## 2 [18F]Fluoride Activation for Aliphatic Nucleophilic S\({}_{\text{N}}\)2 Substitution
### Azeotropic Drying Free Methods for Kryptofix-Mediated Radiofluorinations
The latter one was obtained in greater radiochemical yield (RCY) (54% against reported 30-40% for conventional methods), with only 30 min total synthesis time. However, even as techniques described [16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26] avoid azeotropic drying procedure, the eluting solvent must still be removed by distillation to be replaced with the reaction solvent. There has been a recent focus on developing methodologies with the aim of completely excluding the need for solvent replacement prior to radiofluorination step. [PERSON] and co-workers [27] described an approach using highly concentrated K\({}_{2.2.2}\) /KOH solution in anhydrous MeCN, allowing for quantitative elution of [18F]F\({}^{-}\) under water-free conditions. No solvent evaporation was required to obtain reactive [18F]fluoride species. The applicability of this methodology to the preparation of several well-known radiotracers ([18F]FDG, [18F]FET, [18F]FL, [18F]FAZA, and [18F]fallypride) was confirmed when radiolabeling was carried out using small aliquots of the elate. An example of application of this so-called \"Munich method\" in a full-batch production is the synthesis of 18F-rhPSMA-7 [28], a novel hybrid PSMA radiolligand that contains either 18F or 68 Ga in the same structure. In a manual synthesis [28] [18F]F\({}^{-}\) was eluted from the QMA cartridge (46 mg) with a mixture of K\({}_{2.2.2}\) (110 \(\upmu\)mol) and KOH (100 \(\upmu\)mol) in 0.5 mL of MeCN; the eluent was freshly prepared from the lyophilized kit. The eluate was collected directly into a reaction vessel containing labeling precursor (50-150 nmol) and an oxalic acid (to provide less basic conditions [29]) in 150 \(\upmu\)L DMSO/30 \(\upmu\)L MeCN mixture. Isotopic 19F/18F exchange reaction was completed in 5 min at r.t. providing an RCY of over 55% after cartridge-based purification. Despite the distinct advantages of this time-saving and easy-to-automate protocol, it has not yet been implemented into routine 18F-radiochemistry, possibly due to the need for high amounts of base and subsequently relatively large amount of precursors required. Very recently [30] use of water-free eluent containing KHCO\({}_{3}\) (1.6 mg) and K\({}_{2.2.2}\) (6.0 mg) in MeOH (0.4 mL) for the recovery of [18F]fluoride from the QMA cartridge (46 mg, carbonate form) followed by direct use of the eluate in labeling reaction has been reported. This methodology was previously developed [30] for microscale 18F-radiolabeling with minimization of the amounts of base and cryptand. Synthesis of a 18F-labeled stilbene [30] for \(\upbeta\)-amyloid imaging was achieved using 2 mg of precursor in 0.2 mL of DMSO. When employing conventional azeotropic drying methodology for the same synthesis, a substantial amount of the unlabeled impurities in the reaction mixture was observed. The authors speculate that heating acetonitrile in the presence of K\({}_{2}\)CO\({}_{3}\) and K\({}_{2.2.2}\) promoted dimerization of acetonitrile, leading to the formation of butyronitrile. The latter then reacted with the sulfonyl leaving group of the precursor producing unlabeled impurities. In contrast, no impurities were observed using the water-free methanolic solution in the elution stage with no need for azeotropic drying. Still, in this approach, the eluting solvent needs to be removed before fluorination. Noteworthy, this is the first report pointing out the possibility of MeCN dimerization under azeotropic drying conditions. Small volumes of the  
Figure 2: The structures of PET brain radioligands prepared by aliphatic radiofluorination. solvents employed in the method [31] might be a limitation of this approach's amenability to automation due to possible losses of the radioactivity in the transfer lines. A relatively straightforward method [32] avoiding the need to remove the water is a kryptofix-mediated radiofluorination in a mixed organic solvent system containing only a small amount of water.