## 2 [18F]Fluoride Activation for Aliphatic Nucleophilic S\({}_{\text{N}}\)2 Substitution
### PTC Free Cartridge-Based Radiofluorination of Aliphatic Substrates  
In principle, immobilizing precursor on the solid-phase support to perform an online \({}^{18}\)F-fluorination avoiding [18]F\({}^{-}\) elution, azeotropic evaporation, and PTC additions is a hugely attractive concept. It was successfully applied as early as 1990 [51] in the synthesis of [18]FFDG via resin-based nucleophilic \({}^{18}\)F-fluorination of mannose triflate, using a quaternary 4-(N,\(N\)-dialkylamino)-pyridinium functionalized polystyrene anion-exchange resin (\"4-AP\" resin) as solid support. [18]fluoride was captured on a small resin-packed column. The column was then dried by rinsing it with anhydrous MeCN, and the solution of mannose triflate was slowly pushed through the column heated to 100 \({}^{\circ}\)C. Labeled intermediate was then eluted into reaction vessel for removal of acetyl protecting groups through acidic hydrolysis. This procedure was implemented in the first cassette-based synthesizer (FDG Microlab, GE Medical Systems, Uppsala, Sweden) for routine productions of [18]FFDG [52]. Due to the issues with the manually-packed \"4-AP\" resin columns that had to be stored in methanol and other technical issues, the manufacture, and supply of the cassettes and FDG Microlab modules were seized around 2005.  
Alternatively, [53] the use of commercially available polymer-supported phosphazene base PS-P\({}_{2}\)\({}^{\text{4 Bu}}\) was found to be effective for resin-based \({}^{18}\)F-fluorinations of a series of aliphatic substrates. The phosphazene super bases such as P\({}_{2}\)\({}^{\text{Et}}\) were earlier introduced by [PERSON] and co-workers [54] for elution of [18]F\({}^{-}\) trapped on the QMA cartridge using acetonitrile containing carefully controlled amounts of water (1 mL MeCN, 5-10,000 ppm of water, 45 \(\upmu\)mmol of base). The highly reactive [18]fluoride was obtained without the need of azeotropic drying procedure and effectively used in radiolabeling of the appropriate labeling precursor (up to 40 mg) in a solution containing BTMG (2-tert-butyl-1,1,3,3-tetramethylguanidine) as an additional base.  
For resin-supported fluorination [53], a glass column or PTFE tube filled with 100 \(\upmu\)mol of PS-P\({}_{2}\)\({}^{\text{4 Bu}}\) and 1200 mg of glass beads were employed for trapping [18]F\({}^{-}\) with 98% efficiency. Precursor solution (i.e., mannose triflate, 25 mg in 3 mL of MeCN) was then passed through the column heated to 85 \({}^{\circ}\)C at a flow of 0.55 mL/min. The subsequent online basis hydrolysis on conventional tC18 Sep-Pak cartridge afforded [18]FFDG in 40% RCY in automated synthesis, with starting activity of 120 GBq. However, the success of the method depends to a great extent on the amount of resin, reaction temperature, and column packing efficiency, which, taken together, are considered a major limitation of this elegant but technically demanding production method.  
The aforementioned methodologies address the synthesis of radiotracers via direct nucleophilic substitution of the appropriate leaving groups in aliphatic substrates with activated [\({}^{18}\)F]fluoride as the most common route to routinely used radiotracers. The methods have been evaluated in view of possibilities for their implementation in the automated synthesizers with the aim of production of clinically useful amounts of the radiotracers. In recent years a number of highly innovative strategies to introduce the \({}^{18}\)F-label into aliphatic structures have been introduced, unfortunately, few of them are currently considered to be suitable for routine preparations of radiotracers. There have been several in-depth reviews [3; 41; 55; 56; 57] that offer a good overview of the current state of the art in aliphatic radiofluorinations, and deeper discussion of those more exotic approaches really lies outside the scope of the current review.