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. 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, suggesting that 68Ga3+ in blood is bound to plasma proteins (Aparici et al., 2017).
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). Ga3+ metallates transferrin rapidly in vivo, and transferrin receptor expression is upregulated in many cancer cell types. 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).
Behr SC, Aggarwal R, Seo Y, Aparici CM, Chang E, Gao KT, Tao DH, Small EJ, Evans MJ. A feasibility study showing [68Ga]citrate PET detects prostate cancer. Mol Imaging Biol. 2016; 18: 946-951.
Jensen SB, Nielsen KM, Mewis D, Kaufmann J. Fast and simple one-step preparation of 68Ga citrate for routine clinical PET. Nucl Med Commun. 2013; 34(8): 806-812.
Kumar V, Boddeti DK, Evans SG, Angelides S. 68Ga-Citrate-PET for diagnostic imaging of infection in rats and for intra-abdominal infection in a patient. Curr Radiopharm. 2012; 5(1): 71-75.
Lankinen P, Noponen T, Autio A, Luoto P, Frantzèn J, Löyttyniemi E, Hakanen AJ, Aro HT, Roivainen A. A comparative 68-citrate and 68-chloride PET/CT imaging of Staphylococcus aureus osteomyelitis in the rat tibia. Contrast Media Mol Imaging 2018; 9892604. doi: 10.1155/2018/9892604.
Mintun MA, Dennis DR, Welch MJ, Mathias CJ, Schuster DP. Measurements of pulmonary vascular permeability with PET and gallium-68 transferrin. J Nucl Med. 1987; 28(11): 1704-1716.
Mäkinen TJ, Lankinen P, Pöyhönen T, Jalava J, Aro HT, Roivainen A. Comparison of 18F-FDG and 68Ga PET imaging in the assessment of experimental osteomyelitis due to Staphylococcus aureus. Eur J Nucl Med Mol Imaging 2005; 32: 1259-1268. doi: 10.1007/s00259-005-1841-9.
Nanni C, Marangoni A, Quarta C, Di Pierro D, Rizzello A, Trespidi S, D’Ambrosio D, Ambrosini V, Donati M, Aldini R, Zanotti-Fregonara P, Grassetto G, Rubello D, Fanti S, Cevenini R. Small animal PET for the evaluation of an animal model of genital infection. Clin Physiol Funct Imaging 2009; 29: 187-192.
Nanni C, Errani C, Boriani L, Fantini L, Ambrosini V, Boschi S, Rubello D, Pettinato C, Mercuri M, Gasbarrini A, Fanti S. 68Ga-citrate PET/CT for evaluating patients with infections of the bone: preliminary results. J Nucl Med. 2010; 51: 1932-1936. doi: jnumed.110.080184.
Vorster M, Maes A, Van deWiele C, Sathekge M. Gallium-68: a systematic review of its nononcological applications. Nucl Med Commun. 2013; 34(9): 834-854.
Vorster M, Maes A, van de Wiele C, Sathekge M. Gallium-68 PET: a powerful generator-based alternative to infection and inflammation imaging. Semin Nucl Med. 2016; 46(5): 436-447.
Created at: 2015-01-02
Updated at: 2018-10-04
Written by: Vesa Oikonen, Anne Roivainen