## 4 Copper-Mediated Late-Stage Radiofluorination of Non-Activated Arenes
The limitation of this approach in the original version [91] suggested by [PERSON]'s group is the need for a high amount of the reactants (up to 60 \(\mu\)mol of precursor and 30 \(\mu\)mol of Cu-catalyst). Therefore, in the follow-up studies of the same group possibility of reduction in the amount of Et\({}_{4}\)NHCO\({}_{3}\) was investigated using less viscous and more polar MeOH as an eluting solvent. Correspondingly, the quantities of precursor/copper catalyst could be reduced to 10-15 and 5-10 \(\mu\)mol, respectively [96; 97; 98; 99]. The notable feature of the \"alcohol enhanced\" method is the use of reverse loading/elution protocol (Figure 5) that starts with loading radionuclide onto an AEC (QMA cartridge) from the male side followed by rinsing of the resin with MeOH (2 mL) and drying with air from the same side. Then [18]F]\({}^{-}\) is eluted from the female side using a solution of Et4 NHCO3 (2 mg, 10 umol) in MeOH (0.5 mL). MeOH is evaporated using a flow of air at 80 \({}^{\circ}\)C within 10 min. A solution of ArylBPin precursor (16 umol, 1 eq) and Cu(OTf)2 Py4 (20 umol, 1.25 eq) in DMA/_n_BuOH 2:1 (750 \(\mu\)L) was added to [18F]Et4 NF, and the resulting solution was heated at 110 \({}^{\circ}\)C for 10-20 min under air or argon. This typical protocol has been shown to be robust, displaying broad substrate scope. However, it still required the evaporation of the solvent (MeOH) from the eluent before fluorination. To overcome this problem, further improvements of the methodology were introduced by our group [92] via the employment of Bu4 NOTf as non-basic PTC and low-boiling iPrOH for eluting [18F]fluoride. Using reverse loading/elution protocol in conjunction with QMA cartridge of 130 mg the EE > 90% was achieved using a solution of Bu4 NOTf (5 mg, 12.5 umol) in iPrOH (0.8 mL). Notably, the following Cu-mediated radiofluorination reaction can be performed directly with alcohol as co-solvent with DMA [92] or MeCN [92], offering significant practical benefits through elimination of not only azeotropic drying but any solvent removal steps preceding radiofluorination. Radiofluorination in DMA/iPrOH was fully compatible with various model substrates and ArylBPin precursors for two aromatic amino acids. Radiofuorination in neat iPrOH was substrate-dependent, being particularly effective for the preparation of 6-L-[18F]FDOPA (reaction conditions are shown under Scheme 2). More recently [100], this approach was employed in the automated synthesis of 6-L-[18F]FMT, the radiotracer representing a valuable alternative to 6-L-[18F]FDOPA in the diagnosis and staging of [PERSON]'s disease with simplified kinetic modeling. Using Bpin-substituted chiral Ni(II) complex as a labeling precursor [99], Cu-mediated radiofluorination was performed in highly boiling iPrOH/MeCN mixture in the presence of Bu4 NOTf as the PTC affording the target radiotracer in ca.20% activity yield (non-decay corrected) within 70 min. The radiofluorination proceeds under nitrogen instead of air, usually applied for Cu-mediated 18F-fluorination of boronates. This could be advantageous if the module is also used for the production of other PET tracers, which require inert conditions. The use of Bu4 NOTf as a replacement for KOTf and K2 CO3 was suggested by [PERSON]'s group [103] for the automated synthesis of 6-L-[18F]FDOPA (Scheme 2). An aqueous eluent consisting of 15 mg/mL Bu4 NOTf and 0.2 mg/mL Cs2 CO3 (0.5 mL), respectively, gave good recovery of [18F]F\({}^{-}\) from the QMA cartridge and provided over 50% RCC in radiofluorination in DMF with addition of pyridine. However, the performance of this  
Figure 5: The schematic presentation of reverse loading-elution (back-flushed) protocol [92].