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

[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. [11C]CO is readily available by the reduction of [11C]CO2 over zinc or molybdenum [83, 84]. 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

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

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

**Scheme 4.** Synthesis of [11C]WAY100635.

130 Carbon Dioxide Chemistry, Capture and Oil Recovery

**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].

**4. Future perspectives**

**Author details**

**References**

Lingyun Yang, Peter J. H. Scott and Xia Shao\*

School, Ann Arbor, Michigan, USA

of Physiology. 1945;**145**:253-263

\*Address all correspondence to: xshao@umich.edu

[1] Crane HR, Lauritsen CC. Physics Review. 1934;**45**:497-498

This review introduces the field of canbon-11 radiochemistry through a general overview, but is not meant to be comprehensive. As the field is fast growing, more traditional chemists join the radiochemistry arena worldwide. Carbon-11, one of the most important radioisotopes in nuclear medicine, is foreseen to have endless opportunities for further innovation. Due to the short half-life, efficiency and simplicity is always the key to 11C-labeling techniques. Recently developed transition-metal-mediated reactions have broadened the labeling scope

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

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

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11C-chemistry is a hybrid science between organic chemistry and engineering. To meet the growing demand and increasing regulation of radiopharmaceuticals, the fully automated or kit-like synthetic devices have been developed and will be required to be used in the manu-

Furthermore, synthetic pathways with better economical output and environmental management is another important aspect. The first example of a green radiochemistry laboratory at University of Michigan successfully prepared 11 radiopharmaceuticals for routine clinical application using ethanol as the only organic solvent [105]. The removal of all other organic solvents from the process simplifies production and quality control testing. The robust and

reliable methods are increasingly applied in various PET facilities around the world.

Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical

[2] Ruben S, Hassid WZ, Kamen MD.Journal of the American Chemical Society. 1939;**61**:661-663 [3] Antoni G, Kihlberg T, Långström B. In: Welch MJ, Redvanly CS, editors. Handbook of Radiopharmaceuticals. Chichester, UK: John Wiley & Sons, Ltd; 2005. pp. 141-194

[4] Tobias CA, Lawrence JH, Roughton FJW, Root WS, Gregersen MI. The American Journal

[5] Antoni G. Journal of Labelled Compounds and Radiopharmaceuticals. 2015;**58**:65-72

and allowed 11C-labeling of a range of different bioactive molecules.

[

facture of clinical doses to improve the reliability and safety.

**Scheme 7.** Some transformations in [11C]HCN radiochemistry: (a) radiosynthesis of [11C]methyl-2-cyanoisonicotinate by a Reissert-Kaufmann type reaction; (b) direct formation of [11C]1-succinonitrile via Michael addition; (c) the Strecker reaction for the synthesis of [11C]Sarcosine; (d) and (e): [11C]CuCN can be reacted with aryl halides through the Rosenmund-von Braun reaction to afford [<sup>11</sup>C]LY2232645 and other aromatic [11C]nitriles; (f) copper-mediated synthesis of aromatic [11C] nitriles from arylboronic acids.

the shortcomings, from technical and chemical points of the view [85–88]. The first report was by Kihlberg and co-workers in 1999, where [11C]CO was allowed to react in a small autoclave under high pressure (>350 Bar) [89]. Low-pressure and ambient temperature techniques have been achieved lately [90–92]. The most widely applied 11C-carbonylation method used [11C] CO is the palladium-mediated carbonylation reaction [93–96]. Rhodium-catalyzed carbonylation reactions provide an alternative route for the introduction of [11C]CO into organic molecules [97–99]. Free-radical photoinitiated 11C–carbonylation reactions have been used to synthesize 11C-labeled aliphatic acid, esters and amides recently (**Scheme 8**) [100–104].

**Scheme 8.** Free-radical photoinitiated 11C-carbonylation reaction.
