SPECT, respectively. Gallium citrate or chloride is most often used, but dissolved Ga3+ ion acts as an analogue of ferric ion (Fe3+) and is quickly bound to transferrin, albumin, and some other plasma proteins, regardless of the anion. Neutrophil granulocytes contain lactoferrin, which also binds Ga3+. Transferrin-bound Ga3+ can be internalized via transferrin receptors and stored in tissues. Red blood cells do not bind Ga3+.
Plasma protein bound Ga3+ enters interstitial space in tissues more easily if endothelial junctions of capillaries are loosened because of inflammation or tumour growth. Also leukocytes migrate to the sites of inflammation, and degranulation of neutrophils releases lactoferrin to the extracellular space; lymphocytes have lactoferrin-binding surface receptors. Ga3+ also binds to the siderophore molecules of bacteria and fungi. Therefore increased [68Ga]Ga3+ and [67Ga]Ga3+ uptake can be seen in both infected and inflamed tissue (Tsan, 1985).
[68Ga]Ga3+ in rats is slowly cleared from circulation mainly into the urine, with some retention in the liver and kidneys. Concentration in blood plasma stays at relatively high level. (Autio et al., 2015).
[68Ga]Ga3+ is mostly used to label specific ligands via bifunctional chelating agents (Spang et al., 2016), such as NODAGA, HBED-CC, and DOTA. In such studies, [68Ga]Ga3+ can be rapidly de-chelated in vivo (Kumar et al., 2018), complicating the interpretation of tissue uptake measurements. Information on the tissue kinetics of [68Ga]Ga3+ may be crucial in the analysis. Arterial plasma activity must be corrected for metabolites, [68Ga]Ga3+ being usually a major metabolite.
68Ga can be conveniently obtained without cyclotron by elution from a 68Germanium/68Gallium generator possessing a 1-year life span (Autio et al., 2015). When 68Ga is eluted from the generator with 0.1M HCl solution, it is in the form of hydrated gallium ion, [68Ga(H2O)6]3+, or if water is removed, as 68GaCl3. Plasma pharmacokinetics and ex vivo tissue distribution of the 68Ga eluate in rats has been reported by Autio et al. (2015). Biodistribution of 68Ga-citrate in pigs has been reported by Afzelius et al (2016).
Free Ga3+ in aqueous solution starts to form insoluble Ga(OH)3 in pH > 3. (Green & Welch, 1989). Since the PET tracers need to be prepared in high specific activity, the low amounts of chelating agent leads easily to formation of 68Ga colloids, especially at pH 3.5-4, and the insoluble GaO(OH) at higher pH and especially at higher temperatures (Brom et al., 2016). The tracer must be purified from these colloids and hydroxides to prevent nonspecific uptake in the spleen and liver, and subsequent overestimation of the specific activity (Brom et al., 2016).
67Ga-citrate SPECT has been extensively used for detecting infection and inflammation, but largely replaced by FDG PET as this method has become more widely available. In rat model of bacterial muscle infection, [67Ga]citrate tissue-to-blood ratio was only 1.2±0.7, while for FDG it was ∼10 (Sugawara et al., 1999). 68Ga-citrate PET in rats with induced muscle infection could detect the foci, and the tracer could also localize abdominal infection in a post-operative patient (Kumar et al., 2012). In this infection model, [68Ga]GaCl3 did not localize the infected lesions, while after [68Ga]apo-transferrin administration the lesions were detectable (Kumar et al., 2011).
68Ga-chloride, hydrolysed to gallate, 68Ga(OH)4-, was shown in rat model of tibial osteomyelitis to separate bacterial infection and healing-related inflammatory processes better than FDG (Mäkinen et al., 2005). The uptake of [68Ga]citrate is markedly higher than the uptake of [68Ga]GaCl3 in the same bone infection model, possibly because the chelating properties of citrate prevent the precipitation of [68Ga]Ga(OH)3 (Lankinen et al., 2018). Data was analyzed with SUV in these studies. 68Ga-citrate PET, analyzed with SUVmax, has even shown promise in imaging patients with suspected bone infection (Nanni et al., 2010). However, Nielsen et al (2015) and Jødal et al (2017) did not find 68Ga-citrate PET imaging useful in porcine osteomyelitis model. In human patients with Staphylococcus aureus bacteraemia, 68Ga-citrate PET/CT was comparable to FDG PET/CT for detection of osteomyelitis, but for detection of soft tissue foci FDG performed better than 68Ga-citrate (Salomäki et al., 2017).
68Ga-chloride has been used successfully to follow bacterial infection in mice model using simple target-to-background ratio (Nanni et al., 2009).
[68Ga]apo-transferrin can be used for detecting bacterial infection
In mouse model of myocardial post-infarct inflammation, [68Ga]citrate did not show specific uptake in the myocardium, and tissue-to-blood ratio was 0.9 (Thackeray et al., 2015).
67Ga is known to accumulate in tumours (Tsan et al., 1986). Behr et al (2016) have shown increased 68Ga-citrate uptake in metastatic lesions of prostate cancer. Ga3+ metallates transferrin rapidly in vivo, and transferrin receptor expression is upregulated in many cancer cell types.
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Updated at: 2018-09-27
Created at: 2015-01-02
Written by: Vesa Oikonen, Anne Roivainen