## 10 Small Molecules  
Although several examples of \({}^{18}\)F-radioled peptides and proteins using the organo-silicon building block strategy for \({}^{18}\)F-introduction can be found, small biologically-active molecules have rarely been labeled using this approach. This can be attributed to the high lipophilicity exerted by the bulky hydrophobic substituents on the silicon core used to achieve a high _in vivo_ stability of the Si-\({}^{18}\)F-bond. This high lipophilicity can result in a dramatically altered _in vivo_ biodistribution of the labeled substances, especially in the case of small molecules. Thus, examples for small molecules containing organo-silicon building blocks for the introduction of \({}^{18}\)F are rare, but some approaches have been described recently [46, 47, 48]. One example is the preparation of \({}^{18}\)F-labeled silicon-based nitromidazoles (Figure 15) that were designed as possible alternatives to the clinically relevant tracer [\({}^{18}\)F]FMISO and intended for hypoxia-imaging [46]. The radiosynthesis of these compounds--bearing methyl, _iso_-propyl-,phenyl- and naphthyl-moieties in order to stabilize the Si-\({}^{18}\)F-bond--started from the corresponding alkoxy-silanes and gave good \({}^{18}\)F-incorporation yields at elevated temperatures of 75 \({}^{\circ}\)C for 20 min, but a final HPLC purification of the tracers was necessary. **Figure 15.** Structures of \({}^{18}\)F- silicon-based nitromidazoles **40-43** intended for hypoxia-imaging. Stability studies confirmed the expected stability characteristics of the different \({}^{18}\)F-fluorinated compounds: a very low stability of **40** (\(t_{1/2}<5\)'), a low stability of **42** (\(t_{1/2}=5\)') and **41** (\(t_{1/2}=15\)') and an at least moderate stability of **43** (\(t_{1/2}=130\)'). Interestingly, and despite its short half-life, more favorable results could be obtained in the _in vivo_ experiments in tumor-bearing animals with hypoxic tumor areas using **40** compared to **43**. In the case of **40**, hypoxic tumor areas could at least be visualized, despite a very high background activity, as confirmed by [\({}^{18}\)F]FDG landmarking experiments, whereas in the case of **43**, only an unspecific uptake into the lungs was observed which was attributed to an accumulation of the tracer in the pulmonary capillaries. Thus, an optimization of the _in vivo_ properties of the compounds regarding stability and biodistribution profile remains necessary. Recently, attempts were made to radiolabel nucleosides and nucleotides using the silicon-\({}^{18}\)F-labeling strategy [47]. In order to synthesize the labeling precursors, silicon building blocks, comprising azide and alkyne functionalities were synthesized, introduced into thymidine, derivatized accordingly via copper-catalyzed 1,3-dipolar cycloaddition, and subsequently radiolabeled with \({}^{18}\)F by an H against \({}^{18}\)F exchange reaction (Figure 16 shows the structures of the \({}^{18}\)F-labeled products). Starting from these mono-nucleosides, also model di-nucleotides and a model decameric oligodeoxynucleotide containing all four bases, were synthesized and the labeling conditions were optimized. As the H against \({}^{18}\)F-exchange reaction on the silicon core proceeds less efficiently than the isotopic exchange reaction, elevated temperatures were required to introduce the \({}^{18}\)F-label. Nevertheless, all substances--nucleosides, di-nucleotides and the decameric oligodeoxynucleotide--were compatible with the applied reaction temperatures of 60 \({}^{\circ}\)C, 165 \({}^{\circ}\)C and 100 \({}^{\circ}\)C, respectively,neither affecting the phosphodieser linkage nor the purine bases. However, up to now, no _in vivo_ data are available that would provide information about the biodistribution characteristics of such lipophilic nucleosides and nucleotides.