## 4 Silicon-Fluoride-Acceptors (SiFAs): An introduction  
Isotopic exchange reactions in \({}^{18}\)F-radiochemistry have been deemed an inherently inferior way of labeling and considered only as a last resort if other labeling strategies fail. The reason behind this is the intention to maximize the specific activity of the compound (that is the proportion of radioactive to \({}^{18}\)F-labeled plus \({}^{19}\)F-bearing compound). Usually, in conventional C-\({}^{18}\)F radiochemistry, when activated fluoroarenes are subjected to isotopic exchange reactions, specific activities in the low kBq/\(\upmu\)mol range are accomplishable, most of the time not high enough to enable an _in vivo_ application. Specific activity is an important issue, since the _in vivo_ target of PET tracers are most often receptors or enzymes, which are present in low amounts only. If the specific activity is too low, the receptors are occupied with non-radioactive ligands leading to a loss of the signal resulting from specific binding, and potentially leading to pharmacologic effects. Normally, the amount of labeling precursor needed for isotopic exchange reactions is in the mmol range (a few mg). Unfortunately, the \({}^{19}\)F-labeled molecule cannot be chemically distinguished from the \({}^{18}\)F-labeled compound, meaning that both compounds are inseparable. This impediment in classical \({}^{18}\)F-C chemistry turns into an advantage in the case of \({}^{19}\)F for \({}^{18}\)F exchange at the Si atom. In conventional labeling chemistry, the labeling precursor, being chemically different from the labeled product, has to be removed from the reaction mixture prior to the _in vivo_ application. In isotopic exchange reactions however, labeling precursor and labeled compound are identical, which eliminates the need for purification. If a sufficient specific activity can be achieved with isotopic exchange, the overall labeling procedure would be far more convenient, reducing the synthetic effort. It was found that the fluorosilane _t_Bu2 PhSiF (**16**) could be labeled by isotopic exchange in high radiochemical yields and high specific activities of up to 230 GBq/\(\upmu\)mol, using as little as 1 \(\upmu\)g of the \({}^{19}\)F-fluorosilane in acetonitrile. The purification was exceptionally easy, since the only components in the labeling mixture that had to be removed were un-reacted \({}^{18}\)F (less than 5%), Kryptofix 2.2.2 (a cryptant forming a complex with potassium, the counterion of \({}^{18}\)F-, yielding a highly reactive \"naked\" \({}^{18}\)F- anion in dipolar aprotic solvents) and K\({}_{2}\)CO\({}_{3}\). This could be easily achieved by simply purifying the [\({}^{18}\)F]fluorosilane using a C18 solid phase cartridge. All other components of the labeling reaction mixture pass through the cartridge and are therefore separated from the \({}^{18}\)F-product. This surprisingly efficient isotopic exchange reaction was termed SiFA for Silicon-Fluoride-Acceptor. A great variety of SiFA compounds have been synthesized to date (Figure 3), and successfully labeled with \({}^{18}\)F. In the current wave of click chemistry, [PERSON] and [PERSON] recently reported on the synthesis of SiFA azide (**12**) as a new building block for PET imaging using Click Chemistry [31]. Figure 2: Radioactive \({}^{18}\)F-labeling of **1** yielding the [\({}^{18}\)F]tetrafluorosiliconate “ate” salt **2** in quantitative yields in aqueous buffered solution. SiFA compound **3**, bearing an aldehyde functionality, displayed a remarkably high rate of isotopic exchange even when high radioactivity amounts of \({}^{18}\)F\({}^{-}\) were used. Up to 3 GBq of \({}^{18}\)F\({}^{-}\) reacted with just 1 \(\upmu\)g (3.75 nmol) of **3** within 10 min at room temperature and yielded the [\({}^{18}\)F]fluorosilane in 97% radiochemical yield (RCY). The calculated specific activity is between 225 and 640 GBq/\(\upmu\)mol.