## 2 [18F]Fluoride Activation for Aliphatic Nucleophilic S\({}_{\text{N}}\)2 Substitution
### Tetraalkylammonium Salts (Bu\({}_{4}\)N\({}^{+}\), Et\({}_{4}\)N\({}^{+}\)) as the PTCs
Aliphatic radiofluorination of base-sensitive precursors has received much attention in particular. A recent review [41] summarises various new developments in this field. In particular, success [42; 43; 44] has been achieved by exploiting tetatalkylammonium salts in conjunctions with less basic anions such as mesylate, toylate, and triflate. The first application of these quaternary ammonium salts (Bu\({}_{4}\)NOMs and Bu\({}_{4}\)NOTf) dates back to 2011 [45]. It was shown that the solution of Bu\({}_{4}\)NOMs in methanol (0.6 mL, 10 mg (30 \(\upmu\)mol)) could release over 90% of the radioactivity from the AEC (Chromafix({}^{\text{\textregistered}}\) PSTHCO\({}_{3}\)) and provide over 90% RCC in the radiofluorination of model aliphatic substrates when carried out in tertiary alcohols. The effects induced by conditioning anion replacing bicarbonate ion in the PSHCO\({}_{3}\) resin with other anionic bases such as Na\({}_{2}\)CO\({}_{3}\), K\({}_{2}\)HPO\({}_{4}\), and K\({}_{3}\)PO\({}_{4}\) was also examined in that study. It turned out that conditioning the cartridge with phosphate-based anions (KHPO\({}_{4}\)\({}^{-}\) and K\({}_{2}\)PO\({}_{4}\)\({}^{-}\)) did not only provide the highest RCC in radiofluorination of aliphatic substrates but contributed significantly to creating a mild reaction environment with unreacted precursor remaining almost intact. Although that study demonstrated distinct advantages of Bu\({}_{4}\)NOMs as a neutral PTC, results obtained in fluorination of model compounds were not extended further to the preparation of clinically relevant radiopharmaceutical. Thus with the aim of wider implementation of this concept our group has recently [42] suggested a general protocol where the use of the corresponding toyslate salt, Bu\({}_{4}\)NOTs, was adapted to the routine automated synthesis of a series of \({}^{18}\)F-labeled radiotracers [18F]FDG, [18F]FLT, [18F]FMISO, [18F]FET, [18F]FES as well as common radiolabeling synthon, 2-[18F]fluoroethyl toyslate (I\({}^{18}\)F)FEOTs). The radionuclide initially retained on a QMA cartridge (conditioned with an aq. KHCO\({}_{3}\)) was recovered in a solution of Bu\({}_{4}\)NOTs (1 mg, 2.5 \(\upmu\)mol) in MeOH or EtOH. Following solvent removal, reactive [18F]fluoride was reconstituted in 1 mL of MeCN. In order to achieve release of [18F]F\({}^{-}\) from conventional 130 mg QMA cartridge while using such a low amount of the PTC, a reversed loading/elution procedure was employed of the type that has been demonstrated in radiofluorination of electron-rich arenes [46]. However, in conjunction with a smaller QMA Light carbonate cartridge (46 mg)a straightforward eluting protocol was found to be just as effective in providing high EE using the same amount of Bu4 NOTs dissolved in 2 mL of EtOH. The radiofluorinations were carried out in MeCN, a solvent commonly employed for the aliphatic fluorinations, under typical reaction conditions (100 \({}^{\circ}\)C, 10 min). High RCCs (70-95%) were achieved using significantly reduced amounts (0.2-1.2 mg/0.5-1.2 umol) (Table 1) of precursors compared to traditional approaches. In addition, by reducing the precursor amounts, the sources of chemical impurities in the final preparations are minimized, allowing for simplification of the purification procedures. The practical utility of the method (standard elution protocol, 46 mg QMA cartridge) was demonstrated in automated synthesis of [18F]FET [47], [18F]FES [48], and [18F]FDG [42] on the GE TRACERlab FX N Pro module, one of most common 18F-labeling platform. To further explore the potential of tetralkylammonium salts in respect to reaction basicity and resolublization of the [18F]fluoride, effects of three different salts Bu4 NOMs, Bu4 NOTf, and Bu4 NH2 PO4 were recently investigated by [PERSON] and co-workers [43].