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).
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.
Autio A, Saraste A, Kudomi N, Saanijoki T, Johansson J, Liljenbäck H, Tarkia M, Oikonen V, Sipilä HT, Roivainen A. Assessment of blood flow with 68Ga-DOTA PET in experimental inflammation: a validation study using 15O-water. Am J Nucl Med Mol Imaging 2014; 4(6): 571-579.
Autio A, Virtanen H, Tolvanen T, Liljenbäck H, Oikonen V, Saanijoki T, Siitonen R, Käkelä M, Schüssele A, Teräs M, Roivainen A. Absorption, distribution and excretion of intravenously injected 68Ge/68Ga generator eluate in healthy rats, and estimation of human radiation dosimetry. EJNMMI Res. 2015; 5:40. doi: 10.1186/s13550-015-0117-z.
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.
Breeman WAP, de Blois E, Chan HS, Konijnenberg M, Kwekkeboom DJ, Krenning EP. 68Ga-labeled DOTA-peptides and 68Ga-labeled radiopharmaceuticals for positron emission tomography: current status of research, clinical applications, and future perspectives. Sem Nucl Med. 2011; 41: 314-321.
Chen DCP, Newman B, Turkall RM, Tsan M-F. Transferring receptors and gallium-67 uptake in vitro. Eur J Nucl Med. 1982; 7: 536-540.
Green MA, Welch MJ. Gallium radiopharmaceutical chemistry. Int J Rad Appl Instrum B. 1989; 16(5): 435-448. doi: 10.1016/0883-2897(89)90053-6.
Hayes RL, Carlton JE. A study of the macromolecular binding of 67Ga in normal and malignant animal tissues. Cancer Res. 1973; 33: 3265-3272.
Hayes RL, Rafter JJ, Byrd BL, Carlton JE. Studies of the in vivo entry of Ga-67 into normal and malignant tissue. J Nucl Med. 1981; 22: 325-332.
Hoffer P. Gallium: mechanisms. J Nucl Med. 1980; 21: 282-285.
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, Roesch F, Howman-Giles R. Potential use of 68Ga-apo-transferrin as a PET imaging agent for detecting Staphylococcus aureus infection. Nucl Med Biol. 2011; 38(3): 393-398.
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, 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.
Nelson B, Hayes RLH, Edwards CL, Kniseley RM, Andrews GA. Distribution of gallium in human tissues after intravenous administration. J Nucl Med. 1971; 13(1): 92-100.
Shetty D, Lee YS, Jeong JM. 68Ga-labeled radiopharmaceuticals for positron emission tomography. Nucl Med Mol Imaging 2010; 44(4): 233-240.
Tsan M-F. Mechanism of gallium-67 accumulation in inflammatory lesions. J Nucl Med. 1985; 26(1): 88-92.
Tsan M-F, Scheffel U. Mechanism of gallium-67 accumulation in tumors. J Nucl Med. 1986; 27(7): 1215-1219.
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.
Weiner RE. The mechanism of 67Ga localization in malignant disease. Nucl Med Biol. 1996; 23(6): 745-751.
Updated at: 2018-09-27
Created at: 2015-01-02
Written by: Vesa Oikonen, Anne Roivainen