Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology

Fluorine-18 Radiopharmaceuticals 379

functional groups. This would extend the power of PET imaging to many new applications

in pharmaceutical research and clinical application.

14.5.2 Nucleophilic

18

F - ﬂ uorination in Protic Solvents

Nucleophilic ﬂ uorination using [

18

F]ﬂ uoride ion is a typical displacement reaction that is

generally performed in a polar aprotic solvent such as acetonitrile, dimethyl sulfoxide, or

dimethylformamide [100] . In polar aprotic solvents, the nucleophilicity of anions including

[

18

F]ﬂ uoride is enhanced by the selective solvation of the cations. Conversely, solvation

in protic solvents likely reduces an anion ’ s nucleophilicity by interaction with the partial

Table 14.3 Alkyne substrates and radiochemical yields used in a 1,3 - dipolar cycloaddition

reaction with [

18

F ]ﬂ uoroethylazide

Substrate

Radiochemical yield (%)

a

Method A Method B

84 (7) 56 (10)

O

OH

61 (15) 29 (0)

O

OH

93 (40) 15 (6)

NH

2

> 98 (12)

96 (33)

O

N

H

> 98 ( > 98) > 98 (70)

O

N

H

98 (9) 76 (26)

O

OEt

HN O

> 98 (31)

97 (90)

O

N

H

> 98 (34)

92 (51)

Peptide

N

H

O

(92)

a

Numbers in parentheses are the yields at ambient temperature.

380 Fluorine in Medicinal Chemistry and Chemical Biology

positive charge of the protic solvent. Conventional theory suggests that polar aprotic sol-

vents are much better than protic solvents for nucleophilic substitution [100] .

Recently, a new investigation into nucleophilic displacement reactions using ﬂ uoride

ion in protic solvents has been reported by Kim et al. [101] . In that study, they showed

that sterically hindered protic solvents such as tertiary alcohols, in the absence of any kind

of catalyst, actually enhanced the nucleophilicity of an alkali metal ﬂ uoride (CsF). This

enhanced nucleophilicity dramatically increased the rate of nucleophilic ﬂ uorination com-

pared with conventional methods and reduced formation of typical reaction byproducts

(Figure 14.11 ).

This ﬁ nding is very interesting because it is in direct contrast with the predictions

made from the conventional reaction mechanism. The detailed reaction mechanism of

nucleophilic ﬂ uorination in a protic solvent system is presently not clear. However, a series

of compounds have been investigated (Table 14.4 ) and the corresponding ﬂ uorine -

substituted compounds are produced using this method in comparable or greater yields

than previously reported by other methods [101] .

The ﬂ uorination reaction of mesylates or tosylates has been reported to be less than

twice as fast as that of iodides [101] . However, in the protic solvent system, the ﬂ uorina-

tion rate of a tosylate is approximately 12 times faster than that of the corresponding iodide

(Table 14.4 ). This result suggests that the reaction rate is determined not only by the nature

of the leaving group but also by other types of interactions, such as those between the

solvent ( tert - alcohol) and the leaving group. For example, hydrogen bonding between the

alcohol solvent and the oxygen atoms in the alkanesulfonate leaving group may enhance

its nucleophilic (leaving group) character. Remarkably, using this ﬂ uorination procedure,

a ﬂ uoroproline derivative was prepared in good yield after only 1.5 hours at ambient

temperature from the corresponding triﬂ ate precursor (Table 14.4 ). It is notable that a

triﬂ ate group has six available sites for H - bonding with the solvent alcohol (three oxygens

and three ﬂ uorines). In contrast, ﬂ uorination of reactants with halide groups in the

tert - amyl alcohol media required more than 12 hours as well as vigorous conditions,

although these reactions did eventually produce the ﬂ uorine - substituted product in high

yields (72% and 88%).

The ﬂ uorination of haloethyl or alkanesulfonyloxyethyl aromatic compounds in

conventional methods usually uses a “ naked ” ﬂ uoride ion generated from phase - transfer

catalyst (i.e., potassium ion complexed by a cryptand, or a tetraalkylammonium salt) to

Figure 14.11 Nucleophilic aliphatic substitution of a mesylate ester leaving group using

ﬂ uoride ion as cesium salt in protic and aprotic organic solvents.

Fluorine-18 Radiopharmaceuticals 381

enhance the nucleophilicity and solubility of ﬂ uoride ions. The “ naked ” ﬂ uoride ion, as a

strong base, results in the competing elimination reaction to give the vinylarene by -

product. In Table 14.4 , the ﬂ uorination of 2 - (2 - mesyloxyethyl)naphthalene to 2 - (2 -

ﬂ uoroethyl)naphthalene in a protic solvent proceeds almost to completion, producing the

corresponding ﬂ uoroalkane in 92% yield with only trace quantities of alkene byproduct.

The protic solvents may suppress the formation of side - products by weakening the basicity

of the ﬂ uoride through the formation of hydrogen bonds between ﬂ uoride ion and

alcohol.

Further studies indicated that product yields from protic solvent systems are also

highly dependent on the cations, where cesium generated higher reaction yields than tet-

rabutylammonium (TBA) and potassium cations produced < 1% product [101] . This sug-

gests the protic solvent used may increase the nucleophilicity of the ﬂ uoride ion in the

cesium or tetrabutylammonium complex by weakening ionic bonds between cation and

anion through the formation of hydrogen bonds between ﬂ uoride ion and alcohol. Thus,

the problem of low reactivity due to the strong ionic bond of ﬂ uoride salt in conventional

methods may be overcome. Surrounded by a large size cation (Cs

+

and TBA

+

), ﬂ uoride

ion could form only weak hydrogen bonds with bulk alcohol solvent. This prevents the

reduction of nucleophilicity caused by solvation in protic solvents. Fuller understanding

Table 14.4 Reactions of alkyl halide mesylates with [

18

F ]ﬂ uoride ion in protic

solvent systems

Temperature ( ° C) Time (h) Yield (%) Comment

90 2 93 trace tosylate

90 24 73

18% alkene

trace

iodide

reﬂ ux 12 72 20% alkene

reﬂ ux 18 88 6% alkene

90 3.5 81 12% alkene

90 2.5 92 trace alkene

25 1.5 69 15% alkenes

382 Fluorine in Medicinal Chemistry and Chemical Biology

of the reaction mechanism of protic solvent systems and testing of various other solvents

would be of interest.

Applying this novel ﬂ uorination method to

18

F - ﬂ uorination provides great improve-

ment in radiochemical yields (Table 14.5 ) [101] . The use of a protic solvent in nucleophilic

18

F - ﬂ uorination not only improved the radiochemical yield of widely used radiopharma-

ceuticals such as [

18

F]FLT (3 ′ - deoxy - 3 ′ - [

18

F]ﬂ uorothymidine) [101, 102] , [

18

F]FP - CIT

(3 - [

18

F]ﬂ uoropropyl - 2 - β - carboxymethoxy - 3 - β - (4 - iodophenyl) nortropane) [101, 103] ,

and [

18

F]FMISO ([

18

F]ﬂ uoromisonidazole) [101, 104] , which were difﬁ cult to prepare in

conventional methods under mild conditions. This method has advanced the availability

of these important radiopharmaceuticals, and should help the development of new phar-

maceuticals for research and clinical application in the future.

14.6 The Future of Fuorine - 18

The increasing availability of positron emission (PET) imaging equipment as part of the

normal clinical care in nuclear medicine, and incorporation of PET into the routine tools

of the pharmaceutical industry, portends a growing demand for new

18

F - labeled radiophar-

maceuticals. It is thus expected that the methods for incorporation of the radionuclide into

Table 14.5 Yields of example radiopharmaceuticals labeled with [

18

F ]ﬂ uoride ion using

nucleophilic substitution reactions performed in protic solvent systems compared with

literature methods utilizing aprotic organic solvents

Method Temperature

( ° C)

Time (min) Yield (%)

Method Temp ( ° C) time (min) yield (%)

2 - [

18

F]FDG

Cs[

18

F]/alcohol 100 10

82 +/ − 7.8 (n = 10)

K[

18

F]/acetonitrile 100 5 60 – 70%

[

18

F]FLT Cs[

18

F]/alcohol 120 10

65 +/ − 5.4 (n = 10)

literature 110 7.5

15 +/ − 5.4 (n = 3)

[

18

F]FP - CIT Cs[

18

F]/alcohol 100 20

35 +/ − 5.2 (n = 14)

literature 90 10 1%

[

18

F]FMISO Cs[

18

F]/alcohol 100 10

69.6 +/ − 1.8 (n = 10)

literature 105 6

15.0 +/ − 5.4 (n = 3)

Fluorine-18 Radiopharmaceuticals 383

simple and complex molecules of interest in what has recently been termed “ molecular

imaging ” will continue to be a very active and fruitful area of chemical research.

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