**3. [11C]Carbon dioxide: starting point for labeling PET radiopharmaceuticals**

The simple cyclotron production of [11C]carbon dioxide gave a starting point for the synthesis of important classes of compounds such as carboxylic acids [26], aldehydes [27], and alcohols [28]. However, due to low chemical reactivity of [11C]CO2 , a broad spectrum of different 11C-labeled synthetic intermediates have been prepared as useful secondary labeling precursors (**Scheme 1**). With the increasing importance of PET in medical research and continuous developments of novel organic chemical techniques, 11C-labeling methodology is rapidly growing. This chapter addresses selected commonly used methods and examples. For more detailed information see comprehensive reviews [7, 54, 55]

#### **3.1. [11C]CO2 direct incorporation**

[11C]Carbon dioxide is the most important and versatile primary labeling precursor for 11C-radiolabeling, since it is produced directly from cyclotron. The electrophilic carbon in [11C]

CO2 can be used as a carbonyl source and trapped by an appropriate nucleophilic component. For example, [11C]acetate as a PET radiopharmaceutical for both myocardial imaging and cancer detection was synthesized via methyl magnesium chloride with [11C]CO2 (**Scheme 3**) [56].

The [11C]carboxymagnesium halides also can be converted into more reactive [11C]carboxylic acid chloride to form amide with amines. The important 5HT1A receptor ligand WAY100635 was produced by this manner (**Scheme 4**) [52, 53].

More recently, [11C]CO2 fixation further expanded the synthetic possibility for 11C-labeling by direct incorporation of [11C]CO2 . The first report on [11C]CO2 fixation was the synthesis of 11C-labeled carbamates [57, 58]. The scope of this method was broadened to [11C]ureas and [11C] oxazolidinones via the formation of an 11C-labeled isocyanate or carbamoyl anhydride intermediate [54, 58–60]. For example, the reversible monoamine oxidase B (MAO-B) radioligand, [ <sup>11</sup>C]SL25.1188, previously prepared using the technical demanding [11C]phosgene approach, was radiolabeled in high yield via [11C]CO2 fixation [61, 62]. This radioligand was recently translated for human PET imaging (**Scheme 5**) [54, 63].
