Fluorodeoxyglucose
Encyclopedia
Fludeoxyglucose (INN
) or fluorodeoxyglucose (18F), commonly abbreviated 18F-FDG or FDG, is a radiopharmaceutical used in the medical imaging
modality positron emission tomography
(PET). Chemically, it is 2-deoxy-2-(18F)fluoro-D-glucose, a glucose
analog
, with the positron
-emitting radioactive isotope fluorine-18
substituted for the normal hydroxyl group at the 2' position in the glucose molecule.
After 18F-FDG is injected into a patient, a PET scanner can form images of the distribution of FDG around the body. The images can be assessed by a nuclear medicine
physician or radiologist to provide diagnoses of various medical conditions.
prevents the glucose from being released again from the cell, once it has been absorbed. The 2' hydroxyl group (—OH) in normal glucose is needed for further glycolysis
(metabolism of glucose by splitting it), but FDG is missing this 2' hydroxyl. Thus, in common with its sister molecule 2-deoxy-D-glucose
, FDG cannot be further metabolized in cells. The 18F-FDG-6-phosphate formed when 18F-FDG enters the cell thus cannot move out of the cell before radioactive decay. As a result, the distribution of 18F-FDG is a good reflection of the distribution of glucose uptake and phosphorylation
by cells in the body.
After 18F-FDG decays radioactively, however, its 2'-fluorine is converted to 18O
–, and after picking up a proton
H+ from a hydronium ion in its aqueous environment, the molecule becomes glucose-6-phosphate labeled with harmless nonradioactive "heavy oxygen" in the hydroxyl at the 2' position. The new presence of a 2' hydroxyl now allows it to be metabolized normally in the same way as ordinary glucose, producing non-radioactive end-products.
Although in theory all 18F-FDG is metabolized as above with a radioactivity elimination half-life of 110 minutes (the same as that of fluorine-18), clinical studies have shown that the radioactivity of 18F-FDG partitions into two major fractions. About 75% of the fluorine-18 activity remains in tissues and is eliminated with a half-life of 110 minutes, presumably by decaying in place to O-18 to form 18O-glucose-6-phosphate, which is non-radioactive (this molecule can soon be metabolized to carbon dioxide and water, after nuclear transmutation
of the fluorine to oxygen ceases to prevent metabolism). Another fraction of 18F-FDG, representing about 20% of the total fluorine-18 activity of an injection, is eliminated renally by two hours after a dose of 18F-FDG, with a rapid half-life of about 16 minutes (this portion makes the renal-collecting system and bladder prominent in a normal PET scan). This short biological half-life indicates that this 20% portion of the total fluorine-18 tracer activity is eliminated pharmacokinetically (through the renal system) much more quickly than the isotope itself can decay. The rapidity also suggests that some of this 18F is no longer attached to glucose, since low concentrations of glucose in the blood are retained by the normal kidney and not passed into the urine. Because of this rapidly-excreted urine 18F, the urine of a patient undergoing a PET scan may therefore be especially radioactive for several hours after administration of the isotope.
All radioactivity of 18F-FDG, both the 20% which is rapidly excreted in the first several hours of urine which is made after the exam, and the 80% which remains in the patient, decays with a half-life of 110 minutes (just under 2 hours). Thus, within 24 hours (13 half-lives), the radioactivity in the patient and in any initially-voided urine which may have contaminated bedding or objects after the PET exam, will have decayed to 2−13 = 1/8200th of the initial radioactivity of the dose.
In PET imaging, 18F-FDG can be used for the assessment of glucose metabolism in the heart
, lungs, and the brain
. It is also used for imaging tumours in oncology
, where usually dynamic images are analysed in terms of Standardized Uptake Value
s. 18F-FDG is taken up by cells, phosphorylated by hexokinase
(whose mitochondrial form is greatly elevated in rapidly-growing malignant tumours), and retained by tissues with high metabolic activity, such as most types of malignant tumours. As a result FDG-PET can be used for diagnosis, staging, and monitoring treatment of cancers, particularly in Hodgkin's disease, non-Hodgkin's lymphoma, colorectal cancer
, breast cancer
, melanoma
, and lung cancer
. It has also been approved for use in diagnosing Alzheimer's disease
.
In body-scanning applications in searching for tumor or metastatic disease, a dose of 18F-FDG in solution (typically 5 to 10 millicurie
, 200 to 400 MBq
) is typically injected rapidly into a saline drip running into a vein, in a patient who has been fasting for at least 6 hours, and who has a suitably low blood sugar. (This is a problem for some diabetics; usually PET scanning centers will not administer the isotope to patients with blood glucose levels over about 180 mg/dL = 10 mmol/L, and such patients must be re-scheduled). The patient must then wait about an hour for the sugar to distribute and be taken up into organs which use glucose – a time during which physical activity must be kept to a minimum, in order to minimize uptake of the radioactive sugar in muscles (this causes unwanted artifacts when the organs of interest are inside the body). Then, the patient is placed in the PET scanner for a series of one or more scans which may take from 20 minutes to as long as an hour (often, only about one quarter of the body length may be imaged at a time).
were the first to describe the synthesis of 18F-FDG. The compound was first administered to two normal human volunteers by Abass Alavi
in August, 1976 at the University of Pennsylvania. Brain images obtained with an ordinary (non-PET) nuclear scanner demonstrated the concentration of 18F-FDG in that organ (see history reference below).
. Subsequently, a nucleophilic synthesis was devised. Here, radioactive 18F must be made first as the fluoride anion in the cyclotron
. This may be accomplished by bombardment of neon-20 with deuterons, but usually is done by proton bombardment of 18O-enriched water, causing a (p,n) reaction (sometimes called a "knockout reaction"—a common type of nuclear reaction with high probability) in the 18O. This produces "carrier-free" dissolved 18F-fluoride (18F–) ions in the water. The 109.8 minute half-life of 18F makes rapid and automated chemistry necessary after this point.
To do this chemistry, the 18F– is separated from the aqueous solvent by trapping it on an ion-exchange column, and eluted with an acetonitrile
solution of 2,2,2-cryptand and potassium carbonate, which gives [(crypt-222)K]+ 18F− (2) when dried.
The fluoride anion is not ordinarily very nucleophilic. Anhydrous conditions are required to avoid the competing reaction with hydroxide. The use of the cryptand to sequester the potassium ions avoids ion-pairing between free potassium and fluoride ions, making the fluoride anion more reactive.
Intermediate 2 is reacted with a protected mannose
triflate (1); the fluoride anion displaces the triflate leaving group
in an SN2 reaction, giving the protected fluorinated deoxyglucose (3). Base hydrolysis removes the acetyl protecting groups, giving the desired product (4) after removing the cryptand via ion-exchange:
Recently, on-site cyclotrons with integral shielding and portable chemistry stations for making 18F-FDG have accompanied PET scanners to remote hospitals. This technology holds some promise in the future, for replacing some of the scramble to transport FDG from site of manufacture to site of use.
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
) or fluorodeoxyglucose (18F), commonly abbreviated 18F-FDG or FDG, is a radiopharmaceutical used in the medical imaging
Medical imaging
Medical imaging is the technique and process used to create images of the human body for clinical purposes or medical science...
modality positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
(PET). Chemically, it is 2-deoxy-2-(18F)fluoro-D-glucose, a glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
analog
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
, with the positron
Positron
The positron or antielectron is the antiparticle or the antimatter counterpart of the electron. The positron has an electric charge of +1e, a spin of ½, and has the same mass as an electron...
-emitting radioactive isotope fluorine-18
Fluorine-18
Fluorine-18 is a fluorine radioisotope which is an important source of positrons. It has a mass of 18.0009380 u and its half-life is 109.771 minutes....
substituted for the normal hydroxyl group at the 2' position in the glucose molecule.
After 18F-FDG is injected into a patient, a PET scanner can form images of the distribution of FDG around the body. The images can be assessed by a nuclear medicine
Nuclear medicine
In nuclear medicine procedures, elemental radionuclides are combined with other elements to form chemical compounds, or else combined with existing pharmaceutical compounds, to form radiopharmaceuticals. These radiopharmaceuticals, once administered to the patient, can localize to specific organs...
physician or radiologist to provide diagnoses of various medical conditions.
Mechanism of action, metabolic end-products, and metabolic rate
FDG, as a glucose analog, is taken up by high-glucose-using cells such as brain, kidney, and cancer cells, where phosphorylationPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
prevents the glucose from being released again from the cell, once it has been absorbed. The 2' hydroxyl group (—OH) in normal glucose is needed for further glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
(metabolism of glucose by splitting it), but FDG is missing this 2' hydroxyl. Thus, in common with its sister molecule 2-deoxy-D-glucose
2-Deoxy-D-glucose
2-Deoxy-D-glucose is a glucose molecule which has the 2-hydroxyl group replaced by hydrogen, so that it cannot undergo further glycolysis. Glucose hexokinase traps this substance in most cells so that it makes a good marker for tissue glucose use and hexokinase activity. Many cancers have elevated...
, FDG cannot be further metabolized in cells. The 18F-FDG-6-phosphate formed when 18F-FDG enters the cell thus cannot move out of the cell before radioactive decay. As a result, the distribution of 18F-FDG is a good reflection of the distribution of glucose uptake and phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
by cells in the body.
After 18F-FDG decays radioactively, however, its 2'-fluorine is converted to 18O
Oxygen-18
Oxygen-18 is a natural, stable isotope of oxygen and one of the environmental isotopes.18O is an important precursor for the production of fluorodeoxyglucose used in positron emission tomography...
–, and after picking up a proton
Proton
The proton is a subatomic particle with the symbol or and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number....
H+ from a hydronium ion in its aqueous environment, the molecule becomes glucose-6-phosphate labeled with harmless nonradioactive "heavy oxygen" in the hydroxyl at the 2' position. The new presence of a 2' hydroxyl now allows it to be metabolized normally in the same way as ordinary glucose, producing non-radioactive end-products.
Although in theory all 18F-FDG is metabolized as above with a radioactivity elimination half-life of 110 minutes (the same as that of fluorine-18), clinical studies have shown that the radioactivity of 18F-FDG partitions into two major fractions. About 75% of the fluorine-18 activity remains in tissues and is eliminated with a half-life of 110 minutes, presumably by decaying in place to O-18 to form 18O-glucose-6-phosphate, which is non-radioactive (this molecule can soon be metabolized to carbon dioxide and water, after nuclear transmutation
Nuclear transmutation
Nuclear transmutation is the conversion of one chemical element or isotope into another. In other words, atoms of one element can be changed into atoms of other element by 'transmutation'...
of the fluorine to oxygen ceases to prevent metabolism). Another fraction of 18F-FDG, representing about 20% of the total fluorine-18 activity of an injection, is eliminated renally by two hours after a dose of 18F-FDG, with a rapid half-life of about 16 minutes (this portion makes the renal-collecting system and bladder prominent in a normal PET scan). This short biological half-life indicates that this 20% portion of the total fluorine-18 tracer activity is eliminated pharmacokinetically (through the renal system) much more quickly than the isotope itself can decay. The rapidity also suggests that some of this 18F is no longer attached to glucose, since low concentrations of glucose in the blood are retained by the normal kidney and not passed into the urine. Because of this rapidly-excreted urine 18F, the urine of a patient undergoing a PET scan may therefore be especially radioactive for several hours after administration of the isotope.
All radioactivity of 18F-FDG, both the 20% which is rapidly excreted in the first several hours of urine which is made after the exam, and the 80% which remains in the patient, decays with a half-life of 110 minutes (just under 2 hours). Thus, within 24 hours (13 half-lives), the radioactivity in the patient and in any initially-voided urine which may have contaminated bedding or objects after the PET exam, will have decayed to 2−13 = 1/8200th of the initial radioactivity of the dose.
Applications
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
, lungs, and the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. It is also used for imaging tumours in oncology
Oncology
Oncology is a branch of medicine that deals with cancer...
, where usually dynamic images are analysed in terms of Standardized Uptake Value
Standardized Uptake Value
The Standardized Uptake Value is often used in PET imaging for quantitative analysis of PET. It is useful for a simple analysis of fluorodeoxyglucose images, e.g. to monitor the progress of disease during cancer therapy. It can also be used with other PET agents when no arterial input function is...
s. 18F-FDG is taken up by cells, phosphorylated by hexokinase
Hexokinase
A hexokinase is an enzyme that phosphorylates a six-carbon sugar, a hexose, to a hexose phosphate. In most tissues and organisms, glucose is the most important substrate of hexokinases, and glucose-6-phosphate the most important product....
(whose mitochondrial form is greatly elevated in rapidly-growing malignant tumours), and retained by tissues with high metabolic activity, such as most types of malignant tumours. As a result FDG-PET can be used for diagnosis, staging, and monitoring treatment of cancers, particularly in Hodgkin's disease, non-Hodgkin's lymphoma, colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
, breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
, and lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
. It has also been approved for use in diagnosing Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
In body-scanning applications in searching for tumor or metastatic disease, a dose of 18F-FDG in solution (typically 5 to 10 millicurie
Curie
The curie is a unit of radioactivity, defined asThis is roughly the activity of 1 gram of the radium isotope 226Ra, a substance studied by the pioneers of radiology, Marie and Pierre Curie, for whom the unit was named. In addition to the curie, activity can be measured using an SI derived unit,...
, 200 to 400 MBq
Becquerel
The becquerel is the SI-derived unit of radioactivity. One Bq is defined as the activity of a quantity of radioactive material in which one nucleus decays per second. The Bq unit is therefore equivalent to an inverse second, s−1...
) is typically injected rapidly into a saline drip running into a vein, in a patient who has been fasting for at least 6 hours, and who has a suitably low blood sugar. (This is a problem for some diabetics; usually PET scanning centers will not administer the isotope to patients with blood glucose levels over about 180 mg/dL = 10 mmol/L, and such patients must be re-scheduled). The patient must then wait about an hour for the sugar to distribute and be taken up into organs which use glucose – a time during which physical activity must be kept to a minimum, in order to minimize uptake of the radioactive sugar in muscles (this causes unwanted artifacts when the organs of interest are inside the body). Then, the patient is placed in the PET scanner for a series of one or more scans which may take from 20 minutes to as long as an hour (often, only about one quarter of the body length may be imaged at a time).
History
In the 1970s, Tatsuo Ido and Al Wolf at the Brookhaven National LaboratoryBrookhaven National Laboratory
Brookhaven National Laboratory , is a United States national laboratory located in Upton, New York on Long Island, and was formally established in 1947 at the site of Camp Upton, a former U.S. Army base...
were the first to describe the synthesis of 18F-FDG. The compound was first administered to two normal human volunteers by Abass Alavi
Abass Alavi
Abass Alavi is Professor of Radiology and Neurology. He is currently the Director of Research Education in the Division of Nuclear Medicine at the University of Pennsylvania....
in August, 1976 at the University of Pennsylvania. Brain images obtained with an ordinary (non-PET) nuclear scanner demonstrated the concentration of 18F-FDG in that organ (see history reference below).
Synthesis
18F-FDG was first synthesized via electrochemical fluorinationElectrochemical fluorination
Electrochemical fluorination , or electrofluorination, is a foundational organofluorine chemistry method for the preparation of fluorocarbon-based organofluorine compounds. The general approach represents an application of electrosynthesis...
. Subsequently, a nucleophilic synthesis was devised. Here, radioactive 18F must be made first as the fluoride anion in the cyclotron
Cyclotron
In technology, a cyclotron is a type of particle accelerator. In physics, the cyclotron frequency or gyrofrequency is the frequency of a charged particle moving perpendicularly to the direction of a uniform magnetic field, i.e. a magnetic field of constant magnitude and direction...
. This may be accomplished by bombardment of neon-20 with deuterons, but usually is done by proton bombardment of 18O-enriched water, causing a (p,n) reaction (sometimes called a "knockout reaction"—a common type of nuclear reaction with high probability) in the 18O. This produces "carrier-free" dissolved 18F-fluoride (18F–) ions in the water. The 109.8 minute half-life of 18F makes rapid and automated chemistry necessary after this point.
To do this chemistry, the 18F– is separated from the aqueous solvent by trapping it on an ion-exchange column, and eluted with an acetonitrile
Acetonitrile
Acetonitrile is the chemical compound with formula . This colourless liquid is the simplest organic nitrile. It is produced mainly as a byproduct of acrylonitrile manufacture...
solution of 2,2,2-cryptand and potassium carbonate, which gives [(crypt-222)K]+ 18F− (2) when dried.
The fluoride anion is not ordinarily very nucleophilic. Anhydrous conditions are required to avoid the competing reaction with hydroxide. The use of the cryptand to sequester the potassium ions avoids ion-pairing between free potassium and fluoride ions, making the fluoride anion more reactive.
Intermediate 2 is reacted with a protected mannose
Mannose
Mannose is a sugar monomer of the aldohexose series of carbohydrates. Mannose is a C-2 epimer of glucose. It is not part of human metabolism, but is a component of microbial cell walls, and is therefore a target of the immune system and also of antibiotics....
triflate (1); the fluoride anion displaces the triflate leaving group
Leaving group
In chemistry, a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl−, Br−, and I−, and sulfonate esters, such as para-toluenesulfonate...
in an SN2 reaction, giving the protected fluorinated deoxyglucose (3). Base hydrolysis removes the acetyl protecting groups, giving the desired product (4) after removing the cryptand via ion-exchange:
Distribution
The labeled 18F-FDG compound (still having a half-life only 109.8 minutes, or slightly less than 2 hours), is rapidly shipped to points of use by the fastest possible mode. Due to transport regulations for radioactive compounds, this is normally done by specially licensed road transport, but transport may also include dedicated small commercial jet services, to extend the reach of PET scanning to centres hundreds of miles away from the cyclotron and laboratory which produce the radioisotope-labeled compound.Recently, on-site cyclotrons with integral shielding and portable chemistry stations for making 18F-FDG have accompanied PET scanners to remote hospitals. This technology holds some promise in the future, for replacing some of the scramble to transport FDG from site of manufacture to site of use.