The uptake of [18F]FDG by tissues is a marker for the tissue uptake of glucose, which in turn is closely correlated with certain types of tissue metabolism. After [18F]FDG is injected into a patient, a PET scanner can form two-dimensional or three-dimensional images of the distribution of [18F]FDG within the body.
Since its development in 1976, [18F]FDG had a profound influence on research in the neurosciences.[2] The subsequent discovery in 1980 that [18F]FDG accumulates in tumors underpins the evolution of PET as a major clinical tool in cancer diagnosis.[3] [18F]FDG is now the standard radiotracer used for PET neuroimaging and cancer patient management.[4]
The images can be assessed by a nuclear medicine physician or radiologist to provide diagnoses of various medical conditions.
History
In 1968, Dr. Josef Pacák, Zdeněk Točík and Miloslav Černý at the Department of Organic Chemistry, Charles University, Czechoslovakia were the first to describe the synthesis of FDG.[5] Later, in the 1970s, Tatsuo Ido and Al Wolf at the Brookhaven National Laboratory were the first to describe the synthesis of FDG labeled with fluorine-18.[6] 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).
Beginning in August 1990, and continuing throughout 1991, a shortage of oxygen-18, a raw material for FDG, made it necessary to ration isotope supplies. Israel's oxygen-18 facility had shut down due to the Gulf War, and the U.S. government had shut down its isotopes of carbon, oxygen and nitrogen facility at Los Alamos National Laboratory, leaving Isotec as the main supplier.[7] Please see the comparative figure below for further history of the FDG molecule.
Comparative images of the first X-ray (left) and the first total body FDG-PET scan (right), the latter pioneered by Abass Alavi. These diagnostic tools have revolutionized modern medicine, with the FDG-PET scan having an impact akin to that of the first X-ray.
Synthesis
[18F]FDG was first synthesized via electrophilic fluorination with [18F]F2.[6] Subsequently, a "nucleophilic synthesis" was devised with the same radioisotope.
As with all radioactive18F-labeled radioligands, the fluorine-18 must be made initially as the fluoride anion in a cyclotron. Synthesis of complete [18F]FDG radioactive tracer begins with synthesis of the unattached fluoride radiotracer, since cyclotron bombardment destroys organic molecules of the type usually used for ligands, and in particular, would destroy glucose.
Cyclotron production of fluorine-18 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 where an incoming proton "knocks out" a neutron) in the 18O. This produces "carrier-free" dissolved [18F]fluoride ([18F]F−) ions in the water. The 109.8-minute half-life of fluorine-18 makes rapid and automated chemistry necessary after this point.
Anhydrous fluoride salts, which are easier to handle than fluorine gas, can be produced in a cyclotron.[8] To achieve this chemistry, the [18F]F− 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. Evaporation of the eluate gives [(crypt-222)K]+[18F]F− (2) .
The fluoride anion is nucleophilic but its anhydrous conditions are required to avoid competing reactions involving hydroxide, which is also a good nucleophile. The use of the cryptand to sequester the potassium ions avoids ion-pairing between free potassium and fluoride ions, rendering the fluoride anion more reactive.
Intermediate 2 is treated with the protected mannosetriflate (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:[9][10]
Mechanism of action, metabolic end-products, and metabolic rate
[18F]FDG, as a glucose analog, is taken up by high-glucose-using cells such as brain, brown adipocytes, kidney, and cancer cells, where phosphorylation 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 [18F]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 cannot exit 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.
The fluorine in [18F]FDG decays radioactively via beta-decay to 18O−. 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 C-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[citation needed] by decaying in place to O-18 to form [18O]O-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 excreted 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 renally much more quickly than the isotope itself can decay. Unlike normal glucose, FDG is not fully reabsorbed by the kidney.[11] 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.[12]
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 two hours). Thus, within 24 hours (13 half-lives after the injection), 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 = 1⁄8192 of the initial radioactivity of the dose. In practice, patients who have been injected with [18F]FDG are told to avoid the close vicinity of especially radiation-sensitive persons, such as infants, children and pregnant women, for at least 12 hours (7 half-lives, or decay to 1⁄128 the initial radioactive dose).
Production
Alliance Medical and Siemens Healthcare are[when?] the only producers in the United Kingdom.[citation needed] A dose of FDG in England costs[when?] about £130. In Northern Ireland, where there is a single supplier, doses cost up to £450.[13] IBA Molecular North America and Zevacor Molecular, both of which are owned by Illinois Health and Science (IBAM having been purchased as of 1 August 2015), Siemens' PETNET Solutions (a subsidiary of Siemens Healthcare), and Cardinal Health[14] are producers in the U.S.[15][16][17][18]
Distribution
The labeled [18F]FDG compound has a relatively short shelf life which is dominated by the physical decay of fluorine-18 with a half-life of 109.8 minutes, or slightly less than two hours. Still, this half life is sufficiently long to allow shipping the compound to remote PET scanning facilities, in contrast to other medical radioisotopes like carbon-11. Due to transport regulations for radioactive compounds, delivery is normally done by specially licensed road transport, but means of transport may also include dedicated small commercial jet services. Transport by air allows to expand the distribution area around a [18F]FDG production site to deliver the compound to PET scanning centres even hundreds of miles away.
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 [18F]FDG from site of manufacture to site of use.[19]
Applications
Whole-body PET scan using F-FDG to show liver metastases of a colorectal tumor
In PET imaging, [18F]FDG is primarily used for imaging tumors in oncology, where a static [18F]FDG PET scan is performed and the tumor [18F]FDG uptake is analyzed in terms of Standardized Uptake Value (SUV). FDG PET/CT can be used for the assessment of glucose metabolism in the heart and the brain. [18F]FDG is taken up by cells, and subsequently phosphorylated by hexokinase (whose mitochondrial form is greatly elevated in rapidly growing malignant tumours)[20]. Phosphorylated [18F]FDG cannot be further metabolised and is thus 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,[21] particularly in Hodgkin's disease, non-Hodgkin 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 millicuries or 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 six 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 180mg/dL = 10mmol/L, and such patients must be rescheduled). 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 into muscles (this causes unwanted artifacts in the scan, interfering with reading especially when the organs of interest are inside the body vs. inside the skull). 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).
Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, regional chemical composition, and absorption. Different tracers are used for various imaging purposes, depending on the target process within the body.
Nuclear medicine or nucleology is a medical specialty involving the application of radioactive substances in the diagnosis and treatment of disease. Nuclear imaging, in a sense, is "radiology done inside out" because it records radiation emitted from within the body rather than radiation that is transmitted through the body from external sources like X-ray generators. In addition, nuclear medicine scans differ from radiology, as the emphasis is not on imaging anatomy, but on the function. For such reason, it is called a physiological imaging modality. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) scans are the two most common imaging modalities in nuclear medicine.
A radioactive tracer, radiotracer, or radioactive label is a synthetic derivative of a natural compound in which one or more atoms have been replaced by a radionuclide. By virtue of its radioactive decay, it can be used to explore the mechanism of chemical reactions by tracing the path that the radioisotope follows from reactants to products. Radiolabeling or radiotracing is thus the radioactive form of isotopic labeling. In biological contexts, experiments that use radioisotope tracers are sometimes called radioisotope feeding experiments.
Oxygen-18 is a natural, stable isotope of oxygen and one of the environmental isotopes.
Fluorine-18 (18F) is a fluorine radioisotope which is an important source of positrons. It has a mass of 18.0009380(6) u and its half-life is 109.771(20) minutes. It decays by positron emission 96.7% of the time and electron capture 3.3% of the time. Both modes of decay yield stable oxygen-18.
2-Deoxy-d-glucose is a glucose molecule which has the 2-hydroxyl group replaced by hydrogen, so that it cannot undergo further glycolysis. As such; it acts to competitively inhibit the production of glucose-6-phosphate from glucose at the phosphoglucoisomerase level. 2-Deoxyglucose labeled with tritium or carbon-14 has been a popular ligand for laboratory research in animal models, where distribution is assessed by tissue-slicing followed by autoradiography, sometimes in tandem with either conventional or electron microscopy.
Positron emission tomography–computed tomography is a nuclear medicine technique which combines, in a single gantry, a positron emission tomography (PET) scanner and an x-ray computed tomography (CT) scanner, to acquire sequential images from both devices in the same session, which are combined into a single superposed (co-registered) image. Thus, functional imaging obtained by PET, which depicts the spatial distribution of metabolic or biochemical activity in the body can be more precisely aligned or correlated with anatomic imaging obtained by CT scanning. Two- and three-dimensional image reconstruction may be rendered as a function of a common software and control system.
Cardiac PET is a form of diagnostic imaging in which the presence of heart disease is evaluated using a PET scanner. Intravenous injection of a radiotracer is performed as part of the scan. Commonly used radiotracers are Rubidium-82, Nitrogen-13 ammonia and Oxygen-15 water.
The standardized uptake value (SUV) is a nuclear medicine term, used in positron emission tomography (PET) as well as in modern calibrated single photon emission tomography (SPECT) imaging for a semiquantitative analysis. Its use is particularly common in the analysis of [18F]fluorodeoxyglucose ([18F]FDG) images of cancer patients. It can also be used with other PET agents especially when no arterial input function is available for more detailed pharmacokinetic modeling. Otherwise measures like the fractional uptake rate (FUR) or parameters from more advanced pharmacokinetic modeling may be preferable.
Brain positron emission tomography is a form of positron emission tomography (PET) that is used to measure brain metabolism and the distribution of exogenous radiolabeled chemical agents throughout the brain. PET measures emissions from radioactively labeled metabolically active chemicals that have been injected into the bloodstream. The emission data from brain PET are computer-processed to produce multi-dimensional images of the distribution of the chemicals throughout the brain.
Fluorine may interact with biological systems in the form of fluorine-containing compounds. Though elemental fluorine (F2) is very rare in everyday life, fluorine-containing compounds such as fluorite occur naturally as minerals. Naturally occurring organofluorine compounds are extremely rare. Man-made fluoride compounds are common and are used in medicines, pesticides, and materials. Twenty percent of all commercialized pharmaceuticals contain fluorine, including Lipitor and Prozac. In many contexts, fluorine-containing compounds are harmless or even beneficial to living organisms; in others, they are toxic.
Radiofluorination is the process by which a radioactive isotope of fluorine is attached to a molecule and is preferably performed by nucleophilic substitution using nitro or halogens as leaving groups. Fluorine-18 is the most common isotope used for this procedure. This is due to its 97% positron emission and relatively long 109.8 min half-life. The half-life allows for a long enough time to be incorporated into the molecule and be used without causing exceedingly harmful effects. This process has many applications especially with the use of positron emission tomography (PET) as the aforementioned low positron energy is able to yield a high resolution in PET imaging.
Metabolic trapping refers to a localization mechanism of synthesized radiocompounds in the human body. It can be defined as the intracellular accumulation of a radioactive tracer based on the relative metabolic activity of the body's tissues. It is a basic principle of the design of radiopharmaceuticals as metabolic probes for functional studies or tumor location.
18F-FMISO or fluoromisonidazole is a radiopharmaceutical used for PET imaging of hypoxia. It consists of a 2-nitroimidazole molecule labelled with the positron-emitter fluorine-18.
Jacob M. Hooker is an American chemist and expert in molecular imaging, particularly in the development and application of simultaneous MRI and PET. He has contributed major advances on the entire spectrum of research from fundamental chemistry methodology with radioisotopes to human neuroimaging.
Fluciclovine (18F), also known as anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid, or as Axumin, is a diagnostic agent indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated prostate specific antigen (PSA) levels.
Sandip Basu is an Indian physician of Nuclear Medicine and the Head, Nuclear Medicine Academic Program at the Radiation Medicine Centre. He is also the Dean-Academic (Health-Sciences), BARC at Homi Bhabha National Institute and is known for his services and research in Nuclear Medicine, particularly on Positron emission tomography diagnostics and Targeted Radionuclide Therapy in Cancer. The Council of Scientific and Industrial Research, the apex agency of the Government of India for scientific research, awarded him the Shanti Swarup Bhatnagar Prize for Science and Technology, one of the highest Indian science awards for his contributions to Nuclear Medicine in 2012.
Philip F. Cohen is a Canadian clinical director of Nuclear Medicine working out of the Lions Gate Hospital in North Vancouver, British Columbia. As a nuclear medicine physician, he is a pioneer in the usage of 3-D imaging techniques to improve diagnosis of bone disease and injury in collaboration with the Medical Imaging Research Group at University of British Columbia. Furthermore, Cohen has been involved in clinical research trials of new radiopharmaceuticals. To that effect, Cohen was the first recipient of a research grant from the Lions Gate Hospital Foundation, one of several peer-reviewed awards that would follow.
Carbon-11 choline is the basis of medical imaging technologies. Because of its involvement in biologic processes, choline is related to diseases, leading to the development of medical imaging techniques to monitor its concentration. When radiolabeled with 11CH3, choline is a useful a tracer in PET imaging. Carbon-11 is radioactive with a half-life of 20.38 minutes. By monitoring the gamma radiation resulting from the decay of carbon-11, the uptake, distribution, and retention of carbon-11 choline can be monitored.
Positron emission tomography for bone imaging, as an in vivo tracer technique, allows the measurement of the regional concentration of radioactivity proportional to the image pixel values averaged over a region of interest (ROI) in bones. Positron emission tomography is a functional imaging technique that uses [18F]NaF radiotracer to visualise and quantify regional bone metabolism and blood flow. [18F]NaF has been used for imaging bones for the last 60 years. This article focuses on the pharmacokinetics of [18F]NaF in bones, and various semi-quantitative and quantitative methods for quantifying regional bone metabolism using [18F]NaF PET images.
↑ Newberg A, Alavi A, Reivich M (January 2002). "Determination of regional cerebral function with FDG-PET imaging in neuropsychiatric disorders". Seminars in Nuclear Medicine. 32 (1): 13–34. doi:10.1053/snuc.2002.29276. PMID11839066.
↑ Som P, Atkins HL, Bandoypadhyay D, Fowler JS, MacGregor RR, Matsui K, etal. (July 1980). "A fluorinated glucose analog, 2-fluoro-2-deoxy-D-glucose (F-18): nontoxic tracer for rapid tumor detection". Journal of Nuclear Medicine. 21 (7): 670–5. PMID7391842.
↑ Pacák J, Točík Z, Černý M (1969). "Synthesis of 2-Deoxy-2-fluoro-D-glucose". Journal of the Chemical Society D: Chemical Communications (2): 77. doi:10.1039/C29690000077.
1 2 Ido T, Wan CN, Casella V, Fowler JS, Wolf AP, Reivich M, Kuhl DE (1978). "Labeled 2-deoxy-D-glucose analogs: 18F-labeled 2-deoxy-2-fluoro-D-glucose, 2-deoxy-2-fluoro-D-mannose and 14C-2-deoxy-2-fluoro-D-glucose". J Labeled Compounds Radiopharm. 24 (2): 174–183. doi:10.1002/jlcr.2580140204.
↑ Moran, J. K., Lee, H. B., & Blaufox, M. D. (1999). Optimization of urinary FDG excretion during PET imaging. The Journal of Nuclear Medicine, 40(8), 1352.
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