A Comprehensive Monograph on Dotatate Gallium Ga-68: A Radiopharmaceutical for Neuroendocrine Tumor Imaging

I. Dotatate Gallium Ga-68: A Molecular and Physicochemical Characterization

Dotatate gallium Ga-68 is a sophisticated radiopharmaceutical agent that has fundamentally altered the diagnostic landscape for neuroendocrine tumors. Its design and function are rooted in a modular molecular architecture, combining a biologically active peptide with a positron-emitting radionuclide via a stable chelator. A thorough understanding of its chemical identity and properties is essential to appreciate its mechanism of action and clinical utility.

1.1 Nomenclature and Chemical Identifiers

The agent is most commonly referred to as Dotatate gallium Ga-68 or Gallium (Ga 68) dotatate.[1] Its systematic chemical name, reflecting its intricate structure, is

gallium;2-carbamoyl]-7--16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-7,.[2]

In the clinical and research settings, it is known by several synonyms, including [Ga-68] Dotatate, Gallium oxodotreotide Ga-68, and CHEMBL262135.[2] In the United States, it is commercialized under the brand name

Netspot.[1] Internationally, it has also been referred to by the name Somakit-TATE.[5] For unambiguous identification in scientific databases and regulatory filings, it is assigned specific codes: DrugBank ID DB13925, Chemical Abstracts Service (CAS) Number 1027785-90-5, and Unique Ingredient Identifier (UNII) 9L17Y0H71P.[3]

1.2 Structure, Formula, and Computed Properties

The molecular formula of Dotatate gallium Ga-68 is C65​H87​GaN14​O19​S2​, with a computed molecular weight of approximately 1502.3 g/mol.[2] The molecule is a complex conjugate, meticulously engineered with three distinct functional components:

1. Dotatate (Oxodotreotide): This is the targeting vector of the molecule. It is a synthetic peptide, an analog of the natural hormone somatostatin, designed to bind with high affinity to somatostatin receptors on cell surfaces.[2]
2. DOTA Chelator: The Dotatate peptide is covalently bound to a chelator molecule, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). This macrocyclic molecule acts as a stable "cage" that firmly encapsulates the radioactive metal ion, preventing its release in vivo.[9]
3. Gallium-68 (68Ga): This is the positron-emitting radionuclide that provides the imaging signal. It is securely held within the DOTA chelator, allowing its radioactive properties to be precisely targeted to tumor cells by the Dotatate peptide.[2]

This tripartite structure is a hallmark of modern radiopharmaceutical design. It represents a modular platform where each component serves a specific, engineered purpose. The peptide provides biological specificity, the chelator ensures radiochemical stability, and the radionuclide generates the diagnostic signal. This modularity is not merely a structural curiosity; it is the foundation of the "theranostic" concept. The same peptide-chelator construct (DOTATATE) can be labeled with a diagnostic isotope like 68Ga to visualize a target, or with a therapeutic isotope like Lutetium-177 (177Lu) to deliver a cytotoxic radiation dose to that same target. This inherent design flexibility allows for a seamless transition from diagnosis to targeted therapy using a matched pair of agents, a principle that has revolutionized the management of neuroendocrine tumors.[11]

1.3 Classification

Dotatate gallium Ga-68 is classified as a Small Molecule, and more specifically, as a Peptide Conjugate Radionuclide.[3] Its established pharmacologic class is a Radioactive Diagnostic Agent, a designation that underscores its exclusive use for diagnostic imaging rather than for therapeutic effect.[2] The U.S. Food and Drug Administration (FDA) also granted it Orphan Drug designation, recognizing its importance in managing the rare disease population of patients with neuroendocrine tumors.[13]

Property	Value	Source(s)
DrugBank ID	DB13925	[User Query]
CAS Number	1027785-90-5	3
US Brand Name	Netspot	1
Molecular Formula	C65​H87​GaN14​O19​S2​	2
Molecular Weight	~1502.3 g/mol	2
Drug Type	Small Molecule; Peptide Conjugate Radionuclide	3
Pharmacologic Class	Radioactive Diagnostic Agent	2
Key Synonyms	Gallium (Ga 68) dotatate, [Ga-68] Dotatate, Gallium oxodotreotide Ga-68	2
Table 1: Physicochemical Properties and Identifiers of Dotatate Gallium Ga-68

II. Mechanism of Action: Targeting the Somatostatin Receptor Pathway

The diagnostic efficacy of Dotatate gallium Ga-68 is predicated on an elegant biological mechanism that exploits the specific molecular characteristics of neuroendocrine tumors. The agent functions as a molecular probe, binding to a specific protein target that is highly overexpressed on tumor cells, thereby allowing for their precise visualization with Positron Emission Tomography (PET).

2.1 The Somatostatin Receptor (SSTR) Target

The biological target for Dotatate gallium Ga-68 is the somatostatin receptor (SSTR), a family of G-protein coupled receptors found on the surface of various cells throughout the body.[8] These receptors play a key role in regulating the endocrine system by inhibiting the secretion of numerous hormones and affecting cell proliferation.[8] Neuroendocrine cells, from which neuroendocrine tumors (NETs) arise, are particularly rich in these receptors. A critical feature of many NETs, especially well-differentiated types, is the significant overexpression of SSTRs on their cell membranes.[9] This overexpression, present in an estimated 70-90% of NETs, serves as a highly specific biomarker that distinguishes tumor cells from most normal tissues.[12]

There are five known subtypes of the somatostatin receptor (SSTR1 through SSTR5).[9] While NETs can express a combination of these subtypes, the SSTR subtype 2 (SSTR2) is the most commonly and densely expressed, making it an ideal target for both diagnostic imaging and targeted therapy.[9]

2.2 The Role of the Dotatate Ligand

The Dotatate component of the radiopharmaceutical, also known as DOTA-TATE, is a synthetic peptide designed to mimic the natural hormone somatostatin.[8] It is a cyclic 8-amino acid peptide that functions as a high-affinity ligand for somatostatin receptors.[8] Specifically, Dotatate has been engineered to bind with exceptionally high affinity to the SSTR2 subtype, the predominant receptor on NET cells.[9] This specific and high-affinity binding is the cornerstone of the agent's ability to selectively target and accumulate in tumor tissue while clearing rapidly from non-target areas.[2] This molecular recognition process ensures that the radioactive signal is concentrated at the sites of disease, enabling sensitive detection. While other somatostatin analogs like DOTATOC and DOTANOC exist and target SSTRs, Dotatate's particularly strong affinity for SSTR2 makes it highly effective for imaging the majority of well-differentiated NETs.[9]

2.3 Gallium-68 as the Signaling Radionuclide

The diagnostic signal is generated by Gallium-68 (68Ga), a positron-emitting radionuclide with a conveniently short physical half-life of 68 minutes.[9] When

68Ga-DOTATATE is administered intravenously, it circulates and binds to SSTR2-positive tumor cells. The bound 68Ga then undergoes radioactive decay, emitting a positron (a positively charged electron, β+).[8] This positron travels a very short distance within the tissue (typically less than a millimeter) before it encounters an electron. The subsequent interaction, known as annihilation, converts the mass of both particles into energy in the form of two 511 keV gamma photons, which are emitted in opposite directions (

180∘ apart).[8]

A PET scanner is equipped with a ring of detectors that are designed to register these pairs of gamma photons only when they arrive simultaneously (within a few nanoseconds) at opposite sides of the ring.[8] By electronically mapping millions of these "coincidence events," a computer algorithm can reconstruct a detailed, three-dimensional image that shows the distribution and concentration of the

68Ga-DOTATATE within the body.[1] Tissues with a high density of SSTRs, such as NETs, will accumulate a large amount of the radiotracer and consequently appear as areas of high signal intensity, or "bright spots," on the final PET image.[8]

This mechanism represents a fundamental shift from traditional anatomic imaging (like CT or MRI), which visualizes structural abnormalities, to molecular imaging, which visualizes biological processes. The 68Ga-DOTATATE scan does not primarily show a tumor's size or shape; it reveals the functional expression of a specific molecular target, the SSTR2.[23] This ability to map a biomarker in vivo explains why the technique can detect small tumor deposits that may be missed by conventional imaging and why its utility extends to any SSTR-expressing pathology, providing a powerful tool for personalized medicine.[12]

III. Clinical Pharmacology and Pharmacokinetics

The behavior of Dotatate gallium Ga-68 within the human body—its distribution, metabolism, and excretion—is central to its function as a diagnostic agent. Its pharmacokinetic profile is characterized by rapid targeting of SSTR-expressing tissues and efficient clearance from the bloodstream and non-target organs, a combination that is ideal for high-contrast imaging within a short timeframe.

3.1 Absorption and Distribution (Biodistribution)

Following administration via intravenous bolus injection, 68Ga-DOTATATE is rapidly absorbed into the bloodstream and distributed throughout the body.[1] It quickly accumulates in organs and tissues that have a high physiological expression of SSTR2, as well as in pathological sites of disease.[9]

The normal biodistribution pattern is highly consistent and predictable. The organs with the most avid physiological uptake are the spleen, adrenal glands, kidneys, and pituitary gland.[9] Moderate, more variable uptake is typically observed in the liver, thyroid gland, and salivary glands.[9] In contrast, there is characteristically no uptake in the cerebral cortex or the heart, and uptake in the lungs and thymus is usually low.[9] This distinct pattern of physiological uptake is critical for accurate image interpretation, as nuclear medicine physicians must be able to differentiate normal tracer accumulation from pathological findings. For example, intense uptake in the pituitary gland or adrenal glands is an expected finding and should not be mistaken for metastatic disease.[15]

An interesting phenomenon known as the "sink effect" can occur in patients with a very high burden of SSTR-positive tumors. In such cases, the vast number of receptors on the tumor cells acts as a "sink," sequestering a large fraction of the injected radiotracer. This can result in unusually high uptake in the tumors and a corresponding decrease in the physiological uptake seen in normal organs like the spleen and kidneys.[9]

3.2 Metabolism and Excretion

Dotatate gallium Ga-68 is a stable molecule that is largely unmetabolized in the body.[10] Its clearance is primarily mediated by the renal system, with excretion occurring exclusively via the urine.[9] The clearance from the blood and non-target tissues is rapid, which is a key advantage for imaging.[2] Approximately 12% to 16% of the injected dose is eliminated in the urine within the first four hours after administration.[15] This rapid excretion of unbound radiotracer is essential for reducing background signal, thereby increasing the contrast between the tumor and surrounding healthy tissue and leading to clearer, more easily interpretable images. The agent does exhibit some binding to plasma proteins, although the specific proteins and the extent of binding have not been fully characterized.[2]

3.3 Pharmacodynamics and Half-Life

The pharmacodynamic effect of 68Ga-DOTATATE is directly related to the density of SSTRs in a given tissue; it does not exert a pharmacological effect in the traditional sense.[23] While the principle of SSTR binding has been leveraged for diagnostics since the 1990s, a formal, detailed pharmacodynamic profile of the agent itself has not been extensively reported.[2]

The temporal characteristics of the agent are governed by two distinct half-lives. The physical half-life is determined by the radioactive decay of the Gallium-68 isotope, which is a constant 68 minutes.[9] This short half-life is highly advantageous, as it allows for rapid imaging while minimizing the patient's overall radiation exposure. The

biological half-life, which describes the rate of clearance from the body, is also short, complementing the rapid physical decay.[10]

The interplay of these pharmacokinetic properties directly shapes the clinical imaging protocol. The rapid tumor uptake and blood clearance define the optimal imaging window of 40 to 90 minutes post-injection, a time point where the tumor-to-background ratio is maximized.[10] Scanning too early would result in high background activity from the blood pool, potentially obscuring smaller lesions. Scanning too late would lead to significant signal loss from the rapid decay of

68Ga. Similarly, the primary route of renal excretion makes the urinary bladder wall a critical organ for radiation dosimetry.[15] This pharmacokinetic fact leads directly to the essential patient preparation instruction to ensure adequate hydration and encourage frequent urination, a simple but critical intervention to physically flush the unbound radionuclide from the body and minimize radiation dose.[1]

IV. Approved Indications and Diagnostic Utility in Neuroendocrine Neoplasms

Dotatate gallium Ga-68 has established itself as an indispensable tool in the clinical management of patients with neuroendocrine neoplasms. Its approval by regulatory bodies was based on robust evidence demonstrating its superior ability to localize these often-indolent but metastatic tumors.

4.1 FDA-Approved Indication

The U.S. Food and Drug Administration (FDA) has approved Dotatate gallium Ga-68 (marketed as Netspot), after radiolabeling with Gallium-68, for use with positron emission tomography (PET) for the localization of somatostatin receptor-positive neuroendocrine tumors (NETs) in both adult and pediatric patients.[1] This indication is broad, encompassing the diverse family of NETs that can arise from neuroendocrine cells throughout the body. These include, but are not limited to, gastroenteropancreatic NETs (GEP-NETs), such as carcinoid tumors and pancreatic NETs, as well as lung carcinoids, pheochromocytomas, and paragangliomas.[11] The key qualifier for the indication is that the tumors must be "somatostatin receptor positive," a determination made by the avidity of tracer uptake on the scan itself.

The inclusion of pediatric patients in the primary indication is particularly noteworthy. Many oncologic agents are initially approved only for adults, with pediatric studies following later. The upfront approval for all age groups reflects not only the high efficacy of the agent but also its favorable safety profile, especially its lower radiation dose compared to the previous standard of care, ¹¹¹In-pentetreotide scintigraphy.[15] This is a critical consideration in pediatric imaging, where minimizing long-term radiation-associated risks is paramount.

4.2 Applications in Clinical Management of NETs

The information provided by a 68Ga-DOTATATE PET/CT scan is used at multiple critical decision points in the care of a patient with a NET. Its applications include:

• Initial Staging: At the time of diagnosis, the scan provides a comprehensive, whole-body map of the disease, identifying the primary tumor and the full extent of any metastatic spread.[12] This information is fundamental for accurate staging and is crucial for determining the most appropriate initial treatment strategy. For example, a scan showing localized disease may support an aggressive surgical approach with curative intent, whereas a scan revealing widespread metastases would guide the patient toward systemic therapies.[12]
• Localization of Unknown Primary Tumor: A significant fraction of patients with NETs present with metastatic disease (e.g., in the liver) without an identifiable primary tumor on conventional imaging. In this challenging clinical scenario, 68Ga-DOTATATE PET/CT has proven highly effective at locating the occult primary tumor, which is often a small lesion in the small bowel or pancreas.[15]
• Restaging and Detection of Recurrence: For patients with a known history of NETs, the scan is used to re-evaluate the disease status, particularly when there is clinical or biochemical suspicion of recurrence or progression.[15] Its high sensitivity allows for the early detection of recurrent disease, often before it becomes apparent on anatomic imaging.
• Monitoring Response to Therapy: While CT and MRI remain the primary modalities for assessing changes in tumor size, 68Ga-DOTATATE PET/CT can provide valuable information on the biological response to treatment, particularly for therapies targeting the SSTR pathway.[12]
• Selection for Peptide Receptor Radionuclide Therapy (PRRT): This is one of the most critical applications of the scan. PRRT, using agents like Lutetium-177 (177Lu) Dotatate, is a highly effective therapy for metastatic NETs. However, its efficacy is entirely dependent on the tumors having sufficient SSTR expression to bind the therapeutic agent. The 68Ga-DOTATATE scan serves as the essential predictive biomarker; intense uptake on the PET scan confirms the presence of the target and identifies the patient as a suitable candidate for PRRT.[9]

V. Investigational Applications and the Expanding Clinical Landscape

The success of Dotatate gallium Ga-68 in neuroendocrine tumors has spurred significant research into its utility for other diseases that share the same molecular target: the somatostatin receptor. This expansion of investigational use demonstrates a "biomarker-first" approach, where the presence of the SSTR, regardless of the disease context, provides the rationale for imaging. This strategy is systematically exploring the agent's potential in a diverse range of oncologic and non-oncologic conditions.

5.1 Summary of Investigational Trials

Clinical trials have evaluated or are currently evaluating the diagnostic role of 68Ga-DOTATATE in several areas beyond its primary indication for NETs:

• Endocrine Disorders: A key area of investigation is in the workup of Adrenal Cushing Syndrome. Recruiting Phase 2 clinical trials are assessing the ability of 68Ga-DOTATATE PET/CT to localize ectopic (non-pituitary) tumors that secrete adrenocorticotropic hormone (ACTH), which are often small, difficult to find, and frequently of neuroendocrine origin.[18]
• Mesenchymal and Bone Tumors: Early-phase (Phase 0) trials have explored its potential in identifying rare Mesenchymal Tumors and in localizing the tumors responsible for Tumor-induced Osteomalacia (TIO). The latter is a paraneoplastic syndrome caused by small, SSTR-expressing mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23).[3]
• Pediatric Solid Tumors: Beyond its approved use in pediatric NETs, completed Phase 1/2 trials have investigated its diagnostic performance in other pediatric malignancies known to express SSTRs, such as Neuroblastoma (NB) and Medulloblastomas.[18]
• Other Malignancies: The application of SSTR imaging is being tested in other cancers where a subset of tumors may express the target. Clinical trials have been initiated in Metastatic Breast Cancer, Glioma, and certain subtypes of Metastatic Prostate Cancer with neuroendocrine differentiation.[18]
• Non-Oncologic Inflammatory Conditions: The utility of the agent is not limited to oncology. SSTR2 is also expressed on activated macrophages and lymphocytes, which are key cells in granulomatous inflammation. This has led to investigations into its use for imaging inflammatory conditions. A Phase 4 trial has been completed evaluating its role in diagnosing and assessing the extent of Cardiac Sarcoidosis, a condition that can be challenging to diagnose with conventional methods.[18]

The breadth of these trials underscores a logical, hypothesis-driven strategy for expanding the clinical utility of a targeted agent. The common thread linking these disparate diseases—from endocrine disorders to brain tumors to cardiac inflammation—is the potential expression of the somatostatin receptor. Researchers are leveraging 68Ga-DOTATATE as a non-invasive tool to first confirm the presence of this biomarker in vivo. If successful, this can open a new diagnostic pathway and, potentially, a new therapeutic avenue through the theranostic principle, demonstrating a modern and efficient approach to drug development and indication expansion.

VI. Protocol for Administration, Imaging, and Radiation Dosimetry

The clinical use of Dotatate gallium Ga-68 requires a standardized protocol that encompasses patient preparation, dose administration, and image acquisition. Each step is carefully designed based on the agent's pharmacokinetic and physical properties to maximize diagnostic image quality while adhering to the radiation safety principle of ALARA ("As Low As Reasonably Achievable").

6.1 Patient Preparation

Proper patient preparation is crucial for a successful and safe scan. Two key areas of focus are hydration and the management of interfering medications.

• Hydration: Patients must be instructed to be well-hydrated before the procedure. They should drink a sufficient amount of water prior to the injection of 68Ga-DOTATATE and are strongly encouraged to continue drinking fluids and to urinate frequently for the first few hours following the scan.[1] As the primary route of excretion is renal, this practice helps to rapidly flush unbound radiotracer from the body, which serves two important purposes: it reduces the radiation absorbed dose to the urinary bladder wall and other organs, and it helps to clear background activity, improving image quality.[15]
• Management of Somatostatin Analogs: A critical consideration is the potential for drug-drug interactions with non-radioactive somatostatin analogs, such as octreotide and lanreotide. These therapeutic drugs bind to the same somatostatin receptors as 68Ga-DOTATATE and will competitively block the uptake of the radiotracer, potentially leading to a false-negative scan.[1] Therefore, their administration must be carefully timed relative to the PET scan:
• Short-acting somatostatin analogs (e.g., subcutaneous octreotide) should be withheld for at least 24 hours prior to imaging.[16]
• For patients on long-acting somatostatin analogs (e.g., Octreotide LAR, Lanreotide Autogel), the PET scan should be scheduled to take place just before their next scheduled dose is due.[16]

6.2 Recommended Dosage and Intravenous Administration

The administered dose of 68Ga-DOTATATE is based on patient weight to ensure consistency and to adhere to radiation safety guidelines.

• Recommended Dose: For both adult and pediatric patients, the recommended amount of radioactivity to be administered is 2 MBq/kg (0.054 mCi/kg) of body weight.[15]
• Maximum Dose: There is an upper limit to the total dose. The administered activity should not exceed a maximum of 200 MBq (5.4 mCi), even in heavier patients.[15]
• Administration: The dose is administered as a single bolus injection into a peripheral vein.[1] Following the injection, an intravenous flush with sterile 0.9% sodium chloride is recommended to ensure the entire dose is delivered from the syringe and tubing into the patient's circulation.[16] All handling and administration of the radiopharmaceutical must be performed using appropriate safety measures, including waterproof gloves and effective radiation shielding, to minimize exposure to healthcare personnel.[16]

6.3 PET/CT Image Acquisition

The timing of the scan after injection is determined by the agent's pharmacokinetics to capture the point of optimal tumor-to-background contrast.

• Uptake Time: Image acquisition can begin between 40 and 90 minutes after the intravenous administration of 68Ga-DOTATATE.[15] This allows sufficient time for the tracer to accumulate in SSTR-positive tumors and for background activity in the blood and soft tissues to clear.
• Scan Coverage: A whole-body PET/CT scan is the standard procedure. The recommended scan range is from the skull vertex down to the mid-thigh to ensure all common sites of NET primary tumors and metastases are included.[15]

6.4 Radiation Dosimetry

As with any nuclear medicine procedure, understanding the radiation dose delivered to the patient is a critical component of the risk-benefit assessment.

• Cumulative Exposure: The administration of 68Ga-DOTATATE contributes to a patient's overall long-term cumulative radiation exposure. This exposure is associated with a small but non-zero increased lifetime risk of cancer, a fact that must be communicated to the patient.[17]
• Critical Organs: Due to the agent's biodistribution and primary route of renal excretion, the organs that receive the highest absorbed radiation doses are the spleen, the kidneys/adrenals, and the wall of the urinary bladder.[15] For patients who have had a splenectomy, the radiation dose to other organs may be higher due to altered biodistribution.[23]
• Effective Dose: The total effective radiation dose to the patient is relatively low. The estimated effective dose is approximately 0.021 mSv per MBq of injected activity.[15] For a typical adult dose of 200 MBq, this equates to an effective dose of about 4.2 mSv, which is lower than the dose from an ¹¹¹In-pentetreotide scan and is comparable to the dose from many standard diagnostic CT scans.[15]

Organ/Tissue	Absorbed Dose per Administered Activity (mSv/MBq)	Source(s)
Spleen	0.108	23
Kidneys/Adrenals	0.081	23
Urinary Bladder Wall	0.122	23
Liver	0.041	23
Pituitary Gland	0.027	15
Total Body Effective Dose	0.021	15
Table 2: Estimated Radiation Absorbed Doses in Key Organs from Ga 68 DOTATOC Injection (Note: Data from a closely related agent, Ga 68 DOTATOC, as a proxy for Ga 68 dotatate).23

VII. Safety Profile, Adverse Events, and Risk Management

The safety profile of Dotatate gallium Ga-68 is excellent, with a very low incidence of pharmacological side effects. The primary risks associated with its use are not related to the drug's intrinsic toxicity but are inherent to the nature of radiopharmaceuticals and targeted molecular imaging. A comprehensive risk management strategy involves understanding and mitigating these specific risks.

7.1 Adverse Reactions

Dotatate gallium Ga-68 is generally very well tolerated by patients. The adverse reactions reported in clinical trials and post-marketing surveillance have been infrequent, mild, and transient.[17]

• Common Pharmacological Effects: The most frequently reported adverse events are gastrointestinal in nature, including mild nausea and vomiting.[17]
• Administration Site Reactions: Some patients may experience localized reactions at the injection site, such as pain, a burning sensation, redness, or irritation.[17]
• Hypersensitivity Reactions: While rare, serious allergic or hypersensitivity reactions are possible, as with any intravenously administered agent. These can include anaphylaxis and angioedema. Patients should be monitored for symptoms such as skin rash, itching, hives (urticaria), dizziness, rapid heartbeat (tachycardia), or swelling of the face, lips, tongue, or throat, which require immediate medical attention.[1] The majority of reported hypersensitivity reactions have been limited to mild rash and pruritus, which resolved either spontaneously or with standard symptomatic treatment.[36]

7.2 Contraindications

There are no absolute contraindications listed in the prescribing information for Dotatate gallium Ga-68.[17] The decision to use the agent is based on a clinical assessment of the potential diagnostic benefits versus the risks, primarily the risk of radiation exposure.

7.3 Warnings and Precautions

The FDA label includes two primary warnings that are critical for safe and effective use: radiation risk and the potential for image misinterpretation.

• Radiation Risk: This is the most significant safety consideration.
• Long-Term Exposure: The agent contributes to the patient's long-term cumulative radiation exposure, which is associated with an increased lifetime risk of developing cancer. This risk must be weighed against the immediate benefit of obtaining a diagnosis.[17]
• Protection of Others: Following the injection, the patient becomes a source of radiation. To protect others, especially vulnerable populations, patients are advised to avoid close contact with infants and pregnant women for at least 12 hours after administration of the drug.[1]
• Occupational Exposure: Safe handling and preparation procedures, including the use of appropriate shielding and waterproof gloves, are mandatory to protect healthcare workers from unintentional radiation exposure.[17]
• Risk for Image Misinterpretation: The uptake of 68Ga-DOTATATE is a marker of SSTR expression, not malignancy itself. This creates the potential for misinterpretation if the reader is not aware of the full spectrum of possible findings.
• Lack of Specificity for NETs: While highly expressed in NETs, SSTRs can also be present on a variety of other tumor types, such as meningiomas, some breast cancers, and tumors derived from neural crest tissue. These can also show uptake and mimic NET metastases.[17]
• Uptake in Benign Conditions: Increased uptake can be seen in non-cancerous pathological conditions, including certain thyroid diseases (e.g., Hashimoto's thyroiditis) and sites of subacute inflammation, where activated immune cells express SSTRs.[15]
• Normal Physiologic Variants: As described in the biodistribution section, intense physiologic uptake occurs in several organs. The most common pitfall is focal uptake in the uncinate process of the pancreas, which can be mistaken for a primary pancreatic NET.[15] Other normal variants include uptake in splenules (accessory spleens).[15]
• Clinical Correlation: Because of these possibilities, positive findings on a PET scan may need to be confirmed by histopathology or correlated with other clinical and imaging assessments.[17] Furthermore, a negative scan does not completely rule out the presence of a NET, as a small subset of these tumors may be SSTR-negative.[16]

7.4 Use in Specific Populations

• Pregnancy: There are no adequate and well-controlled studies of 68Ga-DOTATATE in pregnant women. All radiopharmaceuticals have the potential to cause fetal harm due to radiation exposure. The decision to perform a scan in a pregnant patient should only be made after a careful risk-benefit analysis.[17]
• Lactation: It is unknown if Dotatate gallium Ga-68 is excreted in human milk. To minimize potential radiation exposure to a breastfed infant, the standard recommendation is for the mother to interrupt breastfeeding and to pump and discard breast milk for 12 hours following administration of the agent.[1] Some kinetic studies measuring radioactivity in breast milk have suggested that a shorter interruption of 4 hours may be sufficient to reduce the infant dose to a negligible level, but the 12-hour guideline remains the conservative standard.[21]
• Pediatric and Geriatric Use: The safety and efficacy of 68Ga-DOTATATE have been established in the pediatric population, with a safety profile similar to that observed in adults.[1] Likewise, studies have not demonstrated any geriatric-specific problems that would limit its usefulness in elderly patients.[1]

VIII. Clinical Evidence and Comparative Diagnostic Performance

The adoption of Dotatate gallium Ga-68 PET/CT as the new gold standard for imaging neuroendocrine tumors was driven by a substantial body of clinical evidence demonstrating its clear superiority over previous imaging modalities. This evidence base, established through head-to-head comparative studies and meta-analyses, highlights significant improvements in diagnostic accuracy, lesion detection, and overall clinical utility.

8.1 Head-to-Head Comparisons with ¹¹¹In-pentetreotide Scintigraphy (Octreoscan)

For over two decades, scintigraphy using Indium-111 ($^{111}$In) pentetreotide (Octreoscan) was the standard functional imaging modality for NETs.[28] However, direct comparative studies have shown that

68Ga-DOTATATE PET/CT is unequivocally superior.[12]

• Superior Lesion Detection: The most striking advantage of 68Ga-DOTATATE PET/CT is its ability to detect significantly more lesions than Octreoscan in the same patients.[28] This is particularly true for small-volume disease, including small primary tumors and metastases in challenging locations like bone, lymph nodes, and the lungs.[15] In one study involving patients with negative or equivocal Octreoscans, 68Ga-DOTATATE PET was positive in 87% of them and identified 168 lesions compared to just 27 found by the original scan.[38]
• Reasons for Superiority: This dramatic improvement in performance is attributable to two fundamental factors:

1. Superior Chemistry: The Dotatate peptide has a significantly higher binding affinity for the SSTR2 target compared to the pentetreotide peptide used in Octreoscan.[29] This results in more avid and stable tracer accumulation in tumors.
2. Superior Physics: PET is an inherently more sensitive and higher-resolution imaging technology than the Single Photon Emission Computed Tomography (SPECT) used for Octreoscan.[28] This allows for the visualization of smaller lesions and provides clearer, less noisy images.

8.2 Analysis of Diagnostic Accuracy: Sensitivity and Specificity

Quantitative analyses have confirmed the superior diagnostic accuracy of 68Ga-DOTATATE PET/CT.

• High Intrinsic Performance: A systematic review and meta-analysis of the literature calculated a high pooled sensitivity of 90.9% and a pooled specificity of 90.6% for 68Ga-DOTATATE PET/CT in detecting NETs.[39]
• Comparative Accuracy: In a pivotal prospective study that directly compared the two agents in 78 patients, the overall accuracy of 68Ga-DOTATATE was 0.94, which was statistically significantly higher than the 0.82 accuracy of ¹¹¹In-pentetreotide.[28] The study found that the sensitivity of 68Ga-DOTATATE was 96%, compared to only 72% for ¹¹¹In-pentetreotide. The specificity of the two tests was equivalent at 93%.[28] This demonstrates that the primary advantage of the PET agent is its ability to correctly identify patients with disease (higher sensitivity) without an increase in false-positive results.

8.3 Comparison with Anatomic Imaging (CT/MRI)

While CT and MRI are essential for providing detailed anatomical information, 68Ga-DOTATATE PET/CT often provides complementary and sometimes superior information.

• Enhanced Detection: The functional nature of the PET scan allows it to detect SSTR-positive tumors that may be too small or have an appearance on CT/MRI that is indistinguishable from normal tissue.[30] It has shown particular superiority in the detection of bone metastases, which can be subtle on CT scans.[38]
• Complementary Roles: The two modalities are not mutually exclusive but are synergistic. The PET component provides functional information about SSTR expression, while the CT component of the PET/CT scan provides the precise anatomical localization of any abnormal uptake. Anatomic imaging with CT or MRI remains indispensable for monitoring changes in the size of tumors over time and is the primary imaging modality for patients whose tumors are SSTR-negative.[12]

8.4 Complementary Role with ¹⁸F-FDG PET/CT

In the context of NETs, there is often an inverse relationship between SSTR expression and glucose metabolism, a phenomenon sometimes referred to as the "flip-flop" effect.[9]

• Well-Differentiated NETs (Grade 1/2): These tumors are typically slow-growing and have high SSTR expression but low glucose metabolism. Consequently, they are intensely positive on 68Ga-DOTATATE scans and often negative or have only low-grade uptake on a standard ¹⁸F-FDG PET/CT scan.[9]
• Poorly-Differentiated Neuroendocrine Carcinomas (NECs, Grade 3): These are aggressive, rapidly growing cancers that frequently lose SSTR expression and become highly glycolytic. They are often negative on 68Ga-DOTATATE scans but show intense uptake on ¹⁸F-FDG scans.[9]

This biological dichotomy means that the two PET tracers provide complementary information. In patients with intermediate-grade tumors or suspected tumor heterogeneity (coexistence of low- and high-grade disease), performing both scans can provide a more complete biological profile of the cancer, which can be critical for guiding therapy decisions (e.g., PRRT for SSTR-positive disease vs. chemotherapy for FDG-positive disease).[9]

The cumulative clinical evidence has been so compelling that it has led to a paradigm shift in practice. The introduction of 68Ga-DOTATATE PET/CT was not an incremental improvement but a disruptive technological leap, rendering Octreoscan obsolete for most NET indications due to its overwhelming superiority across nearly every metric: diagnostic accuracy, lesion detection, patient convenience (a two-hour protocol versus a two-day protocol), and a lower patient radiation dose.[15]

Metric	⁶⁸Ga-DOTATATE PET/CT	¹¹¹In-pentetreotide Scintigraphy (Octreoscan)	Key Finding/Summary	Source(s)
Sensitivity	91-96%	72%	Significantly higher sensitivity for PET/CT, detecting more true-positive cases.	28
Specificity	91-93%	93%	Equivalent specificity, indicating no increase in false-positive results.	28
Overall Accuracy	94%	82%	Statistically significant improvement in overall diagnostic accuracy for PET/CT.	28
Lesion Detection	Superior	Inferior	Detects significantly more lesions, especially small and bony metastases.	15
Patient Convenience	~2-hour, single-day protocol	24-48 hour, multi-day protocol	Dramatically improved patient experience and workflow efficiency.	38
Radiation Dose	Lower (e.g., ~4.3 mSv)	Higher (e.g., ~12 mSv)	Lower effective radiation dose to the patient.	15
Table 3: Comparative Diagnostic Accuracy and Performance: ⁶⁸Ga-DOTATATE PET/CT vs. ¹¹¹In-pentetreotide Scintigraphy

IX. Impact on Clinical Management and the Theranostic Paradigm

The ultimate measure of a diagnostic test's value is not just its technical accuracy but its ability to positively influence clinical decision-making and patient outcomes. The superior information provided by Dotatate gallium Ga-68 PET/CT translates directly into tangible and often profound changes in patient management, preventing both under-treatment and over-treatment and serving as the gateway to advanced targeted therapies.

9.1 Evidence of Management Changes

Multiple studies have documented the high clinical impact of 68Ga-DOTATATE PET/CT. The findings from the scan lead to a significant alteration in the planned course of treatment for a substantial proportion of patients. Published reports indicate that the scan results prompted a change in management in anywhere from 36% to over 60% of patients with NETs.[15]

These management changes are frequently major and can fundamentally redirect a patient's therapeutic journey. Examples include:

• Altering Surgical Plans: In a patient thought to have localized disease based on conventional imaging, a 68Ga-DOTATATE scan might reveal previously undetected widespread metastases. This finding would lead to the cancellation of a planned major surgery that would have been futile and morbid, instead directing the patient to appropriate systemic therapy.[12] Conversely, in a patient with known metastases but an unknown primary, the scan might identify a resectable primary tumor, opening the door to a potentially curative surgical approach.
• Changing Treatment Modality: The scan's ability to accurately stage the disease often leads to a shift between treatment modalities. A patient may be up-staged from local therapy (surgery) to systemic therapy (somatostatin analogs, PRRT, chemotherapy) or, in some cases, down-staged, making them a candidate for a more aggressive local approach.[28]
• Enabling Peptide Receptor Radionuclide Therapy (PRRT): The scan plays an indispensable role in identifying patients who are eligible for PRRT with agents like 177Lu-DOTATATE. By confirming high SSTR expression in the tumors, the scan provides the necessary evidence to proceed with this highly effective targeted therapy. Studies have shown that 68Ga-DOTATATE correctly identified patients as PRRT candidates who had been incorrectly classified as ineligible by the less sensitive Octreoscan.[12]

The high rate of management change is the ultimate validation of the agent's clinical value. It proves that its superior diagnostic accuracy is not merely an academic finding but a critical driver of more precise, personalized, and effective clinical care. The scan ensures that patients receive the most appropriate treatment for their true stage of disease, which was frequently underestimated by older imaging techniques.

9.2 Role in the "Theranostics" Approach

Dotatate gallium Ga-68 is the quintessential diagnostic component of the SSTR-targeted "theranostic" paradigm. Theranostics, a portmanteau of "therapy" and "diagnostics," refers to the use of a matched pair of compounds where one is used to diagnose and select patients (the diagnostic) and the other is used to deliver therapy to the same molecular target (the therapeutic).

The SSTR-targeted theranostic process follows a logical "see, treat, and follow" pathway:

1. Diagnose/Stage ("See"): A patient with a known or suspected NET undergoes a 68Ga-DOTATATE PET/CT scan. This scan non-invasively visualizes the location, extent, and intensity of SSTR expression throughout the body.[9]
2. Treat: If the scan demonstrates avid uptake in the tumors, confirming the presence of the target, the patient is identified as an excellent candidate for PRRT. They are then treated with a therapeutic agent like 177Lu-DOTATATE. This therapeutic agent uses the exact same Dotatate targeting molecule but carries a beta-emitting radionuclide (177Lu) that delivers a cytotoxic dose of radiation directly to the SSTR-positive cancer cells.[11]
3. Follow: Subsequent 68Ga-DOTATATE PET/CT scans can be used to monitor the biological response to the PRRT, assessing changes in SSTR expression and tumor viability.

In this paradigm, the diagnostic scan does more than just locate the tumor; it acts as a predictive biomarker. The intensity of tracer uptake on the initial 68Ga-DOTATATE scan has been shown to be well-correlated with the likelihood of a positive response to PRRT.[12] This "see what you treat, treat what you see" approach represents a pinnacle of personalized medicine, ensuring that a potent targeted therapy is delivered only to those patients who are most likely to benefit, and has transformed the therapeutic landscape for patients with advanced, inoperable NETs.

X. Regulatory History and Concluding Synthesis

The journey of Dotatate gallium Ga-68 from development to becoming the standard of care is a compelling example of how a radiopharmaceutical with clear clinical advantages can navigate the regulatory process and rapidly transform medical practice. Its history reflects both the significant unmet need in the management of neuroendocrine tumors and the agent's profound impact in addressing that need.

10.1 Development and Commercialization

Dotatate gallium Ga-68 was developed and brought to market by Advanced Accelerator Applications (AAA), an international company specializing in molecular nuclear medicine, which is now part of Novartis.[2] In the United States, the product is commercialized under the brand name

Netspot.[1] A key element of its commercialization strategy was its formulation as a sterile, single-dose kit. This kit allows for the convenient, on-site preparation of the final injectable

68Ga-DOTATATE solution by combining the kit components with the eluate from a commercially available Germanium-68/Gallium-68 (68Ge/68Ga) generator.[14] This decentralized preparation model was crucial for enabling widespread access and adoption by nuclear medicine departments without requiring proximity to a cyclotron.[9]

10.2 Key Milestones in FDA Approval

The regulatory pathway for Netspot was expedited, reflecting its perceived importance and significant advantages over existing technologies.

• Orphan Drug Designation: In March 2014, Gallium Ga 68 dotatate received Orphan Drug Designation from both the U.S. FDA and the European Medicines Agency (EMA).[5] This designation is granted to drugs intended to treat rare diseases (affecting fewer than 200,000 people in the U.S.) and provides incentives, such as tax credits and market exclusivity, to encourage their development.
• Priority Review: The FDA granted Netspot a Priority Review designation.[5] This status is reserved for drugs that, if approved, would represent a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious condition. This signaled that the regulatory agency recognized its potential to provide a major advance in the care of NET patients.
• FDA Approval: Following the priority review, Netspot was officially approved by the U.S. FDA on June 1, 2016.[2] This approval marked the first time a kit for the preparation of a 68Ga-based PET agent was approved in the U.S., paving the way for a new class of diagnostics.

This streamlined regulatory trajectory, from Orphan Drug status to Priority Review and swift approval, serves as a case study in modern drug development. It demonstrates that a product with a clear mechanism of action, a well-defined patient population with an unmet need, and compelling clinical data showing a dramatic improvement over the standard of care can achieve regulatory success efficiently.

10.3 Synthesis and Concluding Remarks

Dotatate gallium Ga-68 is not merely an incremental improvement in imaging; it represents a true paradigm shift in the diagnosis, staging, and management of neuroendocrine tumors. Its introduction has effectively replaced a decades-old standard of care with a molecular imaging technique that is more accurate, more sensitive, faster, more convenient for patients, and delivers a lower radiation dose.

The superior diagnostic performance of 68Ga-DOTATATE PET/CT has been proven to directly and significantly alter clinical management for a large proportion of patients, leading to more appropriate, personalized, and effective treatment strategies. Perhaps most importantly, it serves as the foundational diagnostic pillar of the SSTR-targeted theranostic approach. By enabling a "see what you treat, treat what you see" strategy, it has unlocked the potential of powerful targeted radionuclide therapies like PRRT, transforming the prognosis for many patients with advanced neuroendocrine tumors.

The success of 68Ga-DOTATATE has also catalyzed further innovation in the field, including the development of SSTR-targeted agents labeled with other radionuclides, such as Copper-64 (64Cu), which offers logistical advantages due to a longer half-life, potentially expanding access to this vital imaging modality even further.[20] In conclusion, Dotatate gallium Ga-68 stands as a landmark achievement in nuclear oncology, perfectly illustrating the power of molecular imaging to guide personalized medicine and improve patient care.

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