## 2 [18F]Fluoride Activation for Aliphatic Nucleophilic S\({}_{\text{N}}\)2 Substitution
### Azeotropic Drying Free Methods for Kryptofix-Mediated Radiofluorinations  
In the majority of protocols for kryptofix-mediated fluorinations the AEC resin-bound [\({}^{18}\)F]F\({}^{-}\) is eluted from the cartridge with a solution of K\({}_{2.2.2}\) /K\({}_{2}\)CO\({}_{3}\) dissolved in a mixture of organic solvent and water. The type of anion-exchange cartridge and the amount of packing material substantially influence the efficacy of [\({}^{18}\)F]F\({}^{-}\) elution as well as the subsequent radiolabeling. Currently, the capture-and-release process is usually accomplished using standard AccellTM Plus QMA light Sep-Pak cartridge (filled with 130 mg of quaternary ammonium chloride polymer) or less common ChromafixPS-HCO\({}_{3}\) (filled with 46 mg of quaternary ammonium bicarbonate polymer). Before use, the QMA*Cl\({}^{-}\) cartridge is conditioned with aqueous K\({}_{2}\)CO\({}_{3}\) or KHCO\({}_{3}\) and water, while the PSHCO\({}_{3}\) cartridge is just wetted with water. The QMA resin is also available in a carbonate form, the Sep-Pak Light (46 mg) AccelTM Plus QMA Carbonate cartridge that can be used as is, without any conditioning. These cartridges are used in all types of automated synthesizers as components of pre-assembled disposable cassettes (GE FASTlab) or the appropriate reagents kits (IBA Synthera). Barrel-type cartridges such as Vac QMA 1 cc (100 mg), Oasis WAX 1 cc Vac Cartridge (30 mg), StrataTMXL-A polymeric strong anion, 100 mg/3 mL, and others are commonly encountered in research and development situations but are less common in routine applications. Choosing the right eluent solvent mixture can significantly reduce drying time later on. A 100% aqueous eluent employed in the first published methods provided 100% elution efficiency (EE). However, the azeotropic drying time was too long for the method to be of significant practical use. In the current practice, the acetonitrile-water mixtures with different percentages of water are employed to shorten the drying procedure. Using eluent that contains only 4% of water and 96% of acetonitrile allowed for the dried reactive [K/K\({}_{2.2.2}\)]+[\({}^{18}\)F]\({}^{-}\) complex to be obtained without further addition of acetonitrile. According to this protocol, the radionuclide is trapped on a standard strong anion-exchange cartridge AccellTM Plus QMA light Sep-Pak (130 mg) pre-conditioned with 10 mL of 0.5 M K\({}_{2}\)CO\({}_{3}\) solution and water, each. Trapped [\({}^{18}\)F]fluoride is eluted with 2 mL of MeCN/H\({}_{2}\)O (96/4 \(v/v\)) mixture containing 9.8 mg (25 \(\upmu\)mol) of K\({}_{2.2.2}\) and 1.8 mg (12 \(\upmu\)mol) of K\({}_{2}\)CO\({}_{3}\), with EE >98%. Evaporation of solvents at 110 \({}^{\circ}\)C under a stream of nitrogen (with no vacuum) produces reactive [\({}^{18}\)F]fluoride directly. The general applicability of this methodology, originally developed by our group for automated synthesis of [\({}^{18}\)F]FDG [16,17], was confirmed by applying it to the routine preparations of the tumor imaging agents [\({}^{18}\)F]FMeChol [18], [\({}^{18}\)F]FES [19], [\({}^{18}\)F]FEDBT [20]. Numerous other examples of this method's application to production of other radiotracers were reported in the literature: [\({}^{18}\)F]Flumazenil [21], [\({}^{18}\)F]FEPE2I [22], [\({}^{18}\)F]FP-06684511 [23], [\({}^{18}\)F]MCL524 [24], and others [Figure 2]. [PERSON] and co-authors [25,26] have reported an azeotropic-drying free method using QMA eluent containing 12% of water in acetonitrile with less basic KHCO\({}_{3}\). The [\({}^{18}\)F]F\({}^{-}\) retained on the cartridge (QMA, 130 mg) was eluted with 1 mL of K\({}_{2.2.2}\) /KHCO\({}_{3}\) solution; with vacuum-assisted evaporation to dryness at 72 \({}^{\circ}\)C under a nitrogen flow following, affording reactive [\({}^{18}\)F]fluoride species. Using this protocol, two highly-sought radiotracers, [\({}^{18}\)F]FET [25] and [\({}^{18}\)F]FMISO [26] were synthesized.