5 Pd 0 – Mediated Rapid C – [ 11 C ] Methylation and C – [ 18 F ] Fluoromethylation : Revolutionary Advanced Methods for General Incorporation of Short – Lived Positron – Emitting 11 C and 18 F Radionuclides in an Organic Framework

The study of in vivo bioscience and medical treatment from molecular point of view requires the precise evaluation of molecule behavior in living systems, especially involving the human body. Positron emission tomography (PET) is a non–invasive imaging technology with a good resolution, high sensitivity, and accurate quantification, which makes it possible to timely and spatially analyze the dynamic behavior of molecules in in vivo systems using a specific molecular probe labeled with positron–emitting radionuclides such as 11C, 13N, 18F, and 76Br (Phelps, 2004). PET has been extensively used for the diagnosis of diseases such as cancers, cerebral dysfunction, and etc., and recently, in medical checkups as an early detection approach. In the current paradigm shift to drug discovery, PET molecular imaging will provide an important new scientific platform to execute human microdosing trials during the early stage of drug development, especially from the viewpoint of promoting evidence–based medicine (Lappin & Garner, 2003; Bergström et al., 2003). A core concept and the driving force of molecular imaging would truly be “Seeing is Believing”. It is of significant value to unveil the vital functions and phenomena of living systems by molecular imaging the in vivo behavior of a ligand and the localization of a biologically significant target molecule. The potential of PET molecular imaging in an interdisciplinary scientific area strongly depends on the availability of suitable radioactive molecular probes with specific biological functions. The development of biologically significant novel PET probes will be accomplished by the combination of an efficient synthetic strategy for designed molecules and new advances in the field of labeling chemistry (Schubiger et al., 2007).


Introduction
The study of in vivo bioscience and medical treatment from molecular point of view requires the precise evaluation of molecule behavior in living systems, especially involving the human body.Positron emission tomography (PET) is a non-invasive imaging technology with a good resolution, high sensitivity, and accurate quantification, which makes it possible to timely and spatially analyze the dynamic behavior of molecules in in vivo systems using a specific molecular probe labeled with positron-emitting radionuclides such as 11 C, 13 N, 18 F, and 76 Br (Phelps, 2004).PET has been extensively used for the diagnosis of diseases such as cancers, cerebral dysfunction, and etc., and recently, in medical checkups as an early detection approach.In the current paradigm shift to drug discovery, PET molecular imaging will provide an important new scientific platform to execute human microdosing trials during the early stage of drug development, especially from the viewpoint of promoting evidence-based medicine (Lappin & Garner, 2003;Bergström et al., 2003).A core concept and the driving force of molecular imaging would truly be "Seeing is Believing".It is of significant value to unveil the vital functions and phenomena of living systems by molecular imaging the in vivo behavior of a ligand and the localization of a biologically significant target molecule.The potential of PET molecular imaging in an interdisciplinary scientific area strongly depends on the availability of suitable radioactive molecular probes with specific biological functions.The development of biologically significant novel PET probes will be accomplished by the combination of an efficient synthetic strategy for designed molecules and new advances in the field of labeling chemistry (Schubiger et al., 2007).
Among the short-lived positron-emitting radionuclides, 11 C and 18 F with a half-life of 20.4 and 109.8 min, respectively, have often been used for radiolabeling as the most significant radionuclides from both a chemical and biological perspective as well as from the viewpoint www.intechopen.comPositron Emission Tomography -Current Clinical and Research Aspects 116 of radiation exposure safety.With respect to the 11 C-incorporation on organic carbon frameworks, we have been developing multiple-type Pd 0 -mediated rapid [ 11 C]methylations onto an arene including a heteroaromatic compound, and alkene, alkyne and alkane structures by [ 11 C]carbon-carbon bond forming reactions (rapid C-[ 11 C]methylations) using [ 11 C]methyl iodide and an excess amount of an organostannane or organoboron within a very short time span (5 min) (Suzuki et al., 1997;Hosoya et al., 2004;Hosoya et al., 2006;Doi et al., 2009;Suzuki et al., 2009).These labeling reactions provide a high generality and practicability as groundbreaking methods for introducing the [ 11 C]methyl group into almost any organic framework.Regarding the 18 F radionuclide, a rather longer half-lived positron emitter than 11 C, the 18 F-labeling can be mainly accomplished by ordinary methods involving nucleophile substitution with the 18 F anion, as exemplified by the synthesis of 2-[ 18 F]fluoro-2-deoxy-D-glucose ([ 18 F]FDG) (Ido et al., 1978) and 3'-[ 18 F]fluoro-3'deoxythymidine ([ 18 F]FLT) (Grierson et al, 1997, as cited in Bading & Shields, 2008).In this chapter, newly advanced methodologies for introducing the short-lived 11 C radionuclide into various carbon frameworks (rapid C-[ 11 C]methylations) and the rather longer halflived 18 F radionuclide into a benzene framework (C-[ 18 F]fluoromethylation) are described in detail in addition to their applications for radiolabeling biologically and clinically significant organic molecules.

PET molecular imaging technology-principle, properties, and benefits
The short-lived positron emitting radionuclide 11 C was first produced by Crane and Lauritsen in 1934(Lauritsen et al., 1934, as cited in Allard et al., 2008).They investigated the physical properties of this radionuclide and demonstrated that 11 C undergoes  + decay with a half-life of 20.4 min, yielding 11 B as the stable nuclide (Figure 1).A positron (positively charged electron, e + ) ejected by this process collides with a nearby electron within a few millimeters in tissue to produce two high-energy -ray photons of 511 keV each.These photons travel in opposite directions at 180 degrees, penetrating the body, and can be detected by a pair of opposing scintillation detectors.If the two opposite detectors are simultaneously hit, it is assumed that the photons come from the same decay event.The data are fed to a computer system that can reconstruct the three-dimensional tomographic imaging and provide a highly accurate quantitative analysis of a radiolabeled drug in a body over time, measured as becquerel (Bq) per pixel.Because of the really high specific radioactivity of positron-emitter labeled compounds, PET enables in vivo imaging using an extremely small mass of the compound (sub-femtomole), namely, at extremely low concentrations (sub-picomolar) far below the critical concentration of pharmacological effects.The other typical positron-emitting radionuclides for PET studies, along with their half-lives (t 1/2 ) are: 15 O (t 1/2 = 2.07 min); 13 N (t 1/2 = 9.96 min); 68 Ga (t 1/2 = 67.6 min); 18 F (t 1/2 = 109.7 min); 64 Cu (t 1/2 = 12.7 h).The benefits of the use of PET technology in scientific research areas are as follows: (1) O, N, and C are included as ubiquitous elements constituting a biologically active compound in nature, providing the diversity of the labeled compounds without modifying the properties (or functions) of the molecule; (2) the molecule including the positron emitting radionuclide can be externally and quantitatively measured using a PET camera with a high resolution and sensitivity; (3) a short half-life is very relevant to human PET studies in terms of the high required safety for radiation exposure.
117 Fig. 1.Principle of the brain imaging by PET as shown by 11 C to 11 B decay.

Rapid chemistry needed for 11 C-labeling-working against time
The special aspects of PET radiochemistry such as short half-lives, extremely small amounts of available radionuclides, and relatively high-energy radiation impose severe restrictions on the synthesis of PET probes.In general, the synthesis of a pure, injectable 11 C-labeled probe must be accomplished within 2-half lives of ca.40 min due to the quick decay of the radioactivity.The synthesis process for the pharmaceutical formulation includes the following steps: (1) derivatives of a 11 C isotope produced by a cyclotoron to an appropriate labeling precursor such as 11 CH 4 , 11 CH 3 I, 11 CH 3 OTf, 11 CO, and 11 CO 2 ; (2) evaluation of the reaction efficiency (radiochemical yield) by analytical high performance liquid chromatography (HPLC) after the 11 C-labeling of the target probe; (3) work-up and chromatographic purification of the desired 11 C-labeled probe; and (4) preparation of an injectable solution for an animal/human PET study (pharmaceutical formulation).Therefore, the time allowed for a 11 C-labeling reaction should be less than 5 min, inevitably necessitating a rapid chemical reaction.Another difficulty encountered in the synthesis of a 11 C-labeled PET probe is the availability of an extremely small amount (nano-mol level) of the 11 C-labeling precursor such as [ 11 C]CH 3 I.Therefore, the labeling reaction is usually carried out with a large amount (milli-gram level) of the reacting substrate to promote the reaction.In addition, the efficient and secure purification of a small amount of the synthesized 11 C-labeled probe from a large amount of the remaining substrate must be considered since a PET probe is usually intravenously injected into both living animals and humans.

Attractive features of rapid C-[ 11 C]methylation-four kinds of rapid C-[ 11 C]methylations
Thus far, in the field of PET chemistry, the [ 11 C]methylation of the hetero atoms of N, O, and S has mainly been explored and utilized because of its simple reaction conditions namely, only by mixing 11 CH 3 I and a large amount of the substrate (Allard et al., 2008).However, a carbon-hetero atom bond tends to be readily metabolized to produce 11   , 1984).In such a reaction, however, the use of a moisture-sensitive organolithium compound is difficult to justify the stoichiometry for an extremely small amount of [ 11 C]CH 3 I, resulting in the inevitable production of a large amount of an undesired demethylated derivative due to the use of an excess amount of the lithiated substrate.Furthermore, the undesired side reaction such as the rearrangement of the lithiation position occurs under such drastic conditions.Consequently, the tedious separation of demethylated side products and regioisomers is inevitably needed to purify the desired compound.Thus, the reaction based on the use of "soft metalloids" as nucleophilic substrates was ideal for this requirement, if realized, as described in detail in section 5.

Benefits of using of an organostannane as a trapping substrate for [ 11 C]methyl Iodide
A general protocol for the rapid C-methylation was established for the first time based on a Stille-type reaction using phenyltributylstannane and CH 3 I, then [ 11 C]CH 3 I, a frequentlyused 11 C-labeling precursor (Suzuki et al., 1997).The Stille reaction is among the most generally used C-C bond forming reactions in organic synthesis as a reaction of an organometallic (-metaloid) reagent with an organic electrophile (Stille, 1986).The organotin compounds can be prepared by a number of routes even if containing a variety of reactive functional groups.Moreover, the reagent is not particularly oxygen or moisture sensitive.In the palladium(0)-catalyzed coupling of an organic electrophile with an organotin reagent, essentially only one of the groups on the tin atom selectively enters into the coupling reaction, namely an unsymmetrical organotin reagent comprised of three simple alkyl (except methyl) groups, and the fourth group, such as the arenyl, alkenyl, or alkynyl group.The latter fourth group can selectively transfer.The Stille reaction was thought to be useful for our purpose because of its favorable properties of the triorganostannane compounds, such as (1) their high tolerance to various chemical reactions and chromatographic purification conditions, enabling the incorporation of a radioisotope as the final step of the PET-probe synthesis; and (2) the extremely low polarity of a trialkyltin(IV) derivative, enabling an easy separation of the desired product from a large amount of the remaining tin substrate.However, to the best of our knowledge, at that time, there was little information on the Stille reaction using methyl iodide as an sp 3 -hybridized carbon partner in comparison to its wide applicability to sp 2 -hybridized arenyl or sp 3 -hybridized allylic halides; it seemed rather difficult to realize the methylation in high yield due to the unavoidable scrambling between the methyl group in methyl iodide and phenyl groups in the triphenylphosphine ligand, P(C 6 H 5 ) 3 , by the reaction of methyl iodide with the less reactive phenyltributylstannane in the presence of Pd{P(C 6 H 5 ) 3 } 4 (Morita et al., 1995).The use of the higher reactive phenyltrimethylsytannane as a substrate also induces the competition between 11 CH 3 in 11 CH 3 I and CH 3 groups in the stannane to produce [ 11 C]ethane as a byproduct (Suzuki et al., 1997, also see section 6).Furthermore, the labeledcompound obtained from the trimethyltin derivative resulted in a much lower specific activity than the tributyltin derivative (Samuelsson & Långström, 2003;Madsen et al., 2003).
It should be added that tributyltin derivative is practically non-toxic, while the trimethyland triethyltins have a significant acute toxicity (Smith, 1998;Buck et al., 2003).Consequently, we have been obliged to devise new reaction conditions capable of promoting a rapid cross-coupling reaction using the less reactive tributyltin derivative as a substrate for trapping [ 11 C]CH 3 I.

Realization of Pd 0 -mediated rapid C-methylations by the reaction of methyl iodide with an excess amount of arenyltributylstannanes (rapid coupling between sp 2 (arenyl)-and sp 3 -hybridized carbons)
Keeping the 11 C radiolabeling conditions of a PET-probe synthesis in mind, we set up a model reaction using methyl iodide and an excess amount of phenyltributylstannane (1) (CH 3 I/1 = 1:40 in molar ratio) to possibly restrict the reaction time to less than 5 min (Table 1) (Suzuki et al., 1997).The yield of the methylated product, toluene (2), was determined on the basis of the CH 3 I consumption.As anticipated, the conventional Stille-reaction www.intechopen.com Positron Emission Tomography -Current Clinical and Research Aspects 120 conditions with a reaction time of 30 min did not give the desired product at all (Table 1, Entry 1), leading us to introduce the concept of coordinative unsaturation to activate the palladium catalyst.Thus, we found that the use of a coordinatively unsaturated Pd 0 complex, Pd{P(o-CH 3 C 6 H 4 ) 3 } 2 (Paul et al., 1995), generated in situ by mixing Pd 2 (dba) 3 (dba: dibenzylideneacetone) and the sterically bulky tri-o-tolylphosphine (P(o-CH 3 C 6 H 4 ) 3 ; cone angle, 194°) (Tolman, 1977) instead of triphenylphosphine (P(C 6 H 5 ) 3 ; cone angle 145°) (Tolman, 1977), significantly increased the coupling efficiency (76%, Table 1, Entry 2).Next, we introduced an additional concept to shorten the reaction time (from 30 min to 5 min); the simple heating (80 °C) was less effective for lowering the yield, but the stabilization of the transiently formed palladium catalyst, strongly solvated by N,N-dimethylformamide (DMF), effectively suppressed the decrease in the yield to a considerable extent.Furthermore, we intended to enhance the reactivity by adding a Cu I salt with the expectation of Sn to Cu transmetallation, and K 2 CO 3 in order to react with the (n-C 4 H 9 ) 3 SnX (X = I and/or Cl) generated during the reaction to neutralize the reaction system.Thus, the reaction using the CH 3 I/1/Pd 2 (dba) 3 /P(o-CH 3 C 6 H 4 ) 3 /CuCl/K 2 CO 3 system (1:40:0.5:2:2:2) in DMF at 60 °C for 5 min gave the desired product in 91% yield (Table 1, Entry 6) (Suzuki et al., 1997).It should be noted that when phenyltrimethylstannane was used instead of phenyltributylstannane, the reaction produced toluene (2) in >100% yield (122-129%) together with ethane, indicating the unexpected cross-coupling reactions (scrambling) between the methyl in methyl iodide and the methyl on the tin atom.The reaction between the phenyl and methyl on the tin atom was also contaminated to yield toluene (undesired product in actual PET probe synthesis) to a significant extent (Suzuki et al., 1997)

121
groups and phenyl groups on the tin atom (Madsen et al., 2003).It was assumed from these results that the reaction of [ 11 C]CH 3 I and phenyltrimethylstannane under PET radiolabeling conditions would produce the undesired radioactive and volatile [ 11 C]ethane.As described later (see the section 8.2), these phenomena were observed during the palladium-mediated reaction of 1-(2'-Deoxy-2'-fluoro--D-arabinofuranosyl)-5-(trimethylstannyl)uracil to synthesize 1-(2'-Deoxy-2'-fluoro--D-arabinofuranosyl)-[methyl-11 C]thymidine (Samuelsson & Långström, 2003).Therefore, we concluded that the arenyltributylstannane, though less reactive, would be a much more suitable coupling partner than the arenyltrimethylstannane in view of the increased efficiency of the reaction, relatively low toxicity, and the safety of the radiation exposure.
The conditions of the reaction are significantly different from those of the originally reported Stille coupling reaction.Thus, the coupling of methyl iodide and phenyltributylstannane probably proceeds by the mechanism proposed in Equations 1-5 (Suzuki et al., 1997).In the first step, methyl iodide undergoes oxidative addition with a Pd 0 species to generate methyl-Pd II iodide 3 (oxidative addition, Eq. ( 1)).The Pd II complex 3 may directly react with the phenylstannane 1 to afford the (methyl)(phenyl)Pd II complex 6 (substitution, Eq. ( 4)); however, the formation of the latter would be facilitated by the phenyl-copper compound 4 formed by the preceding Sn/Cu transmetallation (Eq.( 2)).The effect of K 2 CO 3 would be explained by the neutralization of (n-C 4 H 9 ) 3 SnX to form the stable bis(tributylstannyl)carbonate 5 (Eq.( 3)).At the same time, K 2 CO 3 serves to synergically work with a Cu I salt to promote the Sn/Cu transmetallation (Eqs. (2) and ( 3)) (Hosoya et al., 2006).Finally, toluene is formed by reductive elimination from the Pd II complex 6 (reductive elimination, Eq. ( 5)).The significant ligand effect of tri-o-tolylphosphine is attributed to its considerable bulkiness (cone angle = 194°, which is greater than that in tri-tertbutylphosphine (182°)) (Tolman, 1997), which facilitates the generation of the coordinatively unsaturated Pd 0 and Pd II intermediates (Louie & Hartwig, 1995).Transmetallation to give 6 and/or the reductive elimination of toluene requires the formation of the tricoordinate Pd II complex.DMF may stabilize such Pd intermediates even at high temperatures.It should be noted that J. K. Stille et al. p

r e v i o u s l y r e p o r t e d t h e r e a c t i o n o f m e t h y l i o d i d e a n d p-
methoxyphenyltributylstannane in the presence of Pd{P(C 6 H 5 ) 3 } 4 at 50 °C for 24 h, in which the scrambling reaction between the methyl and the phenyl groups in the methyl iodide and triphenylphosphines, respectively, preferably occurred to give the desired pmethoxytoluene in only 3% together with 1-methoxy-4-phenylbenzene as the major (5) (3) byproduct in 8% yield, suggesting that the promotion of the Stille reaction using methyl iodide as an sp 3 -carbon partner could be difficult (Morita et al., 1995) until our successful result was demonstrated (Suzuki et al., 1997).

Application for the synthesis of 15R-[ 11 C]TIC methyl ester as specific probe for prostaglandin receptor (IP 2 ) in the central nervous system
In a preceding study of prostaglangin (PG), we succeeded in developing (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin (15R-TIC, 7), which was selectively responsive to a novel prostacyclin receptor (IP 2 ) in the central nervous system (Suzuki et al., 1996;Suzuki et al., 2000b).The tolyl group in 7 was intended as a trigger component to create a PET molecular probe.Therefore, we planned to apply the rapid C-methylation conditions to the synthesis of a PET molecular probe, the 15R-[ 11 C]TIC methyl ester using [ 11 C]CH 3 I, prepared from [ 11 C]CO 2 according to an established method (Fowler & Wolf, 1997), and the stannane 8 (Suzuki et al., 2000a).However, we found that the C-[ 11 C]methylation under radiolabeling conditions, even after using an excess amount of a Cu I salt, lacked reproducibility for some unknown reasons.During the course to overcome this difficulty along with the actual PETprobe synthesis, we encountered some valuable information that led to a solution of the problem by using CuI instead of CuCl that severely retarded the methylation of the phenyltributylstannane (Table 1, Entry 5).In order to minimize this inhibitory effect of CuI, we changed the one-pot operation to a two-pot stepwise procedure during the actual PETprobe synthesis (Figure 3) (Suzuki et al., 2004).This procedure consists of independent syntheses of a methylpalladium complex and a phenyl copper complex at room temperature (25 °C), and then the mixing of these species in one portion at a higher temperature (65 °C, 5 min).As expected, the highly qualified PET probe, the 15R-TIC methyl ester ([ 11 C]9), was obtained by thus C-[ 11 C]methylation procedure from 8 in an 85% isolated yield (decaycorrected, based on the radioactivity of [ 11 C]CH 3 I trapped in the Pd solution; it indicates the production efficiency) with a purity of greater than 98%, which was applicable for a human PET study with a sufficient radioactivity of 2-3 GBq and high reproducibility (Figure 3).The specific radioactivity was 37-100 GBq mol -1 .The total synthesis time was 35-40 min.
After the ethical committee gave its official approval for a human PET study, the principal author, M. Suzuki, was nominated to be the first volunteer.Thus, the 15R-[ 11 C]TIC methyl ester ([ 11 C]9) was injected into his right arm and it passed through the blood-brain barrier.It was then hydrolyzed in the brain to a free carboxylic acid, which was eventually bound to the IP 2 receptor.PET images of horizontal slices indicated that a new receptor, IP 2 , was distributed throughout various structures in the human brain (Figure 4) (Suzuki et al., 2004).
A PET study of the middle cerebral artery occlusion using a monkey model demonstrated that 15R-TIC revealed a potent neuroprotective effect against focal cerebral ischemia as judged by the [ 15 O]O 2 consumption and the uptake of [ 18 F]FDG (Cui et al., 2006).Recently, rat PET studies using the 15R-[ 11 C]TIC methyl ester ([ 11 C]9) showed that [ 11 C]9 could be useful for the in vivo analyses of the mrp2-mediated hepatobiliary transport (Takashima et al., 2010).Furthermore, the PK/PD studies of [  (Björkman et al., 2000) targeting the receptor of prostaglandin F 2 (PGF 2 ) was also synthesized using a procedure similar to [ 11 C]9.

-mediated rapid coupling of methyl iodide and heteroarenylstannanes applicable to 2-and 3-[ 11 C]methylpyridines
There is a strong demand for the incorporation of a short-lived 11 C-labeled methyl group into the heteroaromatic carbon frameworks, because such structures often appear in major drugs and their promising candidates.The Pd 0 -mediated rapid trapping of methyl iodide with an excess amount of a hetero-aromatic ring-substituted tributylstannane 11a-i was done (Suzuki et al., 2009) by first using our previously developed CH 3 I/11ai/Pd 2 (dba) 3 /P(o-CH 3 C 6 H 4 ) 3 /CuCl/K 2 CO 3 (1:40:0.5:2:2:2)combination system in DMF at 60 °C for 5 min (conditions A; Suzuki et al., 1997), but the reaction produced low yields of the various kinds of heteroaromatic compounds (Table 2, Entries 1-9).An increase in the phosphine ligand (conditions B) significantly improved the yield for the heteroarenyl stannanes, 11b, 11c, and 11i, but the conditions were still insufficient in terms of the range of adaptable heteroaromatic structures.Another CuBr/CsF combination system (conditions C) also provided a result similar to conditions B using an increased amount of the phosphine.Thus, pyridine and the related heteroaromatic compounds still remained as less reactive substrates.Consequently, the problem was overcome by replacing the DMF solvent with Nmethyl-2-pyrolidinone (NMP).It is of interest that such a solvent effect was not observed for the CuCl/K 2 CO 3 combination system, but appeared for the CuBr/CsF reaction system (Table 3, Entry 2), giving 2-methylpyridine (2-picoline, 12d) in 81% yield.The other solvents, except for the amide-type solvent and amine additives, were not effective (Table 3, Entries 4-11).Thus, the reaction in NMP at 60-100°C for 5 min using the CH 3 I/11ai/Pd 2 (dba) 3 /P(o-CH 3 C 6 H 4 ) 3 /CuBr/CsF (1:40:0.5:16:2:5)combination (conditions D) gave the methylated products 12a-i in >80% yields (based on the reaction of CH 3 I) for all of the heteroaromatic compounds listed in this study (Table 2, Entries 1-9).Thus the combined use of NMP and increased amount of the bulky arenylphosphine is important to efficiently promote the reaction.The conditions using a Pd{P(tert-C 4 H 9 ) 3 } 2 /CsF system in NMP reported by G. C. Fu et al. (Littke et al., 2002) were not effective by producing only a poor yield (21%, Table 3, Entry 2) as judged by the methylation of 2-pyridyltributylstannane (11d).The addition of CuBr to this system improved the yield to only a small extent (39%).Table 3.Effect of a solvent and additives in increased phosphine and synergic systems on the rapid trapping of methyl iodide with 2-pyridyltributylstannane (11d) to give 2methylpyridine (12d).
(S)-(+)-2-Methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]homopiperazine (H-1152, or referred to as H-1152P, 13) is known as the most potent, specific, and membrane-permeable inhibitor of small G protein Rho-associated kinase (Rho-kinase).A 11 C-labeled H-1152 as a novel PET probe for imaging Rho-kinases was efficiently synthesized for the first time based on the Pd 0 -mediated rapid C-[ 11 C]methylation for trifluoroacetyl (TFA)-protected heteroarenylstannane precursor using [ 11 C]CH 3 I followed by rapid deprotection of the TFA group (Suzuki et al., 2011a).Thus, the C-[ 11 C]methylation on the isoquinoline derivative was showing that the tumors in the brain, prostate, thorax, and bone could be clearly visualized.However, there is the primary limitation in the use of [ accounting for its localization in the mitochondrion-rich human myocardium.On the other hand, 4'-thiothymine (15b), which resembles the biological properties of thymidine (15a) with a higher stability for the phosphorylase cleavage, underwent the 11 CH 3 -labeling for the tumor imaging using a rat, exhibited a higher potential as an attractive PET probe than [ 18 F]FLT (Toyohara et al., 2008).Although the PET imaging studies using various kinds of 11 C-and 18 F-labeled thymidne analogues have been extensively continued, it is still difficult to synthesize the labeled compounds.
The utility of the rapid methylation of an alkene was well demonstrated by the synthesis of a 11 C-labeled partial retinoid derivative [ 11 C]20l using reaction conditions B or D (X = Br), to produce in the high yield of 85% (radio-HPLC analytical yield) for both conditions (Figure 8) (Hosoya et al., 2006, see also section 11.4).

Rapid C-[ 11 C]methylation of alkynes 10.1 Rapid C-methylation of alkynes (rapid coupling between sp-sp 3 hybridized carbons)
We set up a model reaction using methyl iodide and an excess amount of 1hexynyltributylstannane (21) (CH 3 I/21 = 1:40) with the reaction time fixed at 5 min (Figure 9) (Hosoya et al., 2004).The reaction with Pd{P(C 6 H 5 ) 3 } 4 gave the desired 2heptyne ( 22) in a poor yield.The previous conditions, Pd 2 (dba) 3 /P(o-CH 3 C 6 H 4 ) 3 /CuCl/K 2 CO 3 , established for the sp 2 (arenyl)-sp 3 rapid methylation, were also not applicable for this reaction.Based on the screenings of the phosphine ligand and additives, we found that the bulky and strong -electron-donating ligand, P(tert-C 4 H 9 ) 3 , facilitates the methylation (Hosoya et al., 2004).The combinations with fluoride ions, such as CsF or KF, were extremely efficient in promoting the reaction in a high yield.As a consequence, the reaction in the presence of bis(tri-tert-butylphosphine)palladium(0) (Pd{P(tert-C 4 H 9 ) 3 } 2 ) and KF in DMF at 60 °C for 5 min resulted in forming 22 in 95% yield (Hosoya et al., 2004).The reaction was applicable to various kinds of functionalized alkynylstannanes including the stannyl precursors 23 and 24, which are the substrates with steroid and deoxyribonucleoside frameworks, giving methylated compounds 25 and 26 in 87 and 74% yields, respectively (Hosoya et al., 2004).

Synthesis of [ 11 C]iloprost methyl ester
Iloprost ( 27) is a stable prostacyclin (PGI 2 ) analogue specific for the PGI 2 receptor, IP 1 , in peripheral systems used as a potential therapeutic agent (Skuballa & Vorbrüggen, 1981), having the structure of 1-propynyl on the -side chain.According to the method established in the previous section, the 11

Rapid C-methylations using organoborons as trapping nucleophiles
In general, organoboron compounds are less toxic than organostannanes.Therefore, we intended to elaborate the rapid C-methylation based on the Suzuki-Miyaura coupling reaction (Miyaura & Suzuki, 1995) as a complementary method to the Stille-type rapid Cmethylation.In this context, the Merck group reported the syntheses of [ 11 C]toluene derivatives by the reaction using [ 11 C]methyl iodide and an excess amount of arenylboron in the presence of PdCl 2 (dppf) (dppf = 1,1'-bis(diphenylphosphino)ferrocene) and K 3 PO 4 in DMF under microwave heating at high temperature (Hostetler et al., 2005).In contrast, we intended to establish a more efficient method by moderate thermal conditions based on the use of a Pd 0 complex without using microwaves in view of the careful treatment of a radiolabeled compound, and eventually, succeeded in developing very mild practical reaction conditions thus able to avoid the fear of an accidental radiation exposure (Doi et al., 2009).

Pd 0 -mediated rapid C-methylations by coupling reaction of methyl iodide and a large excess arenyl-or alkenyl boronic acid ester
By keeping an actual PET-probe synthesis in mind, we set up the model reaction using methyl iodide and an excess amount of phenylboronic acid pinacol ester (30) (CH 3 I/30 = 1:40) with the short reaction time fixed at 5 min (Doi et al., 2009).The results are summarized in Table 6.We first attempted the known conditions frequently used for a  a Reaction was carried out with CH3I (10 mol) and 30 (400 mol), Pd 0 (10 mol).b 20 mol of the additive was used.c The yield was determined by GLC based on CH3I.dppf: 1,1'bis(diphenylphosphino)ferrocene.
Suzuki-Miyaura coupling reaction (Miyaura & Suzuki, 1995), but such conditions did not give any satisfactory results (24-39% yields; Table 6, Entries 1-3).Therefore, we attempted the use of a Pd 0 complex coordinated with the bulky phosphine in a non-volatile solvent with a high polarity inspired by our successful studies on the Pd 0 -mediated rapid C-[ 11 C]methylations using organostannanes (Suzuki et al., 1997;Hosoya et al., 2004;Hosoya et al., 2006;Suzuki et al., 2009).As expected, the reaction was dramatically accelerated by the use of the tri-o-tolylphosphine complex in DMF in the presence of K 2 CO 3 , K 2 CO 3 /H 2 O, Cs 2 CO 3 , or K 3 PO 4 to give the desired toluene in 87-94% yields (Table 6, Entries 4-7).
The were found to be versatile for various arenyl, alkenyl, and hetero-aromatic ring substituted borons (Doi et al., 2009).Thus, the reactions with of both arenylborons with both electron-donating and electron-withdrawing groups on their aromatic rings and hetero-aromatic, ring-substituted boron compounds smoothly proceeded under the conditions of CH 3 I/boron/Pd 2 (dba) 3 /P(o-CH 3 C 6 H 4 ) 3 /K 2 CO 3 (1:40:0.5:2:2) in DMF at 60 °C for 5 min, gave the corresponding methylation products in 80-99% yields.The conditions were also applied to the rapid C-methylation of various types of alkenyl compounds, giving the corresponding methylalkenes in 86-99% yields.The E and Z stereoisomers gave the corresponding methylated products with the retention of stereochemistry, which confirmed that the reaction proceeded in a completely stereocontrolled manner.
Boronic acid and the more lipophilic esters showed the same reactivity as the pinacol boronate, making the labeled probe purification easier (Doi et al., 2009).
The actual [ 11 C]methylation using the above-mentioned conditions (Table 6, Entry 4) was well demonstrated in the synthesis of the [ 11 C]p-xylene (Figure 10).Thus, the reaction of the www.intechopen.com

Efficient synthesis of [ 11 C]celecoxib and its metabolites, [ 11 C]SC-62807
Celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzenesulfonamide, 38) is a selective cyclooxygenase (COX)-2 inhibitor that has analgesic and anti-inflammatory effects in patients with rheumatoid arthritis, but has no effect on the COX-1 activity at therapeutic plasma concentrations.In humans, celecoxib is extensively metabolized in the liver via sequential two-step oxidative pathways, initially to a hydroxymethyl metabolite (SC-60613), and upon subsequent further oxidation to a carboxylic acid metabolite (SC-62807, 39).The majority of celecoxib is excreted into the bile as SC-62807.In this context, Wu et al. reported that SC-62807 is a substrate of drug transporters, such as OATP1B1 and BCRP, which presumably mediate its hepatobiliary transport.Therefore, celecoxib or SC-62807 radiolabeled with a short-lived positron-emitting radionuclide could be a potential PET probe for evaluating the function of these drug transporters in hepatobiliary excretion (Takashima-Hirano et al., 2011).
There, nine operations from the [ 11 C]CH 3 I production to the formation of [ 11 C]39 were smoothly done automatically.PET studies in rats and the metabolite analyses of [ 11 C]celecoxib and [ 11 C]SC-62807 showed mostly different excretion processes between these compounds, and consequently, [ 11 C]SC-62807 was rapidly excreted via hepatobiliary excretion without further metabolism (Figure 11D), and therefore evaluated that it has a high potential as a PET probe suitable to investigate the hepatobiliary transport (Takashima-Hirano et al., 2011).

Efficient synthesis of 11 C-incorporated acromelic acid analogue
Acromelic acid A (Figure 12), a minor constituent isolated from Clitocybe acromelalga, induces allodynia in mice by intrathecal (i.t.) administration.If we can identify the receptor involved in the induction of allodynia, it may provide a trigger to develop novel analgesic drugs for use in the treatment of neuropathic pain.In this context, we have synthesized a novel 11 C-labeled PET probe [ 11 C]41, which was designed based on the (phenylthio)pyrrolidine derivative 41 that can competitively block the acromelic acidinduced allodynia (Kanazawa et al., 2011).A protocol in which the Pd 0 -mediated rapid methylation of the pinacol borate precursor 40 with [ 11 C]CH 3 I using Pd 2 (dba) 3 , P(o-CH 3 C 6 H 4 ) 3 , and K 2 CO 3 in DMF and the following deprotection of the TFA-protected amino acid moiety and hydrolysis of methyl esters were successively performed in one-pot within 5 min (4 and 1 min each) was established for the synthesis of a PET probe [ 11 C]41 with > 99% of both radiochemical and chemical purities (Kanazawa et al., 2011).The isolated yield was 34-43% (decay-corrected, based on trapped [ 11 C]CH 3 I).The obtained radioactivity of [ 11 C]41 after an injectable formulation under the nomal conditions was 5.0-6.0GBq and the specific radioactivity was 70-100 GBq mol -1 (Figure 12).The total synthesis time of [ 11 C]41 was within 30 min (Figure 12).The development of the fourth target of the rapid C-[ 11 C]methylations (rapid methylation of an alkane framework) (see Figure 2) by the coupling between sp 3 -sp 3 carbons using 11 CH 3 I and organoborons is also currently underway using a similar procedure in our group.
12.2 Another rapid coupling between sp 3 -sp 3 hybridized carbons: Efficient synthesis of [ 11 C]NSAIDs and these esters In order to perform the in vivo molecular imaging of cyclooxygenases (COXs), well-known as key enzymes in prostaglandin biosynthesis, we intended to develop a novel method to rapidly incorporate a 11 C radionuclide into various 2-arenylpropionic acids that have a common methylated structure, particularly abundant among nonsteroidal antiinflammatory drugs (NSAIDs).Consequently, we elaborated the rapid 11 C-labeling using the reaction of [ 11 C]CH 3 I and an enolate intermediate generated from the corresponding ester under basic conditions, followed by the one-pot hydrolysis to convert it into the 11 Cincorporated acid as [ 11 C]NSAID (Figure 14A) (Takashima-Hirano et al., 2010b).Methoxy 2arenylpropionate is much less polar due to the increase in hydrophobicity of an introduced methyl group and the less hyperconjugation between the C-H bond of the benzylic position and C=O *, which is also possible for the LUMO (*) of a phenyl moiety, allowing easy separation of the desired 11 C-labeled product from the demethylated compound.This method is quite general and utilized for the syntheses of the following six PET probes of NSAIDs:  14B), giving the first successful example of the in vivo molecular imaging of neuroinflammation by the noninvasive PET technology.A metabolite analysis in the rat brain revealed that the intravenously administrated methyl ester was initially taken up in the brain and then underwent hydrolysis to form a pharmacologically active form of the corresponding acids.Hence, we succeeded in the general 11 C-labeling of 2-arenylpropionic acids and their methyl esters as PET probes of NSAIDs to construct a potentially useful PET-probe library for the in vivo imaging of inflammation involved in the COX expression (Shukuri et al., 2011).The above racemic NSADs are readily separated by a chiral column to give an optically pure compound.Tetrabutylammonium fluoride (TBAF) was also effective to promote the rapid [ 11 C]methylation of the enolate in THF as found in our (Takashima-Hirano et al., 2010a) and other group (Kato et al., 2010).The [ 11 C]methylation of an analogous enolate has been www.intechopen.comPositron Emission Tomography -Current Clinical and Research Aspects 142 applied to the synthesis of 11 C-labeled -aminoisobutyric acid as a PET probe for cancer imaging (Kato et al., 2011).(Zhang & Suzuki, 2007).There are many benefits based on the success of the 18 F-labeling by rapid C-[ 18 F]fluoromethylation: (1) capability of a relatively long in vivo study complementary to 11 C, (2) feasible delivery of 18 F-labeled probes to distant PET centers and clinics, (3) insertion of multi-reactions after labeling, and (4) the use as a prosthetic group in click chemistry for the labeling of peptides, nucleic acids, sugars, etc.The application of rapid 18 F-labeling to biologically significant organic compounds will be reported in due course.
Initially, we investigated the Pd 0 -mediated rapid cross-coupling using non-radioactive fluoromethyl iodide and phenyltributylstannane or a boron compound prior to the actual C-[ 18 F]fluoromethylation (Doi et al., 2009).The conditions for rapid C-methylation using an organoboron in Table 6, Entry 4, were efficient for the synthesis of the fluoromethyl arene.Furthermore, a slightly improved condition using the 1:3 ratio of Pd 0 /P(o-CH 3 C 6 H 4 ) 3 was found to be the most effective for promoting the fluoromethylation with pinacol phenylboronate 30, giving the desired benzyl fluoride in 57% yield (Doi et al., 2009).Thus, the conditions using FCH 2 I for the synthesis of an [ 18 F]fluoromethyl-labeled PET probe was established.

Rapid C-[ 18 F]fluoromethylation
We set up the reaction using ca.0.5 GBq of [ 18 F]FCH 2 X (X = Br or I) and a 4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester (56) (Figure 15).First, we found that the labeling reaction using [ 18 F]FCH 2 I and 56 for 5 min at 65 °C gave the desired p-([ 18 F]fluoromethyl)benzoic acid methyl ester ([ 18 F]57) using Pd 2 (dba) 3 /P(o-CH 3 C 6 H 5 ) 3 (1:6) and K 2 CO 3 in DMF.The radio-HPLC analytical yield of [ 18 F]57 was 23 %, but a considerable amount of side products with a high polarity appeared, which might be the [ 18 F]fluoride ion derived from the decomposition of [ 18 F]FCH 2 I.However, to the best of our knowledge, this result was the first evidence for the Pd 0 -mediated rapid C-[ 18 F]fluoromethylation.After a broader investigation of not only labeling chemistry, but also the mechanical operations of our radiolabeling system, we concluded that the C-[ 18 F]fluoromethylation with [ 18 F]FCH 2 Br will be more practical than that with [ 18 F]FCH 2 I. Actually, [ 18 F]FCH 2 I was essentially more reactive to the Pd 0 complex, but [ 18 F]FCH 2 I was not stable and gradually decomposed in the light-exposed solution.For these reasons, we then focused on developing the C-[ 18 F]fluoromethylation using [ 18 F]FCH 2 Br.The reaction was dramatically promoted under the conditions of 120 °C for 5 and 15 min in DMPU/H 2 O (9:1) to give [ 18 F]57 in 48 and 64% yields, respectively.HPLC analyses showed that the reaction for 5 min resulted in the unreacted [ 18 F]FCH 2 Br remaining to a considerable extent, but the reaction for 15 min produced a remarkably sharp peak of [ 18 F]57 as the main product.The C-[ 18 F]fluoromethylation would be completed within 15 min because the reaction for 30 min did not produce a further increase in the yield.The 15-min reaction thus obtained matches well with the 18 F-incorporated PET-probe synthesis because of the longer half-life (110 min) of the 18 F radionuclide compared to 11 C (20.4 min) (Doi et al., 2010).

Conclusions
In this chapter, a ground-braking methodology based on the use of cutting-edge chemistry was introduced for the synthesis of a short-lived 11 C-incorporated PET tracer.First, a general method for the rapid reaction of methyl iodide with an arenyltributylstannane (excess amount) (the Stille-type reaction) was established, producing a methylarene in the presence of the bulky tri-o-tolylphosphine-bound coordinatively unsaturated Pd 0 complex, a Cu I salt, and K 2 CO 3 based on a synergic effect to promote the reaction.The reaction was used for the synthesis of the 15R-[ 11 C]TIC methyl ester as an actual PET probe.The rapid Cmethylation was expanded to other types of rapid methylations including the methylation on heteroaromatic frameworks by adding another Cu I /CsF synergy and choosing the bulky trialkylphosphine for the alkene and alkyne, thus allowing the radio synthesis of various biologically and clinically important molecules.To meet the further demands of an efficient labeling method in PET, we established a rapid methylation using methyl iodide and an organoboron compound (Suzuki-Miyaura type coupling) as a complementary trapping substrate to an organostannane in the presence of Pd 0 , tri-o-tolylphosphine, and K 2 CO 3 or K 2 CO 3 /H 2 O in high yield.The reaction conditions were also applied to the Cfluoromethylation, and, after slight modifications, we realized the incorporation of the rather longer half-lived 18 F radionuclide into organic frameworks (rapid C-[ 18 F]fluoromethylation).Our five original papers (Suzuki et al., 2009;Doi et al., 2009;Hosoya et al., 2006;Koyama et al., 2011;Hosoya et al., 2004, in order for ranking) were ranked Nos.1-5 among the top 10 articles published in the same domain in BioMedLib (search engine for the 20 million articles of MEDLINE, April 2009-June 2011).Accordingly, a "Bible" on the syntheses of 11 C-and 18 F-labeled compounds has been continuously updated to provide valuable information required for a PET chemist.
As shown in Figure 16, RIKEN CMIS has utilized three types of remote-controlled synthesizers for 11 C-and 18 F-labeling, which originally developed with the focus on synthetic organic chemistry.The next step is the application of the descrived synthetic procedure for the synthesis along with the Guidance of Good Manufacturing Practice (GMP) regulation.We also consider that the rapid reactions using a microfluidic system (microreactor) will be important in order to reduce the amount of a substrate (if scarce or very expensive) without lengtheing the reaction time.
The methods thus described have widely been applied by other groups to synthesize 11

Perspectives
Molecular imaging with PET is the only method for elucidating the whole-body pharmacokinetics of molecules in humans.This technique could be adapted for the efficient screening of drug candidates in humans during the early stage of the drug development process (phase 0 as a pre-clinical trial), and accelerating the path leading to clinical trials, resulting in revolutionizing drug development.The chemistry covering a broad range of designs, syntheses, and labelings is expected to play a central role in this interdisciplinary scientific field.
The objective of the study was to develop a novel chemical methodology for in vivo molecular imaging adaptable from animals to humans.As already described, we developed various types of rapid C-[ 11 C]methylations and C-[ 18 F]fluoromethylations by the Pd 0mediated cross-coupling reactions between [ 11 C]methyl iodide or [ 18 F]fluoromethyl idodide (or bromide) and organostannanes or organoborons, respectively, for the synthesis of shortlived PET molecular probes.The synthesis method would also be applicable for the incorporation of other carbon isotope units, such as CH 2 18 F, 13 CH 3 , 14 CH 3 , CD 3 , and CH 2 19 F, allowing the application to accelerator mass spectrometry (AMS) and MRI.In particular, PET and AMS using 11 C and 14 C (use of 10 -20 M), respectively, are two methods capable of promoting a human microdose study under political regulations (Europe, 2004;U.S., 2006;Japan, 2008).
We intend to further expand the rapid C-[ 11 C]methylations and [ 18 F]fluoromethylations and their applications in order to construct a library of 11 C-and 18 F-incorporated biologically significant molecules involved in various diseases important for medical treatment, such as cerebral diseases (Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic laterals sclerosis (ALS), etc.), cardiovascular diseases (hypertention, stroke, glaucoma, etc.), cancer, diabetes, infection (human immunodeficiency virus (HIV), hepatitis C virus (HCV), influenza, prion, etc.), inflammation, neuropathic pain, and transporter dysfunction, as a frontier research to promote in vivo molecular science.

147
In an advanced medical field, tailor-made medicine, personalized medicine based on single nucleotide polymorphism, and evidence-based medicine based on PK/PD studies in humans are emphasized by the rapid progress of genome science.We believe that the advancement of "in vivo molecular science in humans" is strongly required in order to achieve the medical objectives.The progress of in vivo human molecular science will serve to overcome the "Death Valley" existing between a preclinical study and the clinical trials in the drug development process in order to revolutionize disease diagnosis and the drug discovery process.
CH3I, formed from [ 11 C]CO2 according to the established method, was trapped in a solution of Pd2(dba)3 (1.3 mg, 1.4 µmol) and P(o-CH3C6H4)3 (1.7 mg, 5.6 µmol) in DMF (230 µL) at room temperature.The solution was transferred to a vial containing stannyl precursor 8 (2.0 mg, 3.0 µmol), CuCl (1.5 mg, 15µmol), and K2CO3 (2.1 mg, 15 µmol) in DMF (80 µL), and the resulting mixture was heated at 65 °C for 5 min.Prior to the preparative HPLC, a solid phase extraction column was used to remove the salts and palladium residue from the reaction mixture.The desired product, 15R-[ 11 C]TIC methyl ester [ 11 C]9, after HPLC separation and intravenous formulation usually had a isolated radioactivity of approximately 2.5 GBq, sufficient for an in vivo human PET study.

Fig. 6 .
Fig. 6.Assumed equilibration formed in the presence of a Cu I salt.
[ 11 C]compounds were isolated by preparative HPLC after the reaction was www.intechopen.comconducted under slightly improved conditions using a half-amount of phosphine (16 equiv) to give 45 and 42-59% isolated yields (decay-corrected, based on the radioactivity of [ 11 C]CH 3 I trapped in the Pd solution)

Fig. 7 .
Fig. 7. Synthetic scheme of [methyl-11 C]thymidine ([ 11 C]15a) and 4'-[methyl-11 C]thiothymidine ([ 11 C]15b) for a PET study (A), and the HPLC chart for the analysis of [ 11 C]15a, b (B and C, respectively, radioactivity and UV vs. time).The peaks at the retention times of 7.6 and 7.4 min labeled B and C are [ 11 C]15a and b, respectively.For the HPLC chart after the isolation of [ 11 C]15a and b, see supporting information in the ref.Koyama et al., 2011.

a
gave the desired c o m p o u n d i n o n l y t h e s a m e 2 % y i e l d s , a s j u d g e d b y t h e r e a c t i o n o f 1 -cyclohexenyltributylstannane (19e).Furthermore, the stereo isomerization of a double bond under our conditions did not occur at all under these reaction conditions.Reactions were carried out under conditions D using CH3I (10 mol), stannane 19a-l (400 mol), Pd2(dba)3 (5 mol), P(o-CH3C6H4)3 (20 mol), CuBr (20 mol), and CsF (50 mol).For the results under conditions A, B, and C, see ref.Hosoya et al., 2006.b The products were identified by GLC analyses and comparison to authentic samples.The yields were determined by GLC based on CH3I.c Modified conditions: Pd2(dba)3/P(o-CH3C6H4)3/CuBr/CsF (1:8:4:10 in molar ratio).d The reaction using the conditions B: Pd2(dba)3/P(o-CH3C6H4)3/CuCl/K2CO3 (1:8:4:10 in molar ratio) gave 20l in 71% yield.

Fig. 11 .
Fig. 11.Synthetic scheme of [ 11 C]celecoxib ([ 11 C]38) and [ 11 C]SC-62807 ([ 11 C]39) (A), the HPLC chart for the analysis of [ 11 C]38 (B) and [ 11 C]39 (C), and the time profiles of activity in the blood (red point), liver (yellow pont), kidney (pink point), bile (blue point), and urinary bladder (light blue point) determined by PET imaging and blood sampling over 60-min period after administration of [ 11 C]SC-62807 ([ 11 C]39) to male rats (D).The peak at a retention time of 9.6 min labeled B is [ 11 C]38 and the peak at a retention time of 4.4 min labeled C is [ 11 C]39.UV absorbance: 254 nm.

[ 11 CFig. 14 .
Fig. 14.Synthesis of 11 C-labeled 2-arylpropionoc acids and their esters (A), and PET images of [ 11 C]ketoprofen methyl ester ([ 11 C]48, left panel) and [ 11 C]ketoprofen ([ 11 C]54, right panel) in rat brain inflammation induced by lipopolysaccharide injection into the left striatum (B).Left PET image showed high accumulation in the area of inflammation, indicating that the methyl ester penetrated the blood-brain barrier and underwent hydrolysis in the brain to produce carboxylic acid as a pharmacologically active form, accumulating the inflammation area.
The C-[11 C]methylation is associated with C-[ 18 F]fluoromethylation by a similar coupling methodology using [ 18 F]fluoromethyl bromide ([ 18 F]FCH 2 Br) and [ 18 F]fluoromethyl iodide ([ 18 F]FCH 2 I) as the available 18 F-labeling precursor for the synthesis of various types of PET tracers by N-or O-[ 18 F]fluoromethylation

Fig. 16 .
Fig. 16.Our original remote-controlled synthesizer for 11 C-and 18 F-labeling; H19D: an early type system hybridized by septum-cannula and robot-arm method for the solution transfer (A), H20S: the improved model for step-wise labeling operations (B), and H20J: standard model focused on the simplicity and operational stability of the remote controlled synthetic procedures (C).

Table 2 .
General rapid C-methylation on various neutral and basic heteroaromatic rings.
11C]-or [18F]FMAU which is being a relatively poor substrate for TK 1 and a relatively good substrate for TK 2 , probably www.intechopen.comPositron Emission Tomography -Current Clinical and Research Aspects 128
C-labeled iloprost methyl ester ([ 11 C]29) was synthesized using [ 11 C]CH 3 I and a stannyl precursor 28 in up to 72% radio-HPLC analytical yield.The optimization of the synthesis of [ 11 C]29 is currently in progress.