[F]FDG was first synthesized via electrophilic fluorination with [F]F. Subsequently, a "nucleophilic synthesis" was devised with the same radioisotope.
As with all radioactive F-labeled radioligands, the fluorine-18 must be made initially as the fluoride anion in a cyclotron. Synthesis of complete [F]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 O-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 O. This produces "carrier-free" dissolved [F]fluoride ([F]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. To achieve this chemistry, the [F]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] [F]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 S2 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: