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 after intravenous administration Ga3+ is quickly bound to transferrin, albumin, and some other plasma proteins, regardless of the anion in the injectant. Ga3+ is mainly bound to (apo)transferrin in serum, not only because of the metal binding sites on transferrin, but also because of the abundance of transferrin (Vallabhajosula et al., 1980). Transferrin-bound Ga3+ can be internalized via transferrin receptors (TfRs) and stored in tissues. Tissue distributions of 67Ga-citrate and 59Fe-citrate are however different (Sephton et al., 1978). Biodistribution of 68Ga-citrate in pigs has been reported by Afzelius et al (2016).
TfR-positive cancer tissues and inflammatory lesions have shown increased [67Ga]citrate uptake (Tsuchiya et al., 1992). 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). Also in humans, blood activity remains high at least for 4 hours after [68Ga]citrate administration, because 68Ga3+ in blood is bound to plasma proteins (Aparici et al., 2017). PET imaging with 68Ga-citrate results in modest radiation exposure, in the same range as other 68Ga-labelled radiotracers (Suilamo et al., 2022).
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 [18F]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-citrate SUVmax shows potential for detection of malignant and tuberculosis lesions in the lungs, and also extrapulmonary tuberculous lesions (Vorster et al., 2014a and 2014b).
Pulmonary vascular permeability has been assessed using 68Ga-citrate PET. In acute lung injury the pulmonary transcapillary escape rate of [68Ga]transferrin, labelled in vivo by administration of 68Ga-citrate, can be ∼10-fold higher than in normal lung tissue (Mintun et al., 1987).
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).
Animal studies suggest that 68Ga-citrate may be useful in assessing rheumatoid arthritis (Wang et al., 2019 and 2021).
68Ga-citrate can also be used to detect bacterial infection (Kumar et al., 2012).
67Ga is known to accumulate in tumours (Larson, 1978; Tsan et al., 1986). Ga3+ metallates transferrin rapidly in vivo, and transferrin receptor expression is upregulated in many cancer cell types. There may also be transferrin independent uptake mechanisms of Ga3+ (Sohn et al., 1993; Luttropp et al., 1998), also in healthy tissues, especially in renal cortex and bone (Radunović et al., 1997). Increased 68Ga-citrate uptake has been observed in metastatic lesions of prostate cancer (Behr et al., 2016), and uptake is pronounced in patients with high tumour MYC amplification (Aggarwal et al., 2017). Clinical results in hepatocellular carcinoma are also promising (Aparici et al., 2017).
In tumour-bearing mice, the highest tumour-to-blood and tumour-to-muscle ratios have been seen 4-6 h after injection (Aggarwal et al., 2017). Prior down-regulation of MYC mRNA reduced [68Ga]citrate uptake (Aggarwal et al., 2017).
Tumour-to-background contrast may be improved by application of Fe3+ carrier (Schomäcker et al., 1986).
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Tags: Inflammation, Infection, Tumour, Transferrin, Gallium
Updated at: 2022-03-11
Created at: 2015-01-02
Written by: Vesa Oikonen, Anne Roivainen