**3.2. [11C]Methylation**

carbon-12 species during the processes. Typical specific activities of 11C-radiolabeled compounds are in the order of 50–1000 GBq/μmol [34]. For imaging a patient, less than 1 GBq of radioactivity is normally enough. That means very low amounts of compound need to be administered for PET imaging, typically in picomolar to nanomolar scale. This prevents undesired pharmacological or toxic effects during the *in vivo* studies. Thus, a labeling pathway should be designed to minimize contamination of carbon-12 species. Furthermore, due to tracer levels of carbon-11, the amount of the non-radioactive reagents is in large excess (about

 fold), which drives the reaction at pseudo first order kinetics. By consequence, small impurities in reagents or solvents may have a significant influence on the reaction outcomes.

Radiopharmaceuticals can range from the small and simple to the large and complex. A tracer should be designed in such a way that it can be probing a specific function within the organ of interest [3]. It is important that the physical half-life of the radionuclide matches the biological half-life of the studied process. For example, carbon-11 is not suitable for radiolabeled peptides or antibodies, which need a few hours of blood circulation to accumulate the activity in a tumor.

Since its infancy in the early 1960s, PET has attracted increasing attention as a powerful tool for investigating the biochemical transformations of drugs and molecules in the living system. With the development of PET imaging technology and novel synthetic methodology, 11C-labeled radiopharmaceuticals have been extensively used for the highly sensitive noninvasive measurement of biochemical physiological processes in living human subjects. As examples, **Table 1** summarizes 11C-radiotracers available in University of Michigan PET cen-

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 alco-

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

[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]

, a broad spectrum of different

Therefore, the quality of regents used in radiosynthesis needs special attention.

**2.3. Application of carbon-11: examples of radiopharmaceuticals**

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

hols [28]. However, due to low chemical reactivity of [11C]CO2

detailed information see comprehensive reviews [7, 54, 55]

 **direct incorporation**

ter for routine clinical application.

128 Carbon Dioxide Chemistry, Capture and Oil Recovery

**radiopharmaceuticals**

**3.1. [11C]CO2**

103 –104

> The introduction of [11C]methyl iodide as a second labeling precursor 30 years ago was one of the great milestones in PET radiochemistry [64, 65]. So far, the most common method in 11C–labeling is heteroatom (N, O, S) methylation. Converting [11C]MeI to more reactive [11C] methyltriflate ([11C]MeOTf) [64, 66] by passing [11C]MeI through a small column containing silver triflate around 200°C [67] significantly increases efficiencies of 11C–methylation. This innovation makes it possible to 11C-methylate heteroatoms in 3–5 min at room temperature. [11C]Methyl iodide can be prepared via two methods (**Scheme 1**). The so-called "wet" method developed in 1976 [64, 65] is based on reducing [11C]CO2 using LiAlH<sup>4</sup> followed by reaction with hydroiodic acid. An alternative method, referred to as the "gas phase" method, was developed in the 1990s. This method exploits the reduction of [11C]CO2 by H2 /Ni at 350°C and then conversion of [11C]methane into [11C]MeI by iodination with iodine vapor at high temperatures (700–750°C) in the gas phase [66, 68].

> The incorporation of the [11C]methyl group into a target molecule is generally simply alkylation on N-, O-, and S-nucleophiles (e.g., HED, DTBZ, methionine). The tracer amount of [11C]MeII or [11C]MeOTf in the reaction leads to extraordinary stoichiometry. The stoichiometric relation can reach a factor of 104 :1 resulting in pseudo-first order kinetics of heteroatom methylation reactions. Therefore, the conversion rate is highly increased and the reasonable radiochemical yields can be reached within short reaction times of 3–5 min. The problems with polyalkylation in normal stoichiometric methylation of amines.do not occur in the 11C-methylation processes.

**Scheme 3.** Synthesis of [11C]acetate.

To further expand the number of 11C-labeled compounds, the development of novel 11C–C bond forming reactions continues to gain attention. For example, several palladium-mediated cross-coupling reactions have been shown to be effective <sup>11</sup>C-labeling. The first application was reported in 1995 [69]. The feasibility of incorporating [11C]methyl groups into arenes, alkenes as well as alkanes was demonstrated by the reaction with the corresponding organostannanes and boranes in Stille and Suzuki cross-coupling reactions (**Scheme 6**) [70]. Due to the toxicity of the precursor and reagents used, the purification and quality control are more complicated comparing with those of simply methylation. Considering the short half-life of carbon-11, the application of this method for clinical dose production is currently underexploited. With the development of techniques and simplification of processes, this labeling strategy could be

11C]Carbon Dioxide: Starting Point for Labeling PET Radiopharmaceuticals

http://dx.doi.org/10.5772/intechopen.72313

[

[11C]HCN is another important secondary labeling precursor (**Scheme 1**), because nitriles are not only frequently present in biologically active molecules but also represent a versatile functional group that can be readily converted into 11C-labeled amides, carboxylic acids or amines

over nickel (400°C), and then converted into [11C]HCN by reaction with NH3

11C]HCN can be used directly to form [11C]methyl-2-cyanoisonicotinate and [11C]1-succinonitrile by a Reissert-Kaufmann type reaction (**Scheme 7a**) and Michael addition (**Scheme 7b**), respectively [73]. It may convert to [11C]CuCN and react with aryl halides through the Rosenmundvon Braun reaction for the synthesis of [11C]LY2232645(**Scheme 7d**) [74–76]. 11C-labeled amino acids, for example, [11C]Sarcosine, can be prepared using [11C]HCN in the Strecker reaction (**Scheme 7c**) [51, 77, 78]. In recent years, palladium-catalyzed and copper-mediated cyanations have gained increasing attention [79–82]. Vasdev and co-workers employed arylboronic acids and [11C]CsCN to prepare aromatic 11C-nitriles (**Scheme 7f**), which was applicable to a broad

[11C]Carbon monoxide is an attractive secondary precursor for 11C-chemistry since the wide variety of carbonyl containing molecules can be synthesized through carbonylation reactions.

However, the application of [11C]CO was underexploited due to its poor reactivity and low solubility in organic solvents. Until recently, new methods have been developed to overcome

to [11C]CH4

over zinc or molybdenum [83, 84].

,

131

over

(**Scheme 7**) [54, 71]. [11C]HCN is usually prepared by the reduction of [11C]CO2

more widely adopted.

range of substrates [80].

**3.4. [11C]Carbonylation using [11C]CO**

[11C]CO is readily available by the reduction of [11C]CO2

**Scheme 6.** Synthesis of [11C]M-MTEB by Suzuki or Stille reactions.

platinum at elevated temperature (950°C) [72].

**3.3. [11C]Cyanation**

using H2

[

**Scheme 5.** Synthesis of [11C]SL25.1188.

The reaction can be performed using a traditional vial-based approach (e.g., CFN, FMZ) or using solid support either on-cartridge (e.g., choline) or flow-based loop methods (e.g., PIB, DASB, raclopride) (**Figure 3**) [39, 41, 43]. All these methods are very convenient from automation prospective. The use of commercially available fully automated synthesis modules for production of clinical radiopharmaceutical doses enhances the speed, efficiency, reliability, and safety of radiosyntheses, as well as compliance with GMP regulations. For detail procedures see [38–43].

**Figure 3.** Representative 11C-radiotracers labeled by methylation.

To further expand the number of 11C-labeled compounds, the development of novel 11C–C bond forming reactions continues to gain attention. For example, several palladium-mediated cross-coupling reactions have been shown to be effective <sup>11</sup>C-labeling. The first application was reported in 1995 [69]. The feasibility of incorporating [11C]methyl groups into arenes, alkenes as well as alkanes was demonstrated by the reaction with the corresponding organostannanes and boranes in Stille and Suzuki cross-coupling reactions (**Scheme 6**) [70]. Due to the toxicity of the precursor and reagents used, the purification and quality control are more complicated comparing with those of simply methylation. Considering the short half-life of carbon-11, the application of this method for clinical dose production is currently underexploited. With the development of techniques and simplification of processes, this labeling strategy could be more widely adopted.
