Gallium in PET studies


68Ga is a positron emitter with half-life of 67.7 min. Branching ratio is 0.8914, that is, β+ particle is produced in 89.14% of decay events of this isotope. 68Ga has markedly higher maximum positron energy (1.9 MeV) than 18F (0.634 MeV), which causes stronger partial volume effect.

The first-generation 68Ge/68Ga generators became available in the early 1960s, providing positron-emitting isotopes for sites with no access to cyclotron. These generators were essential in the development of positron emission tomography. [68Ga]EDTA and other 68Ga-labelled compounds were immediately used in patient studies, especially in brain imaging. By the availability of 18F and 11C, development of 68Ga radiochemistry slowed down, until new type of 68Ge/68Ga generator became commercially available (Roesch & Riss, 2010). 68Ga can now be conveniently and cost-effectively obtained as chloride by HCl elution from the generator, possessing a 1-year life span, thus opening new possibilities for radiopharmaceutical chemistry. When 68Ga is eluted from the generator with 0.1 M HCl solution, it is in the form of hydrated gallium ion, [68Ga(H2O)6]3+ (Silvola et al., 2011; Autio et al., 2015). Purification and concentration of the elute provides 68Ga3+ usually as chloride, acetate, or citrate, with pH ≤5.

[68Ga]Ga3+ is mostly used to label specific ligands via bifunctional chelating agents (Spang et al., 2016), such as NODAGA, HBED-CC, and DOTA. 68Ga can also be used for non-targeted imaging: albumin, albumin nanoparticles, and albumin macroaggregates have been labelled with 68Ga for imaging tissue plasma volume, perfusion, and vascular permeability; 68Ga-labelled carbon nanoparticle aerosol can be used for measurement of lung ventilation and for diagnosis of pulmonary emboli; 68GaCl, 68Ga-citrate, and 68Ga-labelled transferrin have been used for infection, inflammation, and cancer imaging.


Gallium has numerous isotopes, of which 69Ga and 71Ga are stable, and natural gallium is a mixture of these two isotopes.

67Ga is a gamma (93, 184, 296, and 388 keV) emitter, used in SPECT imaging. It is produced with cyclotrons, and it has half-life of 78.3 hours (3.3 days). 67Ga-citrate and -chloride were extensively used for imaging inflammation and infections of musculoskeletal origin in the 1970s and early 1980s. SPECT imaging was usually started ∼2 days after 67Ga-citrate administration, while for 68Ga-citrate the waiting time is usually 1 hour.


At physiological pH, in aqueous solutions without chelators, 68Ga-chloride is hydrolysed to gallate, Ga(OH)4-. Gallate starts to form insoluble Ga(OH)3 already in pH > 3. (Green & Welch, 1989). Given time, amorphous Ga(OH)3 forms crystalline GaO(OH), which dissolves in basic solutions back to gallate (Bernstein, 1998). At physiological pH, Ga3+ can also form highly insoluble phosphates. In vivo kinetics of [68Ga]GaCl3 and [68Ga]citrate are different, possibly because the chelating properties of citrate prevent the precipitation of [68Ga]Ga(OH)3 (Lankinen et al., 2018). After intravenous administration of [67Ga]citrate, 98-99% of 67Ga is bound to plasma transferrin in rabbits (Vallabhajosula et al., 1980). Since the PET tracers need to be prepared in high specific activity, the low amounts of chelating agent leads easily to formation of gallium 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). Non-chelated [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).

The radioligands containing chelator which binds [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, plasma protein bound [68Ga]Ga3+ being usually a major metabolite.

Mechanism of Ga3+ tissue uptake

While the salts of gallium isotopes 68 and 67 have been used for infection, inflammation, and cancer imaging with PET and SPECT for a long time, the uptake mechanisms are not fully understood. The coordination chemistry of Ga3+ ion resembles that of Al3+ and In3+, but is very similar to ferric ion, Fe3+. Therefore, Ga3+ ion acts as an analogue of ferric ion (Fe3+) and is quickly bound to transferrin, albumin, and some other plasma proteins. Neutrophil granulocytes contain lactoferrin, which also binds Ga3+, and lactoferrin can be released from neutrophils at the site of inflammation. Lactoferrin has higher affinity for Ga3+ than transferrin (Harris, 1986). Transferrin-bound Ga3+ can be internalized via transferrin receptors and stored in tissues, especially in cells of macrophage lineage, bound in ferritin. Mature red blood cells do not take up Ga3+. In contrast to Fe3+, Ga3+ cannot be reduced in physiological conditions, and does not bind to Fe2+-binding molecules such as haemoglobin, myoglobin, and cytochromes. Ga3+ can still substitute Fe3+ in many non-heme enzymes, such as ribonucleotide reductase (Narasimhan et al., 1992). Ga3+ could also substitute Zn2+ in some enzymes. Especially the competing role with iron has led to medical use of gallium (Chitambar, 2016).

Increased perfusion provides more Ga3+ to the inflamed tissue or tumour. Plasma protein bound Ga3+ enters interstitial space in tissues more easily if endothelial junctions of capillaries are loosened because of inflammation or tumour growth. For instance, the acute effect of histamine leads to increased uptake of 67Ga-citrate, parallel to development of tissue oedema (Kohno et al., 1987). Ga3+-transferrin may still not be optimal for assessing vascular permeability because of its insufficient stability (Brunetti et al., 1988; Staker et al., 1991). Also leukocytes migrate to the sites of inflammation, and degranulation of neutrophils releases lactoferrin to the extracellular space; lymphocytes have lactoferrin-binding surface receptors. Monocyte-macrophage lineage cells accumulate iron, and Ga3+ as well (Ujula et al., 2010). Ga3+ has been found to be concentrated in the lysosomes of macrophages, mainly as phosphate precipitates (Berry, 1996).

Ga3+ also binds to the siderophore molecules of bacteria and fungi, and the Ga3+-siderophore complex can them be transported into the pathogenic micro-organisms. Therefore increased [68Ga]Ga3+ and [67Ga]Ga3+ uptake can be seen in both infected and inflamed tissue (Tsan, 1985; Ando et al., 1990).

Cancer cells usually express high levels of transferrin receptors because of high demand for iron.

Ga3+ concentrates in bones, particularly in regions of bone deposition and remodelling, including healing bone fractures. Bone uptake is independent of transferrin receptors. Hydroxyapatite adsorbs Ga3+, and gallium is precipitated as phosphates. In large doses, gallium inhibits bone resorption by osteoclasts, and inhibits the release of PTH, thus affecting also osteoblasts (Bernstein, 1998).

See also:


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Updated at: 2018-10-29
Created at: 2015-01-02
Written by: Vesa Oikonen, Anne Roivainen