## 2 [18F]Fluoride Activation for Aliphatic Nucleophilic S\({}_{\text{N}}\)2 Substitution
### Tetraalkylammonium Salts (Bu\({}_{4}\)N\({}^{+}\), Et\({}_{4}\)N\({}^{+}\)) as the PTCs  
Tetraalkylammonium salts together with basic, non-nucleophilic anions (e.g., CO\({}_{3}\)\({}^{2-}\) or HCO\({}_{3}\)\({}^{-}\)) have been used for the years [13; 34] with Bu\({}_{4}\)NHCO\({}_{3}\) as less basic alternatives to K\({}_{2.2.2}\)/K\({}_{2}\)CO\({}_{3}\). They are characterized by counter-ion exchanging ability with [18]F]fluoride and good solubility in most organic solvents. From this group of the PTCs, Bu\({}_{4}\)NHCO\({}_{3}\) has been the most widely used, demonstrating higher [35; 36] or similar [37] RCYs when compared to conventional kryptofix-mediated fluorinations. The [18]F]F\({}^{-}\) is quantitatively recovered from the AEC with the eluent composed of MeCN (2 mL) and Bu\({}_{4}\)NHCO\({}_{3}\) (0.075 mL, 20% aq., pH 8) [38; 39] followed by conventional azeotropic drying. Quite recently [38], an elution protocol using ethanolic solution of the PTC (0.075 M Bu\({}_{4}\)NHCO\({}_{3}\) in 0.5 mL of EtOH) was described. The reactive [18]F]fluoride species thus produced was further used for the synthesis of [18]FES immediately after simple solvent evaporation without the need for azeotropic drying. For this radiotracer similar RCYs of around 50% (decay-corrected) were obtained regardless of the choice of the PTC--K\({}_{2.2.2}\)/K\({}_{2}\)CO\({}_{3}\) or Bu\({}_{4}\)NHCO\({}_{3}\). Similar to Bu\({}_{4}\)NHCO\({}_{3}\), tetraethylammonium salts were found to be effective in enhancing [18]F]fluoride reactivity in both aliphatic and aromatic nucleophilic substitution scenarios. [PERSON] and [PERSON] [39] demonstrated that Et\({}_{4}\)NHCO\({}_{3}\) (15 mg) dissolved in a polar aprotic solvent (MeCN, DMF, DMSO) containing up to 5% of water could be used to elute QMA-loaded [18F]F\({}^{-}\) with elution performed in the reverse (opposite to loading) direction. The obtained eluate can be used directly in further fluorinations eliminating solvents evaporation steps. The feasibility of this approach was confirmed for a wide range of the aliphatic substrates ([18F]FDG, [18F]fallypride, [18F]FEDAA1106) and model aromatic compound demonstrating similar or increased RCY when compared with conventional kryptofix-mediated procedures. However, it is worth noting that all the labeling reactions were performed using small aliquots of the eluate (50-100 \(\upmu\)L). Thus, the applicability of this methodology for full-batch production needs to be evaluated further, which reduces both the amount of base and the amount of water in the reaction mixture. Thus the applicability of this methodology for full-batch production needs to be evaluated further. In general, in routine clinical application use of Et\({}_{4}\)NHCO\({}_{3}\) is not as common as Bu\({}_{4}\)NHCO\({}_{3}\). In one of the recent protocols [40] that has been implemented into GMP production of [18F]DPA-714, preparation of reactive Et\({}_{4}\)N\({}^{+}\)[18F]F\({}^{-}\) still incorporated steps for \"traditional\" solvent removal. Automated synthesis on a Tasis AllinOne (AIO) cassette-based module involved elution of the [18F]fluoride from the QMA cartridge with a solution of Et\({}_{4}\)NHCO\({}_{3}\) in water/acetonitrile (85/15 \(v\)/\(v\)), followed by azeotropic distillation. Fluorination of the corresponding tosyl precursor in MeCN provided significantly higher RCY (55-71%) if compared with earlier kryptofix-based methods. The authors speculate that Et\({}_{4}\)NHCO\({}_{3}\) could be a better enhancer of [18F]fluoride nucleophilicity than K\({}_{2.2.2}\)/K\({}_{2}\)CO\({}_{3}\) or K\({}_{2.2.2}\)/KHCO\({}_{3}\), probably due to better stabilization of the precursor-fluoride intermediate during the reaction. Apart from developments concerning the elimination of the azeotropic drying step and improvements in automation, considerable efforts have been directed at the control of the basicity of the reaction medium, with aim to reduce amount of precursors used in the reaction.