Fluorodeoxyglucose (18F) (INN), or fluorodeoxyglucose F 18

9 min readJun 14, 2021

Fluorodeoxyglucose (18F) (INN), or fluorodeoxyglucose F 18 (USAN and USP), also commonly called fluorodeoxyglucose and abbreviated [18F]FDG, 18F-FDG or FDG, is a radiopharmaceutical, specifically a radiotracer, 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 radionuclide fluorine-18 substituted for the normal hydroxyl group at the C-2 position in the glucose molecule.

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[edit]

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 18F.[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]

Synthesis[edit]

[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 radioactive 18F-labeled radioligands, the 18F 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 18F may be accomplished by bombardment of neon-20 with deuterons, but usually is done by proton bombardment of 18O-enriched water, causing a (n-p) 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 18F 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 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:[9][10]

Mechanism of action, metabolic end-products, and metabolic rate[edit]

[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.

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 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.

Fluorodeoxyglucose (18F) (INN), or fluorodeoxyglucose F 18

Contents

History[edit]

Synthesis[edit]

Mechanism of action, metabolic end-products, and metabolic rate[edit]

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