A gallium scan is a study that uses intravenously injectable isotopes of gallium to produce nuclear medicine images. Gallium was one of the first radioisotopes used for diagnostic nuclear medicine. Gallium, discovered in 1875 by Paul-Émile Lecoq de Boisbaudran, was first considered for diagnostic and therapeutic medical use in the 1940s by the research of H. C. Dudley and his co-workers. Gallium scans were initially used for localizing tumors and abscesses. Commercially available radiopharmaceuticals gallium-67 (67Ga) and gallium-68 (68Ga) are widely used. Although gallium-72 proved less useful for medical use, gallium-67, produced by proton bombarded zinc, and particularly gallium-68, produced by generator accelerating of germanium-68 (68Ge), emerged as solid contenders after measurement instrumentation became more advanced. Initially, gallium-67 was unexpectedly found to highlight Hodgkin’s lymphoma, although it was intended for osseous cancer. It was later realized that the isotope could be used for a broader range of malignancies and inflammatory processes. Historically, gallium-67 scans were used to diagnose many diseases, including bone infections, cancers (especially lymphomas), fevers of unknown origin, non-specific inflammation, and intra-abdominal abscesses. It was also used to evaluate inflammatory disease of the lungs like sarcoidosis, interstitial pneumonitis, pulmonary tuberculosis, and pulmonary fibrosis. Gallium-67 is used with single-photon emission computed tomography (SPECT), while gallium-68 is used with positron emission tomography (PET).
Gallium is trivalent metal and treated similarly to ferric iron in the body. Gallium-67 is relatively insoluble at normal pH and requires substances like citrate ions to form a complex to dissolve once in the body. Roughly 75% of the administered dose remains in the body after 48-72 hours and distributes evenly in soft tissues, liver, and bone. Around 90% of 67Ga is bound to transferrin in the blood plasma. Subsequently, it dissociates at low pH (exudate, or tumor site) and binds to lactoferrin due to vascular flow increased in the area. White blood cells may bind and transport 67Ga as well. Siderophores produced by bacteria have a good affinity for 67Ga and can form a complex to be taken up by the bacteria. It is also thought that bacteria have direct uptake of 67Ga via facilitated diffusion and nonspecific binding sites.
Gallium-68 (68Ga) is a positron-emitting isotope with a half-life of 68 minutes. It can be generated from germanium-68 or zinc-68. It can be used for the inherent properties in the radiometal itself or the chelated agent's chemical properties (most commonly a somatostatin analog). It is often attached to a specific chelating agent to be used as a tracer (e.g., DOTA-octreotate, also known as DOTATATE). The agent keeps gallium stably bound and free to distribute while binding to a specific receptor molecule. DOTATATE, DOTATOC, and DOTANOC are also referred to as GaTate, GaToc, and GaNoc, respectively. Bifunctional chelating is used to bind the metal (68Ga3+ ion) to a complex. The complex should have a high affinity with gallium for in vivo stability, while the targeting biomolecule (ex. drug, peptide, or antibody) in the complex is free to bind to a specific site and concentrate there. Essentially, gallium is paired with a compound that binds to a target tissue site. The complex is injected intravenously and is imaged with a PET detector at specific times depending on the desired target site uptake, but usually after one hour. In the case of GaTate, affinity is highest to the somatostatin receptor (SSTR) subtype 2. This leads to intense uptake in the spleen, adrenal glands, kidneys (not due to SSTR), and pituitary, with moderate intensity in the liver (not due to SSTR), thyroid, and saliva glands. There is also uptake in other areas such as the pancreas, bone, brain, and lymph nodes. GaToc has a high affinity to SSTR subtype 5, and GaNoc has a high affinity to SSTR subtypes 3 and 5. A homogenous uptake is physiologic, while intense heterogeneous, irregular focal uptake is worrying. The PET scan is usually done with a whole-body computed tomographic (CT) scan for detailed anatomical mapping, referred to as a PET/CT scan.
The renewed interest in gallium is due to its widespread availability as it is generator-produced and has a short half-life. Using gallium, on-site labeling, and radiopharmaceutical use can be done without a cyclotron nearby or delivering the product. The radiolabel paired has varying sensitivity and specificity inherent to the tissue or receptor properties. DOTATATE has recently been given orphan drug status, and that also has renewed some of the interest in gallium-68.
Gallium-67 is a gamma-emitting isotope with a half-life of 3.26 days that was used for imaging many pathologies, although now, fluorine-18 (18F) fluoro-deoxyglucose (FDG) (18F-FDG) has mostly replaced it. Both isotopes require a high-energy cyclotron for production and for doses to be individually purchased; therefore, they are not always available. 18F-FDG, a nonspecific metabolic indicator using glucose metabolism, has mostly replaced gallium-67, but recently there have been new developments in gallium’s utility, now as a gallium-68 labeled radiotracers. This evolution includes a shorter half-life, on-site generation, somatostatin receptor, prostate (68Ga-PSMA-11 PET/MR) tracers, and other cancer diagnoses, including boney and soft tissue metastasis. Gallium-67 (67Ga) is still used for imaging inflammation and granulomatous reactions. It produces low resolution and image quality and has a high radiation burden to patients due to its longer half-life. Imaging takes place at least two days after injection due to this long half-life. Gallium-67 is commonly bonded with citrate or nitrate (both dissociate in the blood when injected, leaving the gallium ion, 67Ga3+). Although WBC SPECT imaging has mostly replaced gallium-67 for infection imaging, there are still specific circumstances for it to be used. Examples include to rule out false negatives on spinal infections, immunocompromised patients, and chronic infections.
Gallium-68 is typically created by a 68Ge/68Ga generator. This process has an advantage over 18F-FDG, as 68Ga does not require a nearby cyclotron, and the parent isotope 68Ge has a half-life of 271 days. 68Ge is usually made from proton bombardment of 69Ga. 68Ge decays through electron capture. 68Ga mostly decays through positron emission (yields 89%) with a mean MeV of 0.89 and maximum energy of 1.9MeV. That is higher energy than 18F (with positron yield 96.7%), which is 0.25 MeV and max 0.63MeV. Since lower positron emission yields and higher endpoint energy emission leads to lower resolution in PET scans, this causes Gallium to have a theoretically lower resolution on imaging. Gallium has lower sensitivity and inferior spatial resolution than 18F, but gallium has a high clinical image contrast when labeled, making lesion detection easier. Moreover, both radionuclides produce high-quality imaging as long as a 3mm detection scanner is used. Imaging can occur in approximately one hour due to the short half-life. The 68Ga3+ cation allows it to join various molecules using oxygen, nitrogen, and sulfur as atom donors. Due to increased gallium-68 demands, it can also be created by a medical cyclotron. Originally 68Ga was paired with ligands such as EDTA (ethylenediaminetetraacetic acid) derivatives, and years later, developed pairing with DTPA (diethylenetriaminepentaacetic acid) or DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-based derivatives. This allowed 68Ga-DOTA-octreotate to become an alternative to Indium-111-DTPA-octreoscan. 68Ga can be paired with many molecules, including citrate, which gives it the same site affinities as 67Ga, but lower half-life. There are currently trials pairing 68Ga with antimicrobials such as ciprofloxacin and DOTA-depsidomycin.