## 3 [\({}^{18}\)F]Fluoride Activation for Conventional Aromatic Nucleophilic Substitution  
Traditional nucleophilic aromatic substitution (S\({}_{\rm N}\)Ar) reactions, including those using [\({}^{18}\)F]fluoride as the nucleophile, require arena substrates with strong electron-withdrawing groups (EWG) such as NO\({}_{2}\), CN, CHO, COR, COOR, and CF\({}_{3}\) in the _ortho_- or _para_-positions of the aromatic structure combined with an appropriate leaving group (NO\({}_{2}\), halides, Me\({}_{3}\)N\({}^{+}\)X\({}^{-}\); \(X^{-}\) = TfO\({}^{-}\), TsO\({}^{-}\), ClO\({}_{4}\)\({}^{-}\), I\({}^{-}\)). Radiofluorinations are usually performed in polar, anhydrous aprotic solvents, such as DMSO, DMF, DMA, or sulfolane at moderate to high temperatures (100-180 \({}^{\circ}\)C) in the presence K\({}_{2.2.2}\)/K\({}_{2}\)CO\({}_{3}\) (KHCO\({}_{3}\)) or Bu\({}_{4}\)NHCO\({}_{3}\). A direct labeling strategy is an effective approach for the synthesis of \({}^{18}\)F-labeled benzaldehydes or other prosthetic groups [15] obtained through radiolabeling of substituted nitrobenzaldehydes. When it comes to the direct introduction of [\({}^{18}\)F]F\({}^{-}\) into biologically active molecules or drug candidates, they usually do not contain a suitably activated aryl ring for fluorination through the addition-elimination mechanism. Notable radiotracers examples accessible via direct nucleophilic substitution include (imaging target is in parenthesis): [\({}^{18}\)F]altanserin [58; 59] (5-HT\({}_{2A}\) receptors); [\({}^{18}\)F]MPPF [60] (5-HT\({}_{1A}\) receptors); [\({}^{18}\)F]fIumazenil [21] (GABA\({}_{A}\) benzodiaazepine receptors); [\({}^{18}\)F]FPEB [61] (metabotropic glutamate 5 receptors) (Figure 3). These radiotracers are usually prepared through classical kryptofix-mediated substitution of a nitro leaving group in low to moderate RCYs; microwave-assisted heating has been used to improve yields [58]. In the case of heteroaromatic substitutions, particularly in the pyridine series, direct S\({}_{\rm N}\)Ar fluorination on the _ortho_- or _para_-positions is feasible with no need for activation of the heteroaromatic ring. Over the years, a number of radiotracers for  
Figure 3: The structures of selected brain receptors radioligands prepared via conventional kryptofix-mediated aromatic nucleophilic radiofluorination of the appropriate nitro-precursors. nicotine acetylcholine receptors [62; 63] as well as for imaging \(\beta\)-amyloid aggregates [64] and other targets have been prepared from the appropriate heteroaromatic precursors. A recent example is the synthesis of [18]F]PSMA-1007, a widely-used radioligand for the diagnosis and non-invasive staging of PSMA-positive prostate cancer developed by [PERSON]'s group [65]. The radiotracer has been synthesized in high RCY (50-70%) from its trimethylammonium salt precursor (1-2 mg) in the presence of Bu4 NHCO3 with heating to 80-90 \({}^{\circ}\)C for 10 min in DMSO. To produce reactive [18]F]fluoride species, the radionuclide was released from the QMA cartridge (130 mg) with 750 \(\mu\)L 0.075 M aqueous TBAHCO3 followed by an azeotropic drying procedure. In general, aryltrimethylammonium salts tend to be more reactive than neutral leaving groups. An additional benefit is that the charged precursor is easily separated from a neutral end-product using cartridge-based purification procedures. Thus, the synthesis of [18]F]PSMA-1007 with SPE purification can be implemented in the majority of currently available automated synthesizers [65] allowing for easy access to this important PSMA imaging agent. The second strategy [65] to introduce 18F into PSMA-1007 relies on using 6-[18]Fluoronictic acid 2,3,5,6-tetrafluorophenyl ester ([18]F]F-Py-TFP), a common prosthetic reagent for the indirect peptides labeling.