## 6 SiFAs and Their High Lipophilicity  
Despite the ease of the isotopic exchange and its specificity, the SiFA chemistry exhibits a very unfortunate characteristic: its inherent, structure-related lipophilicity. Why is lipophilicity an issue? The ultimate utilization of the SiFA chemistry will be in the field of diagnostic radiotracer development for PET. This means that the new SiFA-based tracer probes will be administered intravenously to an animal or even to a human being for the purpose of acquiring _in vivo_ information about certain diseases related to the specific binding of the tracer. However, if the lipophilicity of the injected compound is too high, the administered tracer will most probably end up in the liver, accumulating there and being no longer available for binding to its intended binding site. Compounds exhibiting a very high lipophilicity show such a rapid first pass effect. The liver basically siphons these compounds out of the blood stream obviating a proper binding to the target. In terms of brain imaging, a certain degree of lipophilicity is required for passive transport across the blood-brain barrier, as only lipophilic, lipid soluble compounds pass through that protective membrane. However, if a compound is too lipophilic (logD \(>\) 4), a passive diffusion across the blood brain-barrier is less likely and the compound is trapped in the lipid layer. The first small model SiFA compounds (Figure 5) all exhibited a very high lipophilicity, as displayed by the 1-octanol:buffer\({}_{\mathrm{pH7,4}}\) partition coefficient (logD) of \(>\)4, basically as a result of the hydrophobic _tert_-butyl groups. None of these compounds are water soluble, but dissolve readily in organic solvents. Most of the time, compounds for PET imaging are used in nanomolar quantities. In this concentration range, the solubility product plays only a minor role, and so compounds usually insoluble in water can nevertheless be used for _in vivo_ applications. When SiFA compound [\({}^{18}\)F]**17** was administered to a rat, dynamic PET data were acquired over 1h. The liver uptake was initially high and the radioactivity uptake in bones became predominant over time, suggesting the hydrolysis of the Si-\({}^{18}\)F bond. As already pointed out, just one _tert_-butyl group is not sufficiently bulky to protect the Si-\({}^{18}\)F bond from hydrolysis. These results were independently corroborated by [PERSON] and co-workers and are discussed in detail later. However, when the _bis-tert_-butyl SiFA [\({}^{18}\)F]**16** was administered to rats, the compound did not lose its radiolabel _in vivo_ (no bone uptake) and was primarily metabolized in the liver and excreted via the colon. The lipophilicity introduced by the SiFA moiety was later shown to be responsible for a SiFA-peptide conjugate to accumulate almost exclusively in the liver and not bind to its tumor target (_cf._ Section 8). One can certainly conclude that the high lipophilicity of the SiFA moiety is the biggest hurdle in the clinical setting. Efforts are currently underway to overcome this obstacle by reducing the high lipophilicity of the SiFA building blocks by introducing charges and hydrophilic moieties. [PERSON] _et al._ in 2011 synthesized the first positively-charged SiFA compound, termed SiFAN\({}^{+}\)Br\({}^{-}\), as a lead compound for a new generation of SiFA building blocks with reduced lipophilicity [32]. The compound could be labeled in high radiochemical yields of up to 90% by isotopic exchange and specific activities of 20 GBq/mol could be achieved. These first results of adding a positive charge to the SiFA molecule are encouraging. In the following sections, we will discuss practical examples of silicon-\({}^{18}\)F chemistry used for peptide as well as protein labeling. At the end, we will present the first few small molecules modified with a silicon \({}^{18}\)F motif intended for PET imaging.