Technetium-99m (DB14227): A Comprehensive Review of its Properties and Clinical Utility

Executive Summary

Technetium-99m (99mTc) stands as the most indispensable medical radioisotope in modern nuclear medicine, utilized in tens of millions of diagnostic procedures annually across the globe.[1] Its preeminence is rooted in a nearly ideal combination of physicochemical and radiochemical properties. With a short physical half-life of approximately 6 hours and a principal gamma emission of 140.5 keV,

99mTc allows for high-quality diagnostic imaging with minimal radiation dose to the patient.[1] The isotope's versatile coordination chemistry enables it to be chelated to a vast array of carrier molecules, or ligands, creating a diverse portfolio of radiopharmaceuticals, each designed to trace specific physiological pathways or target particular organ systems.[5] This report provides a comprehensive analysis of Technetium-99m, detailing its fundamental properties, the principles of its radiopharmacology, its extensive clinical applications in functional imaging, and its safety profile. Furthermore, it examines the critical logistical framework of its production via Molybdenum-99 (

99Mo) generators, a system that underpins its global availability but also presents significant supply chain challenges.[7]

Introduction: The Cornerstone of Nuclear Medicine

Technetium-99m (99mTc) is a metastable nuclear isomer of the artificially produced element technetium.[1] First isolated in 1938 as a decay product of Molybdenum-99 (

99Mo), its potential as a medical tool remained largely unrealized for over two decades.[9] The field of nuclear medicine was fundamentally transformed in 1960 when Powell Richards at Brookhaven National Laboratory first proposed the use of

99mTc as a medical tracer, recognizing its unique potential for diagnostic imaging.[7] Since then,

99mTc has become the undisputed "workhorse" of diagnostic nuclear medicine, accounting for over 80% of all procedures worldwide.[10]

The profound impact of 99mTc stems from its ability to provide functional, metabolic, and physiological information about the body, which is often unattainable through purely anatomical imaging modalities such as computed tomography (CT) or magnetic resonance imaging (MRI).[9] It is not a therapeutic agent in itself but serves as a radioactive label, or radiotracer. When attached to a specific carrier molecule (ligand), it forms a radiopharmaceutical that can be administered to a patient to visualize organ function, blood flow, or metabolic activity.[5] The gamma radiation emitted by

99mTc is detected externally by a gamma camera, generating images (scintigrams) that map the in vivo distribution of the tracer, thereby revealing the physiological status of the tissue or organ of interest.[9]

Physicochemical and Radiochemical Properties

Elemental and Isotopic Characteristics

Technetium (Tc), with atomic number 43, is a transition metal located in Group 7 of the periodic table.[13] It is a silvery-gray, radioactive metal that was the first element to be produced artificially, a feat accomplished by Carlo Perrier and Emilio Segrè in 1937.[3] A key characteristic of technetium is that all of its isotopes are radioactive; it has no stable form. The longest-lived isotope has a half-life that is short relative to the age of the Earth, explaining why any primordial technetium has long since decayed and why it was not discovered in nature.[13]

The isotope of interest, Technetium-99m, is a metastable nuclear isomer of Technetium-99 (99Tc), as indicated by the "m" suffix.[1] Its nucleus contains 43 protons and 56 neutrons.[1] It is identified by the CAS Number 14133-76-7 and has an average isotopic mass of approximately 98.9063 Da.[8] The chemical versatility of technetium is central to its utility. It can exist in a wide range of oxidation states, from -1 to +7, with the +4 and +7 states being the most common and stable.[16] This property allows it to form stable coordination complexes with an extensive variety of ligands, which is the foundational principle of creating diverse radiopharmaceuticals.[4] In the chemical form eluted from a generator, technetium exists as the pertechnetate ion,

TcO4−​, where it possesses a +7 oxidation state.[18]

Radiodecay and Dosimetry

The physical properties of 99mTc decay are exceptionally well-suited for medical imaging, representing a unique convergence of ideal characteristics that balance imaging quality, logistical feasibility, and patient safety.

The decay of 99mTc to its ground state, 99Tc, occurs via an isomeric transition.[3] This process is characterized by the emission of a single, monoenergetic gamma ray with a principal photon energy of 140.5 keV, which accounts for approximately 89% of decays.[1] This gamma energy is high enough to readily escape the body for external detection, yet low enough to be efficiently absorbed by the sodium iodide crystals used in conventional gamma cameras and to be effectively collimated by lead shielding, which is essential for producing high-resolution images.[3]

Crucially, this decay occurs without the emission of primary particulate radiation, such as alpha or beta particles.[4] These particles deposit their energy locally within tissues, contributing significantly to the patient's radiation dose without providing any useful imaging information. The absence of such emissions is a major factor in the favorable dosimetric profile and safety of

99mTc.[3]

The physical half-life of 99mTc is approximately 6 hours (often cited with high precision as 6.0066 or 6.02 hours).[1] This duration is long enough to permit the necessary steps of production, radiopharmaceutical preparation, administration, and biological distribution before imaging. At the same time, it is short enough to ensure that the majority of the radioactivity (93.7%) has decayed within 24 hours, thereby minimizing the patient's total radiation exposure.[1] The decay product,

99Tc, is itself radioactive but possesses a very long half-life of 211,000 years, meaning that the radioactivity from its decay is negligible and contributes trivially to the overall patient radiation dose.[4]

Property	Value	Source(s)
Atomic Number (Z)	43	1
Mass Number (A)	99	8
Neutron Number (N)	56	1
Isotopic Mass	~98.9063 Da	1
Physical Half-Life	~6.02 hours	3
Decay Mode	Isomeric Transition	3
Primary Emission	Gamma Ray	3
Principal Photon Energy	140.5 keV	1
Parent Isotope	Molybdenum-99 (99Mo)	1
Parent Half-Life	~66 hours	7
Decay Product	Technetium-99 (99Tc)	1
Table 1: Key Physicochemical and Isotopic Properties of Technetium-99m

Production and Availability: The Molybdenum-99/Technetium-99m Generator

The short half-life of 99mTc makes it impossible to produce centrally and distribute to hospitals for clinical use. This logistical challenge was overcome by the development of the 99Mo/99mTc generator system, a critical innovation that enabled the widespread adoption of 99mTc.[7] This system decentralizes the final step of production, allowing for a reliable, on-demand supply of

99mTc at the clinical site.

The process begins with the production of the parent isotope, 99Mo, which has a much longer half-life of 66 hours, making it suitable for transport over long distances.[7] The vast majority of the world's

99Mo is produced in a small number of nuclear research reactors by the neutron irradiation of highly enriched uranium-235 targets. 99Mo is one of the fission products generated, which is then chemically separated and purified.[1]

This purified 99Mo is the core component of the 99mTc generator, often colloquially referred to as a "moly cow." The generator itself is a column chromatography system. 99Mo, in the chemical form of molybdate ([99Mo]MoO42−​), is adsorbed onto an alumina (Al2​O3​) column contained within a lead shield.[5] As the parent

99Mo decays, it transforms into 99mTc, which exists in the chemical form of pertechnetate (TcO4−​). Due to its single negative charge, pertechnetate is less tightly bound to the alumina column than the doubly-charged molybdate.[5]

This difference in binding affinity allows for their separation through a process called elution. By passing a sterile saline solution through the column, the more weakly bound, soluble sodium pertechnetate is washed off, or "eluted," while the parent 99Mo remains adsorbed on the column.[7] This process, often called "milking the cow," can be performed daily at the hospital or radiopharmacy to obtain a fresh supply of sterile, pyrogen-free

99mTc for preparing patient doses. Due to the 66-hour half-life of 99Mo, the generators have a useful life of about one week and must be replaced regularly.[7] This generator system is the linchpin of the global

99mTc supply chain, but its reliance on a few aging reactors also makes it a point of significant vulnerability, with reactor shutdowns in the past leading to global shortages of this vital medical isotope.[1]

Principles of Technetium-99m Radiopharmacology

The Radiotracer Concept: Mechanism of Action

The fundamental mechanism of action for all 99mTc-based agents is that of a radioactive tracer.[1] The

99mTc atom itself exerts no pharmacological effect and has no inherent biological role.[13] Its sole purpose is to serve as a detectable source of gamma radiation that can be tracked from outside the body.

The true biological activity resides in the ligand, or carrier molecule, to which the 99mTc is attached. Once the complete radiopharmaceutical is administered to the patient, its biodistribution is dictated by the physicochemical properties of the ligand.[9] The ligand is designed to participate in a specific physiological or metabolic process, causing the radiopharmaceutical to accumulate in a target organ or tissue. The gamma rays subsequently emitted from the localized

99mTc are detected by a gamma camera, which constructs a scintigraphic image mapping the tracer's concentration. This image is a direct representation of the physiological function being studied, such as regional blood flow, metabolic activity, or receptor density.[9] This ability to visualize function is a key distinction from anatomical imaging modalities like CT and MRI, providing a complementary and often unique diagnostic perspective.[9]

Coordination Chemistry and Ligand Design

The remarkable versatility of 99mTc as a diagnostic tool is a direct consequence of its flexible coordination chemistry.[5] The pertechnetate ion (

TcO4−​) eluted from the generator, where technetium is in the +7 oxidation state, is relatively non-reactive and does not readily form complexes with most ligands.[19]

To create a radiopharmaceutical, the technetium must first be reduced to a lower, more reactive oxidation state, such as +1, +3, +4, or +5. This reduction is typically achieved by adding a reducing agent, with stannous ion (Sn2+) being the most common agent used in commercially available kits.[19] Once in a reduced state, the technetium atom can act as a central metal ion, readily forming stable coordinate covalent bonds with one or more ligand molecules, a process known as chelation.[6]

The choice of ligand is what defines the final product's biological behavior and clinical application. This modular design has led to the development of a wide array of agents:

• Diphosphonates (e.g., Medronate, Oxidronate): These molecules have a strong affinity for the hydroxyapatite mineral component of bone, targeting areas of high bone turnover and osteoblastic activity.[27]
• Lipophilic Cations (e.g., Sestamibi, Tetrofosmin): These positively charged, fat-soluble molecules are taken up by myocardial cells in proportion to regional blood flow, making them ideal for cardiac perfusion imaging.[9]
• Colloidal Particles (e.g., Sulfur Colloid): When injected intravenously, these microscopic particles are recognized as foreign and are cleared from the blood via phagocytosis by cells of the reticuloendothelial system (RES), primarily in the liver, spleen, and bone marrow.[9]
• Lipophilic Chelates (e.g., Exametazime [HMPAO]): These neutral, lipid-soluble complexes are able to cross the intact blood-brain barrier and become trapped in brain tissue, allowing for the imaging of cerebral perfusion.[31]
• Renal Agents (e.g., Mertiatide [MAG3], Pentetate): These are small molecules that are rapidly cleared from the body by the kidneys, each via a specific mechanism (tubular secretion for MAG3, glomerular filtration for DTPA), enabling detailed assessment of renal function.[33]

Quality Control and Radiochemical Purity

The in-hospital preparation of 99mTc radiopharmaceuticals from kits is a chemical reaction that is not always 100% efficient, potentially leading to the formation of radiochemical impurities.[19] The presence of these impurities can lead to unintended biodistribution of radioactivity, which may degrade image quality or lead to misinterpretation. Therefore, assessing the radiochemical purity of the final preparation is a critical quality control step before administration to a patient.[19]

The two most common impurities are:

1. Free Pertechnetate (TcO4−​): This occurs when the reduction of Tc(VII) is incomplete, or if the reducing agent (stannous ion) has been oxidized by the introduction of air into the kit vial. Free pertechnetate will not bind to the ligand and will distribute to the thyroid gland, salivary glands, and stomach, which can interfere with the interpretation of the intended scan.[19]
2. Hydrolyzed-Reduced Technetium (TcO2​): This insoluble colloidal impurity forms when the reduced technetium hydrolyzes with water before it can be successfully chelated by the ligand. These particles are phagocytized by the RES, leading to unintended uptake in the liver and spleen, which can obscure adjacent target organs.[19]

Quality control is routinely performed using simple and rapid chromatographic techniques, such as paper chromatography or instant thin-layer chromatography (ITLC), to separate the desired radiopharmaceutical from these potential impurities and ensure the preparation meets purity specifications before patient administration.[25]

Pharmacokinetics: Biodistribution and Clearance

Administration and Distribution

The route of administration for 99mTc radiopharmaceuticals is tailored to the specific diagnostic question. The vast majority are administered via intravenous injection.[27] However, specialized applications may require alternative routes, such as oral administration of

99mTc-sulfur colloid for gastric emptying and reflux studies, or inhalation of an aerosolized form like 99mTc-DTPA or Technegas for lung ventilation imaging.[36]

Following administration, the distribution pattern is entirely governed by the properties of the ligand attached to the 99mTc.

• For bone imaging, 99mTc-diphosphonates are rapidly cleared from the bloodstream. Within a few hours, approximately 50% of the injected dose localizes to the skeleton, while the remainder is taken up by the kidneys for excretion. The blood clearance follows a tri-exponential pattern, reflecting initial mixing, tissue uptake, and slower clearance of protein-bound fractions.[38]
• For brain imaging, 99mTc-exametazime shows rapid blood clearance, with peak brain uptake of up to 7% of the dose occurring within the first minute after injection. The remaining activity is distributed widely throughout the body, particularly in muscle and soft tissues.[31]
• For RES imaging, intravenous 99mTc-sulfur colloid is cleared from the blood with a nominal half-life of only 2.5 minutes. The particles are phagocytized, with 80-90% accumulating in the liver's Kupffer cells, 5-10% in the spleen, and the balance in the bone marrow.[36]
• For lymphatic mapping, 99mTc-tilmanocept is injected near a tumor. It is cleared from the injection site via lymphatic channels and accumulates in the draining sentinel lymph nodes, where it can be detected within 10 minutes of injection.[39]

Metabolism and Excretion

Unlike most conventional drugs, 99mTc radiopharmaceuticals typically do not undergo metabolic transformation. The chelate bond between the technetium and the ligand is designed to be stable in vivo, and the entire complex is cleared from the body chemically unaltered.[27]

The primary route of elimination for most small-molecule radiopharmaceuticals is renal excretion into the urine.[27] This rapid urinary clearance makes the bladder wall the critical organ for radiation dose considerations in many procedures. Consequently, patients are routinely instructed to maintain good hydration and to void their bladder frequently after the scan to minimize the radiation dose to the bladder wall.[35] Certain agents, particularly larger molecules or those designed for hepatobiliary imaging, are cleared predominantly through the liver and excreted via the biliary system into the feces.[29] Agents administered orally for gastrointestinal studies are not absorbed systemically and are eliminated entirely through the feces.[36]

Biological vs. Physical Half-Life: The Concept of Effective Half-Life

The rate at which radioactivity disappears from the body is determined by two distinct processes: physical decay and biological clearance. Understanding the interplay between these two is fundamental to radiopharmaceutical dosimetry.

• Physical Half-Life (Tp​): This is an immutable property of the radionuclide, representing the time required for half of the radioactive atoms in a sample to undergo decay. For 99mTc, Tp​ is a constant of approximately 6 hours.[1]
• Biological Half-Life (Tb​): This is a physiological parameter, representing the time it takes for the body's biological processes (primarily excretion) to eliminate half of the administered chemical substance. Tb​ is highly variable and depends on the specific radiopharmaceutical. For example, the overall biological half-life of 99mTc is often generalized as 24 hours (1 day), but for specific agents like 99mTc-tilmanocept, the clearance from the injection site has a biological half-life of only 1.8 to 3.1 hours.[42]
• Effective Half-Life (Te​): This represents the net effect of both physical decay and biological clearance occurring simultaneously. The effective half-life is always shorter than either the physical or biological half-life alone and is calculated using the formula: Te​=(Tp​×Tb​)/(Tp​+Tb​). For a typical 99mTc agent with a Tp​ of 6 hours and a Tb​ of 24 hours, the effective half-life is approximately 4.8 hours.[44]

This rapid effective clearance is a key advantage of 99mTc. Even if a compound has slow biological clearance, the short physical half-life of the radionuclide ensures that the radiation exposure diminishes quickly. This duality allows for high-quality images to be obtained while keeping the total radiation dose to the patient as low as reasonably achievable.

Clinical Applications in Diagnostic Imaging

The versatility of 99mTc has led to its application in nearly every organ system. The ability to label a wide variety of molecules allows for the targeted visualization of diverse physiological processes. Imaging is performed using planar scintigraphy, single-photon emission computed tomography (SPECT), or hybrid SPECT/CT, which fuses functional and anatomical images.

Radiopharmaceutical (Generic Name)	Common Brand Name(s)	Target/Mechanism	Primary Clinical Application(s)
99mTc Medronate (MDP)	Osteolite, CIS-MDP	Hydroxyapatite binding	Skeletal Scintigraphy (Bone Scan)
99mTc Sestamibi	Cardiolite, Miraluma	Myocardial perfusion	Myocardial Perfusion Imaging (MPI), Breast Imaging
99mTc Tetrofosmin	Myoview	Myocardial perfusion	Myocardial Perfusion Imaging (MPI)
99mTc Mertiatide (MAG3)	Technescan MAG3	Renal tubular secretion	Renal Function/Flow Scan
99mTc Pentetate (DTPA)	Techneplex	Glomerular filtration	Renal GFR Scan, Lung Ventilation Scan
99mTc Succimer (DMSA)	NephroScan	Renal cortical binding	Renal Cortical Scan
99mTc Exametazime (HMPAO)	Ceretec	Cerebral perfusion	Brain Perfusion Scan, WBC Labeling
99mTc Sulfur Colloid	N/A	RES phagocytosis	Liver/Spleen Scan, GI Motility Studies
99mTc Tilmanocept	Lymphoseek	CD206 receptor binding	Sentinel Lymph Node Mapping
99mTc Pertechnetate	Drytec, TechneLite	Iodide analog	Thyroid Scan, Meckel's Diverticulum Scan
99mTc MAA	Pulmolite	Pulmonary capillary blockade	Lung Perfusion Scan
99mTc Carbon	Technegas	Gas-like dispersion	Lung Ventilation Scan
Table 2: Major Technetium-99m Radiopharmaceuticals and Their Clinical Applications 6

Skeletal Scintigraphy (Bone Scan)

Bone scanning is one of the most common nuclear medicine procedures. It utilizes 99mTc labeled to diphosphonate compounds like medronate (MDP) or oxidronate (HDP).[27] These agents undergo chemisorption onto the hydroxyapatite mineral matrix of bone. The degree of uptake is proportional to local blood flow and osteoblastic (bone-forming) activity.[27] This makes the bone scan highly sensitive for detecting areas of abnormal bone turnover. Key indications include the screening for and follow-up of skeletal metastases from cancers like prostate and breast cancer, detection of subtle or radiographically occult fractures (e.g., stress fractures), diagnosis of osteomyelitis (bone infection), and evaluation of metabolic bone diseases like Paget's disease.[27]

Myocardial Perfusion Imaging (MPI)

MPI is a cornerstone in the non-invasive diagnosis of coronary artery disease (CAD). The primary agents used are 99mTc-sestamibi and 99mTc-tetrofosmin.[9] These are lipophilic, cationic complexes that are taken up by viable myocardial cells in proportion to coronary blood flow.[29] The standard protocol involves imaging the heart under two conditions: rest and stress (induced by exercise or pharmacologic agents). By comparing the rest and stress images, clinicians can identify areas of ischemia (reduced blood flow under stress, appearing as a "reversible" defect) and infarction (scar tissue with no blood flow, appearing as a "fixed" defect).[12]

Renal Scintigraphy

A variety of 99mTc agents are used to provide a comprehensive assessment of kidney function and anatomy. 99mTc-mertiatide (MAG3) is primarily cleared by tubular secretion and is used to assess effective renal plasma flow and evaluate for urinary tract obstruction.[46]

99mTc-pentetate (DTPA) is cleared exclusively by glomerular filtration, allowing for the measurement of GFR.[34] In contrast,

99mTc-succimer (DMSA) binds to the cortical tubules and is used for high-resolution static imaging of the renal parenchyma to identify scarring from infection or reflux.[20]

Cerebral Perfusion Imaging

Agents such as 99mTc-exametazime (HMPAO) and 99mTc-bicisate (ECD) are used to visualize regional cerebral blood flow.[9] These are neutral, lipophilic compounds that can cross the intact blood-brain barrier and become trapped in brain tissue. The resulting SPECT images can help localize the area of stroke, identify seizure foci, and aid in the differential diagnosis of dementia.[31]

Pulmonary Scintigraphy (V/Q Scan)

This procedure is primarily used to diagnose pulmonary embolism. It involves two separate scans. A ventilation scan is performed by having the patient inhale an aerosol of 99mTc-DTPA or the ultrafine carbon particle dispersion known as Technegas.[6] A perfusion scan is then performed after an intravenous injection of

99mTc-macroaggregated albumin (MAA), which consists of particles that become temporarily trapped in the pulmonary capillaries, mapping blood flow.[9] A pulmonary embolism is typically identified as a region of the lung that is ventilated but not perfused (a "V/Q mismatch").

Hepatobiliary and Reticuloendothelial System Imaging

Hepatobiliary iminodiacetic acid (HIDA) scans use agents like 99mTc-mebrofenin, which are taken up by hepatocytes and excreted into the bile. This allows for the functional assessment of the gallbladder and biliary ducts, primarily to diagnose acute cholecystitis.[6] Separately, intravenous injection of

99mTc-sulfur colloid is used to image the reticuloendothelial system. The colloid particles are phagocytized by Kupffer cells in the liver and by cells in the spleen and bone marrow, allowing for evaluation of liver disease and splenic function.[9]

Oncological and Lymphatic Imaging

In oncology, 99mTc is crucial for sentinel lymph node mapping in patients with breast cancer and melanoma. An injection of 99mTc-sulfur colloid or the more targeted agent 99mTc-tilmanocept near the primary tumor allows for the identification of the first draining ("sentinel") lymph node(s).[9] This technique guides surgeons, allowing for a less invasive biopsy and more accurate staging. Clinical trials are also exploring new

99mTc-labeled agents for imaging specific cancers, such as metastatic renal cell carcinoma and prostate cancer.[55]

Other Specialized Applications

The versatility of 99mTc extends to numerous other diagnostic tests, including:

• Thyroid Scintigraphy: Using 99mTc-pertechnetate, which is trapped by the thyroid gland similarly to iodide, to evaluate thyroid nodules and function.[9]
• Gastrointestinal Bleeding Scan: Using 99mTc-labeled red blood cells to localize the site of active bleeding in the GI tract.[6]
• Meckel's Scintigraphy: Using 99mTc-pertechnetate to identify ectopic gastric mucosa present in a Meckel's diverticulum, a common cause of pediatric GI bleeding.[9]
• Infection Imaging: Using 99mTc-exametazime (HMPAO) to label a patient's own white blood cells, which are then re-injected to localize sites of infection or inflammation.[6]

Safety, Regulation, and Clinical Practice

Adverse Effects and Contraindications

Technetium-99m radiopharmaceuticals are generally well-tolerated, and adverse reactions are infrequent.[9] When they do occur, they are most often hypersensitivity-type reactions, which can range from mild skin manifestations like rash, urticaria, and pruritus to severe, life-threatening anaphylaxis.[9] Other reported systemic effects include transient hypotension or hypertension, syncope, seizures, and cardiac arrhythmias.[9] Some adverse effects are specific to the chelating ligand; for instance,

99mTc-sestamibi has been associated with a metallic or bitter taste (dysgeusia), and chest pain.[9]

The use of 99mTc is generally contraindicated during pregnancy (Pregnancy Category C) due to the potential radiation risk to the developing fetus, although it may be used if the diagnostic benefit is deemed to significantly outweigh this risk.[9] As

99mTc is excreted in breast milk, breastfeeding is also a contraindication. Guidelines recommend that nursing mothers temporarily interrupt breastfeeding for 12 to 24 hours following administration, expressing and discarding milk during this period to minimize radiation exposure to the infant.[15] A specific contraindication exists for the use of

99mTc-MAA in patients with severe pulmonary hypertension, where fatalities have been reported.[9]

Category	Details/Examples	Key Considerations	Source(s)
Common Adverse Effects	Hypersensitivity reactions (rash, urticaria, itching), gastrointestinal symptoms (nausea, vomiting), transient blood pressure changes.	Reactions are typically mild and self-limiting. Cardiopulmonary resuscitation equipment should be available.	9
Serious Adverse Effects	Anaphylaxis, seizures, cardiac arrhythmias. Mortality reported with 99mTc-MAA in patients with severe pulmonary hypertension.	Although rare, the potential for severe reactions necessitates clinical vigilance during and after administration.	9
Contraindications	Known severe hypersensitivity to the agent. Pregnancy (Category C). Breastfeeding.	Benefits versus risks must be carefully weighed in pregnant patients. Breastfeeding should be temporarily discontinued.	9
Key Warnings	All radiopharmaceuticals contribute to a patient's long-term cumulative radiation exposure, which is associated with an increased risk of cancer.	Procedures must be clinically justified and optimized to use the lowest radiation dose possible (ALARA principle).	48
Table 3: Summary of Safety Profile and Contraindications

Radiation Safety and Patient Management

The guiding principle for all procedures involving ionizing radiation is ALARA: As Low As Reasonably Achievable.[60] For patients, this involves ensuring the clinical indication is appropriate and using the minimum amount of radioactivity necessary to obtain a diagnostic-quality image. Patient preparation often includes adequate hydration before the procedure, and post-procedure instructions emphasize continued hydration and frequent bladder voiding. This helps to accelerate the renal clearance of the radiopharmaceutical, thereby reducing the radiation dose to the bladder wall and the total body.[35]

For healthcare professionals, radiation safety involves minimizing time spent near the radioactive source, maximizing distance, and using appropriate shielding.[60] This includes handling vials and syringes in lead shields, using tungsten syringe shields during injection, and wearing personal protective equipment and dosimetry badges to monitor exposure.[41]

Drug Interactions

Drug interactions can potentially alter the biodistribution of a 99mTc radiopharmaceutical, which can compromise the diagnostic accuracy of the scan. For instance, some drugs can affect the function of the target organ or the clearance of the tracer. Proton pump inhibitors (PPIs) may reduce the efficacy of 99mTc-sestamibi for myocardial imaging and should be withheld prior to the scan.[9] Numerous medications can affect the renal excretion rate of agents like

99mTc-exametazime, potentially increasing or decreasing serum levels and altering image quality.[31] A large number of drugs that are substrates or inhibitors of P-glycoprotein transporters can theoretically alter the pharmacokinetics of

99mTc-sestamibi.[63] A thorough patient medication history is therefore essential.

Regulatory Landscape and Commercial Formulations

Technetium-99m and the non-radioactive kits used to prepare its various formulations are regulated as pharmaceutical drugs by national health authorities such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and Australia's Therapeutic Goods Administration (TGA).[64] These agencies oversee the approval, manufacturing, and quality control of both the

99Mo/99mTc generators and the individual radiopharmaceutical kits.

The FDA has approved numerous 99mTc-based agents and generators over several decades.[9] Recent approvals include Technegas (

99mTc-carbon) for lung ventilation imaging in 2023.[37] In response to supply chain vulnerabilities, the FDA has also approved domestic production systems for

99mTc, such as the RadioGenix System, to ensure a more stable supply for U.S. patients.[67] In Europe, the EMA provides centralized guidance and authorizes products, such as the list of nationally authorized products for

99mTc-mebrofenin (Bridatec), and is actively developing strategies to secure the European radioisotope supply.[68] Similarly, the TGA regulates the supply in Australia, licensing facilities like those operated by the Australian Nuclear Science and Technology Organisation (ANSTO) for domestic production.[66]

A wide variety of commercial formulations are available, often marketed under specific brand names. These include:

• Generators: TechneLite, Drytec, RadioGenix System.[18]
• Bone Agents: Osteolite (99mTc-medronate), TechneScan HDP (99mTc-oxidronate).[27]
• Cardiac Agents: Cardiolite (99mTc-sestamibi), Myoview (99mTc-tetrofosmin).[29]
• Brain Agents: Ceretec (99mTc-exametazime), Neurolite (99mTc-bicisate).[31]
• Renal Agents: Technescan MAG3 (99mTc-mertiatide), NephroScan (99mTc-succimer).[47]
• Lymphatic Mapping: Lymphoseek (99mTc-tilmanocept).[49]

Conclusion and Future Perspectives

For over half a century, Technetium-99m has been the cornerstone of diagnostic nuclear medicine. Its enduring prominence is a testament to a unique and fortuitous combination of physical and chemical properties: a near-ideal half-life, a clean and easily detectable gamma emission, and an exceptionally versatile chemistry. This report has detailed how these characteristics have enabled the development of a vast armamentarium of radiopharmaceuticals capable of providing non-invasive, functional insights into nearly every organ system in the human body. The paradigm of 99mTc imaging—where the ligand dictates the biological target and the radioisotope serves as the signal—has proven to be a powerful and adaptable platform for medical diagnosis.

Despite its long history of success, the future of 99mTc is shaped by both challenges and opportunities. The primary challenge remains the fragile global supply chain for its parent isotope, 99Mo, which is dependent on a small number of aging nuclear reactors. This has spurred significant international effort and innovation aimed at diversifying production methods, including non-uranium-based approaches and cyclotron production, to ensure a more stable and secure supply for patients.[10]

Concurrently, the field continues to evolve with the development of novel ligands designed to target more specific molecular pathways, particularly in oncology, where there is a growing need for agents that can characterize tumors and monitor therapeutic response.[55] While positron emission tomography (PET) has emerged as a powerful functional imaging modality, the accessibility, lower cost, and established infrastructure of SPECT imaging with

99mTc ensure its continued relevance. The fundamental advantages of Technetium-99m, which have made it indispensable for decades, are poised to sustain its vital role in global healthcare for the foreseeable future.

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