**2. Carbon-11 chemistry**

limited in next 20 years [5]. This delay was a consequence of easy access to reactor-produced carbon-14 from the 1950s, which superseded the use of cyclotron-produced carbon-11. Until late 1950s, the concepts of emission and transmission tomography were introduced by David Kuhl and Roy Edwards. The interest in carbon-11 was renewed and the application of carbon-11

<sup>11</sup> C →<sup>11</sup> B + β<sup>+</sup> + ve + 0.96 MeV 98.1%

Positron emission tomography (PET) is a type of functional molecular imaging technique using probes, known as radiotracers, consisting of bioactive molecules tagged with positronemitting radionuclides [6]. As carbon-11 undergoes positron emission decay, it emits a positron. The positron travels a short distance in the surrounding tissue until it collides with an electron. The annihilation produces a pair of gamma rays, which are emitted simultaneously in nearly opposite directions with energy of 511 keV each. The photons can be detected by pairs of collinearly aligned detectors in coincidence. The detectors of a PET system are installed in a ring-like pattern, which allows measurement of radioactivity through the organ of interesting at large angles and radial distances. The three-dimensional images can be generated by reconstruction (**Figure 1**). The ability to image and monitor molecular events *in vivo* and in real time is of great value for unveiling a detailed picture of fundamental biochemical and physiological processes in living organisms [7]. Information about metabolism, receptor/ enzyme function, and biochemical mechanisms in living subjects can be obtained directly from PET imaging studies. The recent development of hybrid instrument combines functional PET with an anatomical modality such as computerized tomography (CT) or magnetic

**Figure 1.** The principle behind PET imaging: (a) the injection of radiopharmaceuticals; (b) positron travels a short distance and collides with an electron, then two 511 keV gamma rays emit simultaneously at approximately 180° to each

other after annihilation; (c) system detects gamma rays and then generates three-dimensional images.

Decay of carbon-11 by positron emission or electron capture.

11 C <sup>+</sup> <sup>e</sup><sup>−</sup> <sup>→</sup><sup>11</sup> <sup>B</sup> <sup>+</sup> ve <sup>+</sup> 1.98 MeV 0.19% (1)

was extended in 1960s.

124 Carbon Dioxide Chemistry, Capture and Oil Recovery

#### **2.1. Cyclotron: generation of carbon-11**

Several nuclear reactions can be used to produce carbon-11 [29, 30]. Among these processes the <sup>14</sup>N(p,α)11C nuclear reaction is by far the most convenient and most commonly used method

**Scheme 2.** Generation of primary labeling precursors from cyclotron.

of producing carbon-11. The reaction is performed by high-energy proton bombardment of a cyclotron target containing nitrogen gas. Depending on the addition of gas (up to 2% of O2 or 5–10% of H<sup>2</sup> ) to the nitrogen gas in the target, carbon-11 can be obtained as [11C]CO2 or [11C]CH4 (**Scheme 2**). [11C]Carbon dioxide is the most important and versatile primary labeling precursor for 11C-labeling. Cyclotron-produced [11C]CO2 can be used directly for the 11C-labeling of organic molecules (**Scheme 1**).

### **2.2. Radiochemistry: general considerations**

Carbon-11 is a radionuclide that emits high-energy radiation. Therefore, the traditional handson manipulations used in synthetic chemistry are not feasible. In order to avoid unnecessary radiation exposure to the operators, the radiosynthesis of PET tracer needs to be undertaken by automated or remote-controlled synthesis equipment housed inside lead-shielded fume hoods (hot-cells) [6, 7]. This is also important from the perspective of good manufacturing practice (GMP) where a reproducible and operator-independent production is required to control the quality of the radiopharmaceuticals. **Figure 2** shows the radiochemistry laboratory at University of Michigan and a typical carbon-11 radiosynthesis module.

The half-life of carbon-11 is sufficiently long for synthesis and purification. However, the radiochemical yield is a function of chemical yield and radioactive decay. Thus the radiosynthesis time should be kept as short as possible. Ideally, a 11C-radiopharmaceutical is synthesized,

purified, formulated and analyzed within a timeframe of roughly 2–3 physical half-lives of the radionuclide, or 40–60 min for carbon-11. In addition, the strategies for the radiolabeling

The specific radioactivity (SA), a measure of the radioactivity per unit mass of the final radiolabeled compound, is another important aspect of 11C-chemistry. Since only a trace amount of [11C]carbon dioxide is generated in the cyclotron, the theoretical maximum specific radioac-

sible to achieve this number, because of unavoidable isotopic dilution by naturally occurring

GBq/μmol. However, it is practically impos-

should aim to introduce carbon-11 in the synthetic sequence as late as possible [31–33].

**Radiotracers Labeling methods Targets References**

11C]CFNa Methylation Opioid [36, 38–40]

11C]Choline Methylation Oncology [36, 41, 42]

11C]DASBb Methylation Serotonin transporter [36, 43]

11C]DTBZc Methylation Vesicular monoamine transporter 2 [36, 44]

11C]FMZd Methylation GABAA receptor [36]

11C]HEDe Methylation Adrenergic [36]

11C]Methionine Methylation Oncology [36]

11C]OMARf Methylation Cannabinoid receptor 1 [45]

11C]Palmitate Grignard reaction Cardiac [35]

11C]PiBh Methylation Amyloid [36]

11C]Sarcosine Strecker reaction Prostate cancer [51]

3-Amino-4-(2-[11C]dimethylaminomethylphenylsulfanyl)-benzonitrile.

*N*-acetyl-*N*-(2-[11C]methoxybenzyl)-2-phenoxy-5-pyridinamine.

<sup>11</sup>C]WAY100635<sup>j</sup> Grignard reaction 5HT1A receptor [52, 53]

1-(2,4-dichlorophenyl)-4-cyano-5-(4-[11C]methoxyphenyl)-N-(piperidin-1-yl)-1*H*–pyrazole-3-carboxamide.

N-[2-[4-(2-[11C]methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide).

**Table 1.** <sup>11</sup>C-radiotracers in University of Michigan PET center for clinical application.

11C]PMPi Methylation Acetylcholinesterase [36, 49]

11C]Raclopride Methylation Dopamine [36, 40, 43, 50]

11C]PBR28g Methylation Neuro, cardiac and oncology [36, 46–48]

11C]Butanol Grignard reaction Blood flow [37]

Oncology

[35, 36]

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

127

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

[11C]Acetate Grignard reaction Tricarboxylic acid cycle—Cardiac,

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

a

b

c

e

f

g

i

j

[11C]Carfentanil.

d[11C]Flumazenil.

[11C]Dihydrotetrabenazine.

[11C]Meta-hydroxyephedrine.

h[11C] Pittsburgh Compound B.

1-[11C]Methyl-piperidin-4-yl propionate.

tivity for 11C-radiolabeled compound is 3.4 × 10<sup>5</sup>

**Figure 2.** Automatical synthesis equipment in lead-shielded fume hoods.


a [11C]Carfentanil.

or

or [11C]CH4

can be used directly for the 11C-labeling of

b 3-Amino-4-(2-[11C]dimethylaminomethylphenylsulfanyl)-benzonitrile.

c [11C]Dihydrotetrabenazine.

d[11C]Flumazenil.

**Figure 2.** Automatical synthesis equipment in lead-shielded fume hoods.

of producing carbon-11. The reaction is performed by high-energy proton bombardment of a cyclotron target containing nitrogen gas. Depending on the addition of gas (up to 2% of O2

) to the nitrogen gas in the target, carbon-11 can be obtained as [11C]CO2

(**Scheme 2**). [11C]Carbon dioxide is the most important and versatile primary labeling precur-

Carbon-11 is a radionuclide that emits high-energy radiation. Therefore, the traditional handson manipulations used in synthetic chemistry are not feasible. In order to avoid unnecessary radiation exposure to the operators, the radiosynthesis of PET tracer needs to be undertaken by automated or remote-controlled synthesis equipment housed inside lead-shielded fume hoods (hot-cells) [6, 7]. This is also important from the perspective of good manufacturing practice (GMP) where a reproducible and operator-independent production is required to control the quality of the radiopharmaceuticals. **Figure 2** shows the radiochemistry laboratory

The half-life of carbon-11 is sufficiently long for synthesis and purification. However, the radiochemical yield is a function of chemical yield and radioactive decay. Thus the radiosynthesis time should be kept as short as possible. Ideally, a 11C-radiopharmaceutical is synthesized,

at University of Michigan and a typical carbon-11 radiosynthesis module.

5–10% of H<sup>2</sup>

sor for 11C-labeling. Cyclotron-produced [11C]CO2

**Scheme 2.** Generation of primary labeling precursors from cyclotron.

**2.2. Radiochemistry: general considerations**

organic molecules (**Scheme 1**).

126 Carbon Dioxide Chemistry, Capture and Oil Recovery

e [11C]Meta-hydroxyephedrine.

f *N*-acetyl-*N*-(2-[11C]methoxybenzyl)-2-phenoxy-5-pyridinamine.

g 1-(2,4-dichlorophenyl)-4-cyano-5-(4-[11C]methoxyphenyl)-N-(piperidin-1-yl)-1*H*–pyrazole-3-carboxamide.

h[ <sup>11</sup>C] Pittsburgh Compound B.

i 1-[11C]Methyl-piperidin-4-yl propionate.

j N-[2-[4-(2-[11C]methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide).

**Table 1.** <sup>11</sup>C-radiotracers in University of Michigan PET center for clinical application.

purified, formulated and analyzed within a timeframe of roughly 2–3 physical half-lives of the radionuclide, or 40–60 min for carbon-11. In addition, the strategies for the radiolabeling should aim to introduce carbon-11 in the synthetic sequence as late as possible [31–33].

The specific radioactivity (SA), a measure of the radioactivity per unit mass of the final radiolabeled compound, is another important aspect of 11C-chemistry. Since only a trace amount of [11C]carbon dioxide is generated in the cyclotron, the theoretical maximum specific radioactivity for 11C-radiolabeled compound is 3.4 × 10<sup>5</sup> GBq/μmol. However, it is practically impossible to achieve this number, because of unavoidable isotopic dilution by naturally occurring 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 103 –104 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. Therefore, the quality of regents used in radiosynthesis needs special attention.

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 can-

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

. The first report on [11C]CO2

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,

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

with hydroiodic acid. An alternative method, referred to as the "gas phase" method, was

and then conversion of [11C]methane into [11C]MeI by iodination with iodine vapor at high

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

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.

fixation further expanded the synthetic possibility for 11C-labeling

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

(**Scheme 3**) [56].

129

fixation was the synthesis of

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

followed by reaction

/Ni at 350°C

by H2

fixation [61, 62]. This radioligand was recently

using LiAlH<sup>4</sup>

:1 resulting in pseudo-first order kinetics of heteroatom methylation

cer detection was synthesized via methyl magnesium chloride with [11C]CO2

[

was produced by this manner (**Scheme 4**) [52, 53].

was radiolabeled in high yield via [11C]CO2

translated for human PET imaging (**Scheme 5**) [54, 63].

developed in 1976 [64, 65] is based on reducing [11C]CO2

temperatures (700–750°C) in the gas phase [66, 68].

developed in the 1990s. This method exploits the reduction of [11C]CO2

More recently, [11C]CO2

**3.2. [11C]Methylation**

can reach a factor of 104

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

by direct incorporation of [11C]CO2

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.

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

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 center for routine clinical application.
