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Gallium-67 scan
SynonymsGallium imaging
ICD-10-PCSC?1?LZZ (planar) C?2?LZZ (tomographic)
ICD-9-CM92.18
OPS-301 code3-70c
MedlinePlus003450

A gallium scan is a type of nuclear medicine diagnostic investigation that uses either a gallium-67 (67Ga) or gallium-68 (68Ga) radiopharmaceutical to obtain images of a specific type of tissue, or disease state of tissue. The gamma emission of gallium-67 is imaged by a gamma camera, while the positron emission of gallium-68 is imaged by positron emission tomography (PET). Gallium salts like gallium citrate and gallium nitrate may be used. The form of salt is not important, since it is the freely dissolved gallium ion Ga3+ which is active.[1] As they are isotopic, Both 67Ga and 68Ga salts have the same uptake mechanisms.[2] The gallium(III) is rapidly bound by transferrin, which then preferentially accumulates in tumors, inflammation, and both acute and chronic infection,[3][4] allowing these pathological processes to be imaged. Gallium is particularly useful in imaging osteomyelitis that involves the spine, and in imaging older and chronic infections that may be the cause of a fever of unknown origin.[5][6] Due to lack of disease specificity, imaging with radioactive gallium(III) salts or complexes, such as 67Ga citrate, has gradually become less important over time and is rarely used these days.

However, the mentioned gallium(III) radionuclides, particularly 68Ga, are frequently used as radiolabels for peptides, proteins, oligonucleotides, drugs, and drug-like substance, turning these from regular pharmaceuticals into radiotracers. A popular class of such radiopharmaceuticals is formed by 68Ga-labeled small-molecule inhibitors for prostate-specific membrane antigen (PSMA), which are increasingly used for prostate cancer imaging. Furthermore, Gallium-68 labeled octreotide analogs, such as 68Ga-DOTATOC, were among the first clinically successful 68Ga PET tracers and have meanwhile replaced indium-111 labeled octreotides for diagnostic imaging of somatostatin receptor positive neuroendocrine tumors. Investigations with 68Ga-labeled peptides etc. are however not commonly referred to as 'gallium scan'. Usually they are named after the addressed target or labeled bioligand, e.g., 'PSMA scan' or 'DOTATOC scan'.

Gallium citrate scan

[edit]
Gallium scan showing panda (A) and lambda (B) patterns, considered specific for sarcoidosis in the absence of histological confirmation

In the past, the gallium scan was the gold standard for lymphoma staging, until it was replaced by positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG).[7][8] 67Ga-citrate imaging is still used to image inflammation and chronic infections, and it still sometimes locates unsuspected tumors as it is taken up by many kinds of cancer cells in amounts that exceed those of normal tissues. Thus, an increased uptake of gallium-67 may indicate a new or old infection, an inflammatory focus from any cause, or a cancerous tumor.

It has been suggested that gallium imaging may become an obsolete technique, with indium leukocyte imaging and technetium antigranulocyte antibodies replacing it as a detection mechanism for infections. For detection of tumors, especially lymphomas, gallium-67 imaging is still in use, but may be completely replaced by Fluorodeoxyglucose18F-fluorodeoxyglucose PET imaging in the future.[9]

In infections, the gallium scan has an advantage over indium leukocyte imaging in imaging osteomyelitis (bone infection) of the spine, lung infections and inflammation, and for chronic infections. In part this is because gallium binds to neutrophil membranes, even after neutrophil death. Indium leukocyte imaging is better for acute infections (where neutrophils are still rapidly and actively localizing to the infection), and also for osteomyelitis that does not involve the spine, and for abdominal and pelvic infections. Both the gallium scan and indium leukocyte imaging may be used to image fever of unknown origin (elevated temperature without an explanation). However, the indium leukocyte scan will image only the 25% of such cases which are caused by acute infections, while gallium will also localize to other sources of fever, such as chronic infections and tumors.[10][11]

Mechanism

[edit]

The body generally handles Ga3+ as though it were ferric iron (Fe3+), and thus the free ion is bound (and concentrates) in areas of inflammation, such as an infection site, and also areas of rapid cell division.[12] Gallium (III) (Ga3+) binds to transferrin, leukocyte lactoferrin, bacterial siderophores, inflammatory proteins, and cell-membranes in neutrophils, both living and dead.[13]

Lactoferrin is contained within leukocytes. Gallium may bind to lactoferrin and be transported to sites of inflammation, or binds to lactoferrin released during bacterial phagocytosis at infection sites (and remains due to binding with macrophage receptors).[14] Gallium-67 also attaches to the siderophore molecules of bacteria themselves, and for this reason can be used in leukopenic patients with bacterial infection (here it attaches directly to bacterial proteins, and leukocytes are not needed).[15] Uptake is thought to be associated with a range of tumour properties including transferring receptors, anaerobic tumor metabolism and tumor perfusion and vascular permeability.[16][17]

Common indications

[edit]
  • Whole-body survey to localize source of fever in patients with fever of unknown origin.[18]
  • Detection of pulmonary and mediastinal inflammation/infection, especially in the immunocompromised patient.[19]
  • Evaluation and follow-up of active lymphocytic or granulomatous inflammatory processes such as sarcoidosis or tuberculosis.[20]
  • Diagnosing vertebral osteomyelitis and/or disk space infection where gallium-67 is preferred over labeled leukocytes.
  • Diagnosis and follow-up of medical treatment of retroperitoneal fibrosis.
  • Evaluation and follow-up of drug-induced pulmonary toxicity (e.g. Bleomycin, Amiodarone)
  • Evaluation of patients who are not candidates for WBC scans (WBC count less than 6,000).

Note that all of these conditions are also seen in PET scans using gallium-68.

Technique

[edit]

The main (67Ga) technique uses scintigraphy to produce two-dimensional images. After the tracer has been injected, images are typically taken by a gamma camera at 24, 48, and in some cases, 72, and 96 hours later.[21][22] Each set of images takes 30–60 minutes, depending on the size of the area being imaged. The resulting image will have bright areas that collected large amounts of tracer, because inflammation is present or rapid cell division is occurring. Single-photon emission computed tomography (SPECT) images may also be acquired. In some imaging centers, SPECT images may be combined with computed tomography (CT) scan using either fusion software or SPECT/CT hybrid cameras to superimpose both physiological image-information from the gallium scan, and anatomical information from the CT scan.

A common injection dose is around 150 megabecquerels.[23] Imaging should not usually be sooner than 24 hours as high background at this time produces false negatives. Forty-eight-hour whole body images are appropriate. Delayed imaging can be obtained even 1 week or longer after injection if bowel is confounding. SPECT can be performed as needed. Oral laxatives or enemas can be given before imaging to reduce bowel activity and reduce dose to large bowel; however, the usefulness of bowel preparation is controversial.[22]

10% to 25% of the dose of gallium-67 is excreted within 24 hours after injection (the majority of which is excreted through the kidneys). After 24 hours the principal excretory pathway is the colon.[22] The "target organ" (organ that receives the largest radiation dose in the average scan) is the colon (large bowel).[21]

In a normal scan, uptake of gallium is seen in wide range of locations which do not indicate a positive finding. These typically include soft tissues, liver, and bone. Other sites of localisation can be nasopharyngeal and lacrimal glands, breasts (particularly in lactation or pregnancy), normally healing wounds, kidneys, bladder and colon.[24]

Gallium PSMA scan

[edit]

See also: PSMA scan
CT scan (left) and gallium PSMA PET scan (right) of patient with prostate cancer metastases in the bones

The positron emitting isotope, 68Ga, can be used to target prostate-specific membrane antigen (PSMA), a protein which is present in prostate cancer cells. The technique has been shown to improve detection of metastatic disease compared to MRI or CT scans.[25]

In December 2020, the U.S. Food and Drug Administration (FDA) approved 68Ga PSMA-11 for medical use in the United States.[26][27] It is indicated for positron emission tomography (PET) of prostate specific membrane antigen (PSMA) positive lesions in men with prostate cancer.[28][27] It is manufactured by the UCLA Biomedical Cyclotron Facility.[27] The FDA approved 68Ga PSMA-11 based on evidence from two clinical trials (Trial 1/NCT0336847 identical to NCT02919111 and Trial 2/NCT02940262 identical to NCT02918357) of male participants with prostate cancer.[27] Some participants were recently diagnosed with the prostate cancer.[27] Other participants were treated before, but there was suspicion that the cancer was spreading because of rising prostate specific antigen or PSA.[27] The trials were conducted at two sites in the United States.[27]

The FDA considers 68Ga PSMA-11 to be a first-in-class medication.[29]

Common indications

[edit]

Gallium PSMA scanning is recommended primarily in cases of biochemical recurrence of prostate cancer, particularly for patients with low PSA values, and in patients with high risk disease where metastases are considered likely.[30][31]

Technique

[edit]

An intravenous administration of 1.8–2.2 megabecquerels of 68Ga PSMA-11 per kilogram of bodyweight is recommended. Imaging should commence approximately 60 minutes after administration with an acquisition from mid-thigh to the base of the skull.[30][32]

Gallium DOTA scans

[edit]

68Ga DOTA conjugated peptides (including 68Ga DOTA-TATE, DOTA-TOC and DOTA-NOC) are used in positron emission tomography (PET) imaging of neuroendocrine tumours (NETs). The scan is similar to the SPECT octreotide scan in that an octreotide-based somatostatin analogue (such as edotreotide) is used as the radioligand, and there are similar indications and uses as octreotide scans, however image quality is significantly improved.[33] Somatostatin receptors are overexpressed in many NETs, so that the 68Ga DOTA conjugated peptide is preferentially taken up in these locations, and visualised on the scan.[34] As well as diagnosis and staging of NETs, 68Ga DOTA conjugated peptide imaging may be used for planning and dosimetry in preparation for lutetium-177 or yttrium-90 DOTA therapy.[35][36]

In June 2016, Netspot (kit for the preparation of gallium Ga-68 dotatate injection) was approved for medical use in the United States.[37][38]

In August 2019, 68Ga edotreotide injection (68Ga DOTATOC) was approved for medical use in the United States for use with PET imaging for the localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adults and children.[39][40][41]

The U.S. Food and Drug Administration (FDA) approved 68Ga edotreotide (DOTATOC) based on evidence from three clinical trials (Trial 1/NCT#1619865, Trial 2/NCT#1869725, Trial 3/NCT#2441062) of 334 known or suspected neuro-endocrine tumors.[40] The trials were conducted in the United States.[40]

Gallium (68Ga) oxodotreotide was approved for medical use in Canada as Netspot in July 2019,[42] and as Netvision in May 2022.[43]

The combination germanium (68Ge) chloride / gallium (68Ga) chloride was approved for medical use in the European Union in August 2024.[44]

Other gallium-68 based PET scanning agents may also be based on the principle of attaching peptides to chelators, such as the in-development drug Ga-68-Trivehexin.

Radiochemistry of gallium-67

[edit]

Gallium-67 is produced by a cyclotron, using charged-particle (proton) bombardment of enriched Zn-68. The gallium-67 is then complexed with citric acid to form gallium citrate. The half-life of gallium-67 is 3.2617 days.[45] It decays by electron capture, also emitting gamma rays that are detected by a gamma camera. The primary emissions are at 93 keV (39% of decays), followed by 185 keV (21%) and 300 keV (17%).[46] For imaging, multiple gamma camera energy windows are used, typically centred around 93 and 184 keV or 93, 184, and 296 keV.[22]

Radiochemistry of gallium-68

[edit]
See also: Gallium-68 generator

Gallium-68, which has a half-life much shorter than gallium-67 at 67.84 minutes, is produced in a gallium-68 generator by decay of germanium-68 with a 271.05 day half-life or, as with gallium-67, by the irradiation of zinc-68 in a cyclotron. Use of a generator means a supply of 68Ga can be produced easily with minimal infrastructure, for example at sites without a cyclotron, commonly used to produce other PET isotopes. It decays by positron emission and electron capture into zinc-68;[45] the maximum energy of the desired positron emission is 1.899 MeV.[46]

References

[edit]
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Gallium scan

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from Grokipedia
A gallium scan, also known as gallium scintigraphy, is a nuclear medicine imaging procedure that uses the radioactive isotope gallium-67 (Ga-67) as a tracer to detect areas of rapid cell division, inflammation, infection, or malignancy in the body.[1] The technique originated in the late 1940s with early studies on gallium's affinity for tumors and inflammatory sites, and was first clinically applied in the 1970s for imaging lymphomas and infections.[2] The tracer accumulates in tissues where cells are actively dividing or responding to inflammatory signals, allowing a gamma camera to capture images of these "hot spots" over a period of hours to days after injection.[3] This test is particularly valued for its ability to provide whole-body or targeted views, helping clinicians identify abnormalities that may not be visible on standard X-rays or CT scans.[4] The procedure begins with an intravenous injection of gallium citrate Ga-67, a radiopharmaceutical prepared under sterile conditions, typically administered by a nuclear medicine specialist.[5] Imaging is performed 6 to 72 hours later—often in multiple sessions—to allow the tracer to distribute and bind to target sites, with each scan lasting 30 to 60 minutes while the patient lies still under the camera.[6] Preparation may include bowel cleansing with laxatives or enemas to reduce interference from normal gallium uptake in the intestines, and patients are advised to avoid certain medications like bismuth-containing antacids.[3] The radiation exposure is low and comparable to other nuclear scans, with the isotope decaying naturally and being excreted primarily through urine and stool over several days.[4] Gallium scans are commonly used to diagnose and stage cancers such as Hodgkin's lymphoma, non-Hodgkin's lymphoma, and lung cancer, as well as to evaluate unexplained fevers, osteomyelitis, sarcoidosis, and other inflammatory conditions.[5] They can also assess treatment response by monitoring changes in tracer uptake post-therapy.[6] However, the test has limitations: not all cancers concentrate gallium, normal uptake occurs in organs like the liver, spleen, and bones, and false positives may arise from non-malignant inflammation such as surgical scars.[3] It is generally contraindicated in pregnancy due to radiation risks to the fetus, and alternatives like PET scans with gallium-68 are increasingly preferred for higher resolution in modern practice.[1]

Introduction

Definition and purpose

A gallium scan is a nuclear imaging technique in nuclear medicine that employs radioactive isotopes of gallium, such as gallium-67 or gallium-68, to detect sites of inflammation, infection, or malignancy by visualizing the uptake of the radiotracer in abnormal tissues.[2] This method relies on the affinity of gallium for areas of increased metabolic activity or cellular proliferation, allowing clinicians to identify pathological processes that may not be evident through other imaging modalities.[7] The primary purposes of gallium scans include identifying occult infections, such as those causing fever of unknown origin or osteomyelitis; staging lymphomas by assessing disease extent; detecting certain tumors like those in lung cancer or neuroendocrine systems; and monitoring treatment response in malignancies to evaluate residual disease after therapy.[6][8] These applications leverage gallium's ability to accumulate in infected, inflamed, or neoplastic tissues, providing diagnostic insights that guide therapeutic decisions.[2] Gallium scans can utilize single-photon emission computed tomography (SPECT) for gallium-67, which offers whole-body imaging with moderate resolution, or positron emission tomography (PET) for gallium-68, which provides higher sensitivity and spatial resolution for more precise localization.[2] Over time, the technique has evolved from initial planar imaging methods, which provided two-dimensional views, to advanced SPECT and hybrid PET/CT systems that integrate anatomical and functional data for enhanced diagnostic accuracy.[2] For instance, gallium-68 PET is commonly applied in prostate-specific membrane antigen (PSMA) imaging for prostate cancer evaluation.[2]

Historical development

The discovery of gallium's affinity for tumors originated in the 1950s through studies at Oak Ridge National Laboratory, where researcher Raymond L. Hayes and colleagues observed that radioactive gallium isotopes, such as Ga-67, accumulated preferentially in malignant tissues during animal experiments with tumor-bearing rodents.[9] These initial investigations, building on earlier 1940s biodistribution work, laid the groundwork for gallium's potential as a tumor-localizing agent, though early attempts with other isotopes like Ga-72 proved impractical due to suboptimal decay properties.[10] The first clinical application of Ga-67 occurred in 1969, when Hayes and C.L. Edwards reported its use in human imaging, specifically detecting lymph node involvement in a patient with Hodgkin's lymphoma during a routine skeletal scan.[11] This serendipitous finding spurred further research into Ga-67 citrate as a diagnostic tool for lymphomas and other malignancies, leading to its formal FDA approval in 1977 for commercial distribution and widespread clinical use in detecting infections, inflammations, and cancers.[12] By the 2000s, attention shifted toward Ga-68 for positron emission tomography (PET) imaging, facilitated by the development of Ge-68/Ga-68 generators that enabled on-site production without reliance on distant cyclotrons, offering superior resolution and quantification compared to Ga-67 scintigraphy.[10] Key advancements in the 2010s included the integration of Ga-68 scans with computed tomography (CT) in hybrid PET/CT systems, enhancing anatomical correlation and diagnostic accuracy for various applications.[2] The approval of Ga-68 PSMA-11 by the FDA in December 2020 marked a pivotal milestone, specifically for prostate cancer imaging, accelerating the adoption of targeted Ga-68 tracers.[13] This evolution contributed to the decline of Ga-67 scans post-2015, as PET's advantages in sensitivity and specificity, coupled with the rise of specialized Ga-68 radiopharmaceuticals like those for somatostatin receptors and PSMA, rendered the older modality largely obsolete for most oncology and infection imaging.[14]

Radiochemistry

Gallium-67 properties

Gallium-67 is produced in a cyclotron through the bombardment of enriched zinc-68 targets with protons, typically via the reaction ^{68}Zn(p,2n)^{67}Ga, yielding a carrier-free isotope suitable for radiopharmaceutical applications.[15] It possesses a physical half-life of 78.3 hours, allowing for extended distribution and imaging timelines in clinical settings.[2] The isotope decays primarily by electron capture to stable zinc-67, with a total decay energy of approximately 1.0 MeV, emitting characteristic gamma rays at principal energies of 93 keV (37-40% abundance), 185 keV (20-24% abundance), and 300 keV (16-17% abundance), which are suitable for detection in single-photon emission computed tomography (SPECT) systems.[16] Chemically, gallium-67 behaves as a trivalent cation (Ga^{3+}) akin to iron(III) due to its position in group 13 of the periodic table and similar ionic radius and charge density, enabling it to bind to iron-transport proteins like transferrin and form stable chelates with ligands such as citrate for targeted biodistribution.[17] This iron-mimicking property underlies its utility in labeling compounds for nuclear medicine, where the citrate complex, for instance, promotes accumulation in inflammatory and neoplastic tissues via lactoferrin and siderophore interactions.[18] The radioactive decay of gallium-67 adheres to the standard exponential decay law:
N(t)=N0e−λt N(t) = N_0 e^{-\lambda t}
where N(t)N(t) is the number of undecayed nuclei at time tt, N0N_0 is the initial number, and the decay constant λ=ln⁡(2)/T1/2≈0.00885\lambda = \ln(2) / T_{1/2} \approx 0.00885 h^{-1}) with T1/2=78.3T_{1/2} = 78.3 hours; this formulation determines the optimal imaging windows, typically 48-72 hours post-injection, as sufficient activity persists while background clears.[15] The prolonged half-life of gallium-67 offers the advantage of flexible scheduling for delayed imaging to enhance contrast between target lesions and normal tissues, accommodating logistical needs in facilities without on-site production.[19] Conversely, it imparts a higher effective radiation dose to patients—approximately 0.1-0.2 mSv/MBq—compared to shorter-lived positron emitters, and SPECT imaging with its gamma emissions yields lower spatial resolution (around 10-15 mm) than positron emission tomography (PET).[20][14]

Gallium-68 properties

Gallium-68 (Ga-68) is a positron-emitting radioisotope produced on-site via elution from a germanium-68 (Ge-68)/Ga-68 generator system, where the parent Ge-68, with a half-life of 270.95 days, decays to Ga-68 through electron capture.[21] Ga-68 has a physical half-life of 67.71 minutes and primarily decays (89%) by positron emission with a maximum energy of 1.899 MeV (mean 0.89 MeV), accompanied by 11% electron capture; the positrons annihilate with electrons to produce two 511 keV photons suitable for positron emission tomography (PET) detection.[21][22] In terms of coordination chemistry, Ga-68 in its +3 oxidation state exhibits high thermodynamic stability when complexed with macrocyclic chelators such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), forming kinetically inert complexes at near-physiological pH and temperatures.[23] These chelators facilitate the radiolabeling of biomolecular targeting agents, including prostate-specific membrane antigen (PSMA) inhibitors and somatostatin analogs like DOTATATE, enabling specific accumulation in diseased tissues.[23][24] The available activity of Ga-68 for labeling post-elution from the generator follows the ingrowth dynamics under secular equilibrium, approximated by the equation
A(t)=A0(1−e−λt) A(t) = A_0 \left(1 - e^{-\lambda t}\right)
where A0A_0 is the equilibrium activity (approximately equal to the Ge-68 activity, given the large difference in decay constants), λ\lambda is the decay constant of Ga-68 (λ=ln⁡(2)/67.71\lambda = \ln(2)/67.71 min−1^{-1}), and tt is the time since elution; this governs the optimal timing for on-site preparation to achieve high yields.[22] The short half-life of Ga-68 minimizes patient radiation exposure compared to longer-lived isotopes while leveraging the high sensitivity of PET imaging through efficient detection of the 511 keV annihilation photons.[22] However, this brevity requires rapid post-elution processing and synthesis, typically within 30-60 minutes, to ensure sufficient activity for clinical use.[25] These attributes position Ga-68 as ideal for targeted PET applications, such as PSMA and somatostatin receptor imaging.[22]

Gallium-67 Citrate Scans

Mechanism of action

The mechanism of action of gallium-67 (Ga-67) citrate involves its chemical similarity to ferric iron (Fe³⁺), allowing it to bind to iron-transport proteins and accumulate in sites of inflammation and malignancy. Upon intravenous injection as Ga-67 citrate, approximately 90% of the radiotracer rapidly binds to transferrin in plasma, forming a Ga-67-transferrin complex that mimics iron transport.[2] This complex is taken up by cells expressing transferrin receptors, which are overexpressed on inflammatory cells, such as macrophages and lymphocytes, and on tumor cells due to their high metabolic demands for iron.[26] Additionally, Ga-67 dissociates from transferrin at sites of low pH, such as in inflammatory exudates or necrotic tumor areas, and binds to lactoferrin, an iron-binding protein abundant in neutrophils and present at infection sites.[27] This dual binding promotes accumulation in pathological tissues, including abscesses and lymphomas, where inflammatory cells predominate.[2] The biodistribution of Ga-67 citrate is characterized by initial clearance through the liver and spleen, with about 75% of the injected dose retained in the body after 48-72 hours, distributing to soft tissues, bone marrow, and the reticuloendothelial system.[2] In pathological conditions, Ga-67 accumulates preferentially in abscesses and lymphomas within this timeframe, driven by enhanced delivery via the transferrin mechanism and local retention.[28] Bacterial uptake may also contribute in infections, as Ga-67 is incorporated via siderophores or nonspecific diffusion into pathogens.[2] A non-specific component of Ga-67 localization arises from increased vascular permeability in inflamed or neoplastic tissues, allowing interstitial accumulation of the unbound or protein-complexed tracer beyond receptor-mediated uptake.[29] Differentiation from normal physiologic uptake, which occurs evenly in bone marrow, liver, and spleen, relies on the intensity and focal pattern of accumulation; pathological sites typically show higher, irregular uptake compared to the diffuse baseline distribution.[30]

Clinical indications

Gallium-67 citrate scans are primarily indicated for evaluating fever of unknown origin (FUO), where they help identify occult infectious or inflammatory sources when other diagnostics are inconclusive.[2] They are also useful in diagnosing chronic osteomyelitis, particularly in cases superimposed on underlying bone abnormalities, demonstrating higher specificity than radiolabeled leukocyte scans for conditions like discitis or spinal osteomyelitis. In sarcoidosis, these scans aid in assessing disease activity and extent, especially in pulmonary involvement, with uptake patterns reflecting granulomatous inflammation.[27] For oncology, staging of non-Hodgkin lymphoma is a key application, with gallium-67 scans providing valuable information on disease distribution prior to treatment.[2] In oncologic contexts, gallium-67 citrate scans facilitate detection of bronchogenic carcinoma by highlighting primary lung tumors and metastatic sites, aiding in differentiation from benign lesions.[31] They are similarly employed for identifying hepatocellular carcinoma, particularly in cirrhotic livers, where abnormal uptake correlates with tumor sites in a majority of cases.[32] Additionally, these scans support monitoring treatment response in lymphomas, including both Hodgkin and non-Hodgkin types, by assessing residual disease viability post-therapy.[33] Studies from the 1980s, such as those evaluating high-dose gallium imaging, reported sensitivities of 90% or greater for lymphoma detection across nodal sites.[34] For infectious applications, gallium-67 scans are indicated in pulmonary infections among immunocompromised patients, such as Pneumocystis carinii pneumonia (PCP) in AIDS, where they exhibit high sensitivity (up to 95%) for early detection even with normal chest radiographs.[35] They also prove effective in localizing abdominal abscesses, including subphrenic or postoperative collections, guiding surgical intervention by delineating inflammatory foci.[15] Gallium-67 scans can be useful for chronic inflammatory processes where white blood cell scans are limited, such as in spinal osteomyelitis, due to its accumulation in non-acute sites. However, gallium-67 scans have largely been supplanted by 18F-FDG PET in modern practice for higher sensitivity and resolution (as of 2025).[36]

Imaging procedure

Patient preparation for a gallium-67 (Ga-67) citrate scan emphasizes hydration and bowel clearance to enhance image quality by reducing non-specific accumulation in the gastrointestinal tract and urinary system. Patients are instructed to drink ample fluids, typically at least 8 glasses of water per day leading up to and following injection unless contraindicated by fluid restrictions, to promote renal excretion of the tracer. Laxatives, such as magnesium citrate (10 oz) or bisacodyl, are commonly administered to patients with infrequent bowel movements, often starting the evening before injection or concurrently with it, to minimize colonic activity that could obscure abdominal findings.[37][38] The radiopharmaceutical, Ga-67 citrate, is injected intravenously, usually into an arm vein, at a dose of 2-5 mCi (74-185 MBq) for adults, with pediatric dosing scaled by weight at 0.1-0.2 mCi/kg (3.7-7.4 MBq/kg).[15][2] Injection occurs under sterile conditions, and patients should avoid recent blood transfusions or gadolinium-based contrast agents within 24 hours to prevent interference. Prior to each imaging session, patients are asked to empty their bladder to decrease pelvic background noise.[36] Imaging utilizes a gamma camera system fitted with medium-energy parallel-hole collimators designed for the 93-300 keV energy range of Ga-67 emissions, including principal photopeaks at 93 keV (37%), 185 keV (20%), and 300 keV (17%). Hybrid SPECT/CT scanners are routinely employed for precise attenuation correction via low-dose CT and to provide anatomical localization of uptake. Energy windows are configured at 15-20% width centered on these photopeaks, with the 93 keV window sometimes omitted in cases of recent Tc-99m studies or high patient body mass to reduce scatter.[39][36] Planar or SPECT imaging is conducted 48-72 hours after injection for optimal tumor-to-background contrast in whole-body surveys or region-specific views, such as for lymphoma evaluation; this delay permits clearance from normal tissues while retaining accumulation in pathological sites. Optional early planar images at 6 hours post-injection can delineate blood pool distribution if vascular involvement is suspected. Whole-body planar acquisition employs a dual-head camera at 6-10 cm/min speed to collect 1.5-2 million counts total, or targeted spot views at 1-3 million counts per projection on a 256x256 or 512x512 matrix; SPECT involves 60-128 projections over 360 degrees at 20-40 seconds per stop on a 128x128 matrix, followed by CT for fusion. Each session lasts 30-60 minutes, depending on the extent of coverage.[39][36] Following the procedure, patients should continue hydration and frequent voiding to facilitate tracer elimination, with no restrictions on diet or activity otherwise. Additional delayed imaging at 96 hours or beyond may be arranged if initial scans show persistent bowel or hepatic activity masking lesions.[6][38]

Gallium-68 PET Scans

Prostate-specific membrane antigen (PSMA) imaging

Prostate-specific membrane antigen (PSMA) imaging utilizes gallium-68 (Ga-68) labeled to PSMA inhibitors, such as PSMA-11 (also known as PSMA-HBED-CC), which specifically bind to PSMA overexpressed on the surface of prostate cancer cells.[13][40] This binding allows for targeted visualization of prostate cancer lesions via positron emission tomography (PET), as Ga-68 emits positrons that produce detectable signals upon decay.[41] The radiotracer is typically chelated using agents like HBED-CC to stably bind Ga-68, enabling its delivery to PSMA-expressing tissues.[42] Clinical indications for Ga-68 PSMA PET primarily include the detection of biochemical recurrence in patients with prostate-specific antigen (PSA) levels greater than 0.2 ng/mL following initial treatment, such as radical prostatectomy or radiation therapy.[43][44] It is also used for staging high-risk prostate cancer at initial diagnosis and for identifying metastases in lymph nodes or bone, providing superior detection compared to conventional imaging modalities.[13][45] The imaging procedure involves an intravenous injection of 3 to 7 millicuries (mCi) of Ga-68 PSMA-11, followed by PET/CT acquisition starting 50 to 100 minutes post-injection to allow optimal tracer uptake.[13][46] Scanning covers the whole body from skull base to mid-thigh, with the patient instructed to void immediately before imaging to minimize bladder interference.[13] The total procedure duration is approximately 2 hours, including uptake time.[47] Ga-68 PSMA PET received FDA approval on December 1, 2020, marking a significant advancement in prostate cancer management due to its high sensitivity, often exceeding 90% for detecting lesions as small as 2 mm or smaller in biochemical recurrence settings.[48][49] This imaging modality guides therapeutic decisions, including selection for radioligand therapies like lutetium-177 PSMA, by confirming PSMA expression in metastatic castration-resistant prostate cancer.[13][50]

Somatostatin receptor imaging

Somatostatin receptor imaging utilizes gallium-68 (Ga-68) labeled DOTA-conjugated somatostatin analogs, primarily Ga-68 DOTATATE and Ga-68 DOTATOC, which bind with high affinity to somatostatin receptors (SSTR), especially subtypes 2 and 5 overexpressed on neuroendocrine tumors (NETs).[51] These tracers enable precise localization of SSTR-positive lesions through positron emission tomography/computed tomography (PET/CT), offering superior spatial resolution compared to earlier scintigraphic methods.[52] Clinical indications for Ga-68 DOTATATE and DOTATOC scans encompass the diagnosis and staging of gastroenteropancreatic NETs, as well as the detection of pheochromocytoma and paraganglioma, particularly in cases of suspected extra-adrenal involvement.[53] Additionally, these scans play a crucial role in patient selection for peptide receptor radionuclide therapy (PRRT) by assessing SSTR expression levels to predict therapeutic response.[51] The imaging procedure involves a total visit duration of 2–3 hours.[54][55] Patients check in and answer a questionnaire, followed by placement of an IV line in the arm or hand, which involves a quick pinch similar to a blood draw.[54][55] The tracer, 3-5 mCi (111-185 MBq) of Ga-68 DOTATATE, is then administered intravenously through the IV, typically calculated as 2 MBq/kg up to a maximum of 200 MBq, with no immediate effects felt by the patient.[56][54][55] Following injection, patients relax in a quiet waiting area for 45–60 minutes (up to 1 hour) while the tracer circulates and binds; permitted activities include reading, listening to music, sleeping, or watching videos, and blankets are available if the area is cool.[54][55] Patients are advised to empty their bladder just before scanning.[54] PET/CT acquisition starts 60 minutes post-injection to optimize tumor-to-background contrast. Patients are advised to hydrate adequately before and after injection to minimize physiological uptake in organs like the kidneys and spleen; multi-phase imaging protocols may be employed if needed to differentiate pathological from normal SSTR expression in tissues such as the pituitary or pancreas.[51] Ga-68 DOTATATE PET/CT exhibits higher sensitivity than In-111 octreotide scintigraphy (Octreoscan) for NET detection, with studies showing improved lesion identification rates, particularly for small or low-uptake tumors.[57] Studies have also demonstrated superiority of Ga-68 DOTATATE PET/CT over other modalities in detecting medullary thyroid carcinoma in the presence of high serum calcitonin levels.[58]

Emerging applications

Recent research has explored gallium-68 (Ga-68) fibroblast activation protein inhibitor (FAPI) tracers for imaging fibroblast activation in various cancers, targeting the fibroblast activation protein (FAP) overexpressed in the tumor stroma. In pancreatic cancer, Ga-68 FAPI PET demonstrates high accuracy and superior lesion detection rates compared to 18F-FDG PET, enabling better visualization of primary tumors and metastases. Similarly, in breast cancer, Ga-68 FAPI uptake correlates with FAP expression in stromal fibroblasts, offering potential for staging and monitoring therapy response in FAP-positive lesions.[59][60][60] Investigational Ga-68 avidin-based approaches, leveraging the biotin-avidin system for pre-targeting, show promise in infection imaging by enhancing specificity for bacterial binding sites and reducing background uptake. These tracers facilitate PET detection of infectious foci, particularly in complex cases like osteomyelitis, where preliminary studies indicate improved contrast over traditional agents.[61][62] As of 2025, phase II and III trials are evaluating Ga-68 FAPI theranostics for sarcoma, combining diagnostic imaging with lutetium-177 therapy targeting FAP in soft tissue and bone sarcomas, with early data showing superior detection rates and safety profiles compared to FDG PET. Additionally, Ga-68 tracers like DOTATATE and pentixafor hold potential for imaging cardiovascular inflammation, such as in atherosclerosis, where they detect macrophage activity in plaques with higher specificity than FDG, aiding risk stratification in high-risk patients.[63][64][65] Ga-68 PET offers advantages over Ga-67 scintigraphy, including superior spatial resolution for detecting small lesions due to positron emission and coincidence detection, alongside shorter imaging times (1 hour post-injection versus 48-72 hours). However, challenges persist with Ga-68 tracer availability, reliant on short-half-life generators or cyclotrons, and higher production costs that limit widespread adoption in resource-constrained settings.[66][67][68] Future directions include integrating artificial intelligence for automated quantification of Ga-68 uptake, as AI models have demonstrated accuracy in measuring whole-body tumor burden and lesion volumes on scans like Ga-68 DOTATATE PET, potentially standardizing assessments and improving prognostic predictions. Expanded FDA approvals for novel Ga-68 tracers, such as edotreotide for broader neuroendocrine applications, are anticipated by 2026, which could accelerate theranostic integration in oncology and beyond.[69][70]

Clinical Considerations

Safety and radiation dosimetry

Gallium scans, encompassing both Ga-67 citrate scintigraphy and Ga-68 PET imaging, involve administration of radiopharmaceuticals that expose patients to ionizing radiation, necessitating careful consideration of dosimetry to minimize risks while adhering to the ALARA (as low as reasonably achievable) principle. The effective dose for Ga-67 citrate is approximately 0.1 mSv/MBq, resulting in a total exposure of about 10-20 mSv for a typical adult administered activity of 185 MBq, which is higher for whole-body imaging protocols due to prolonged retention and multiple imaging sessions. In contrast, Ga-68-based tracers deliver a lower effective dose of around 0.019-0.023 mSv/MBq, yielding 3-5 mSv for a standard 150-200 MBq dose, primarily attributable to the isotope's short 68-minute half-life that limits cumulative exposure. These dosimetry values are derived from biokinetic models and are influenced by patient-specific factors such as body weight and biodistribution. Patient risks from gallium scans are generally minimal, with no significant acute effects reported beyond rare instances of mild nausea, rash, or allergic reactions to the radiopharmaceutical components. Long-term stochastic risks, including potential carcinogenesis, are low and comparable to the radiation exposure from 1-5 diagnostic CT scans, depending on the isotope and protocol, as the effective doses fall within the range of 3-20 mSv where cancer risk increases minimally (approximately 1 in 2,000 per 10 mSv). Gallium scans are contraindicated in pregnancy due to fetal radiosensitivity, with alternatives preferred unless benefits outweigh risks exceeding 50 mGy to the fetus; the ALARA principle guides deferral or dose reduction in such cases to protect embryonic development. Precautions include encouraging hydration before and after injection to promote renal excretion and reduce absorbed dose to the bladder and kidneys, which receive the highest organ doses in both Ga-67 and Ga-68 scans. Screening for allergies to chelating agents, such as DOTA used in Ga-68 tracers, is essential, though hypersensitivity reactions are uncommon. For pediatric patients, administered activities are weight-based (e.g., 1.5-2.6 MBq/kg for Ga-67, with minimum doses of 9-18 MBq) to adjust for smaller body size and higher relative sensitivity, ensuring doses remain proportional to diagnostic needs. Regulatory frameworks emphasize dose optimization in nuclear medicine, with the International Commission on Radiological Protection (ICRP) providing guidelines for patient dosimetry in diagnostic procedures. Draft reports as of 2025 propose incorporating hybrid imaging (e.g., PET/CT or SPECT/CT) to refine diagnostic reference levels and minimize combined radiation burdens from radiopharmaceuticals and CT components.[71] These ICRP recommendations promote protocol standardization, such as activity adjustments and low-dose CT attenuation correction, to balance image quality with exposure reduction in gallium scan applications.

Interpretation and limitations

Interpretation of gallium scans involves assessing the distribution and intensity of radiotracer uptake in images acquired at specific time points post-injection. For gallium-67 citrate scintigraphy, planar or SPECT images are typically obtained 48 to 72 hours after administration, with delayed imaging up to 5 days to better delineate lesions; homogeneous uptake in physiologic sites such as the liver, spleen, and bone marrow is normal, while focal, intense, and irregular uptake indicates potential pathology like tumors, infections, or inflammation.[2] Diffuse uptake patterns, such as in bone marrow, may reflect stimulation from conditions like anemia or chemotherapy rather than malignancy.[72] In gallium-68 PET scans, such as those using PSMA or DOTATATE tracers, standardized uptake value (SUV) quantification provides a semi-quantitative measure of lesion avidity, with SUVmax thresholds (e.g., >5.4 for PSMA) aiding in distinguishing significant pathology from background; focal uptake correlates with receptor expression in prostate cancer or neuroendocrine tumors.[73] Limitations of gallium scans stem primarily from their non-specificity and technical constraints. Gallium-67 uptake occurs in both malignant and benign processes, leading to false positives in healing fractures, post-surgical sites, or inflammatory conditions like sarcoidosis, necessitating correlation with clinical history and other imaging.[2] Physiological variants, including variable colonic activity or lacrimal/salivary gland uptake in gallium-68 PSMA PET, can mimic disease, while non-oncologic uptake in degenerative joints or ganglia further complicates interpretation.[74] SPECT-based gallium-67 imaging has lower spatial resolution, reducing sensitivity for small lesions (<1 cm), and overall image quality is inferior to modern PET techniques.[72] Compared to other modalities, gallium scans excel in whole-body assessment of inflammation or infection but are generally outperformed by 18F-FDG PET for detecting metabolically active tumors due to the latter's higher resolution, faster imaging, and better quantification.[2] While superior to MRI for functional whole-body evaluation in oncology, gallium scans provide less anatomic detail than MRI, often requiring hybrid SPECT/CT or PET/CT fusion for precise localization.[75] Recent advances, particularly in 2025, include AI tools like the aPROMISE platform for gallium-68 PSMA PET/CT, which enhance interpretation by reducing false positives—such as in benign nodal uptake—through automated staging with up to 100% specificity in select metastatic categories, while maintaining high sensitivity.[76] Despite these improvements, definitive diagnosis often requires correlation with biopsy or CT/MRI to confirm findings and mitigate interpretive errors.[74]

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