## 7 Silicon Building Blocks Containing H, OH and Alkoxy moieties as Leaving Groups  
In 2008, a group of researchers around [PERSON] and Ametamey published their pioneering work on silicon-based building blocks for the one-step \({}^{18}\)F-radiolabeling of peptides (_cf._ Section 8). This innovative labeling approach, based on the exchange of leaving groups such as alkoxyl moieties, OH and H by \({}^{18}\)F\({}^{-}\) under slightly acidic conditions, ultimately arrived at the same silicon-\({}^{18}\)F building block structures as described by [PERSON] and [PERSON] in 2006. It was confirmed that the steric hindrance as exerted by _iso_-propyl or _tert_-butyl groups is crucial for the compounds' hydrolytic stability. A very important finding was that the linker group used for further bioconjugation does not necessarily need to be an aryl group. Allyl linkers were proven to be hydrolytically stable as well, which significantly expands the potential structural variation of the silicon building blocks. Before  
Figure 5: **(A) Isotopic exchange mechanism resulting in a pentacoordinated silicon intermediate. The back-reaction yielding the original \({}^{19}\)F-SiFA compound is statistically not favored. (B) Density Functional Theory calculations on three model SiFAs result in a Gibbs free energy of \(-\)50 to \(-\)40 kcal/mol in gas phase and \(+\)5 to 10 kcal/mol in acetonitrile. **  
labeling larger organic compounds such as peptides, some silicon-based building blocks modified with hydrogen, methyl, _iso_-propyl, _tert_-butyl, aryl and various _n_-alkyl moieties were successfully labeled with \({}^{18}\)F\({}^{-}\) (Figure 6). Some of the investigated compounds could be labeled in very high RCYs. It became apparent that in case of H as a leaving group, the addition of acid did not significantly influence the formation of the Si-\({}^{18}\)F bond and was therefore regarded as the most promising strategy for further investigations. Using alkoxyl moieties or OH leaving groups requires the presence of protons to amplify the leaving group's exchange tendency via oxygen protonation. This can be difficult to achieve, since the \({}^{18}\)F\({}^{-}\), in the form of its potassium-Kryptofix2.2.2 complex salt, is highly basic and before protonating the leaving group, the protons neutralize the K\({}_{2}\)CO\({}_{3}\) (in the form of a [K\({}^{+}\)/Kryptofix]\({}_{2}\)/CO\({}_{3}\)\({}^{2-}\) salt, also present in the labeling cocktail). This labeling strategy requires elevated labeling temperatures ranging from 30 \({}^{\circ}\)C up to 90 \({}^{\circ}\)C, which is in stark contrast to the SiFA labeling procedure (isotopic exchange) that works at room temperature or below. In particular, the hydrolytically stabilizing _tert_-butyl group-bearing building blocks require higher reaction temperatures, most probably as a result of steric effects. The hydrolytic stability of a large variety of different silicon building blocks was investigated in detail by [PERSON] and co-workers [33]. Macroscopic amounts of the organofluorosilanes (15 compounds were tested) showed variable stability toward hydrolysis in a mixture of acetonitrile and buffer at pH 7. Although these conditions do not exactly resemble physiological conditions (pH 7.4 and no co-solvent), the trend of hydrolytic susceptibility discovered experimentally should not be influenced by this difference in pH and the fact that acetonitrile is present as co-solvent. However, the actual hydrolytic half-lives might be different and potentially shorter under true physiological conditions, especially when using very small amounts of \({}^{18}\)F-silicon building blocks. It would be  
Figure 6: Radioactive labeling of silicon building blocks bearing different leaving groups (LG = alkoxyl moiety, OH, H), sterically demanding residues (R = _iso_-propyl, _tert_-butyl) and linker structures (Linker).