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

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Fluorine-18 Radiopharmaceuticals 369

instability under usual conditions of nucleophilic or electrophilic

F - ﬂ uorination, or insol-

ubility in solvent systems typically used), or if the needed synthetic precursor for direct

substitution proves too hard to prepare. Examples of small aromatic molecules used

as prosthetic groups include 4 - [

F]ﬂ uorophenacyl bromide [17] , N - succimidyl -

4 - [

F]ﬂ uorobenzoate [27] , N - succimidyl - 4 - ([

F]ﬂ uoromethyl)benzoate [28] , and 4 -

[

F]ﬂ uorobenzaldehyde [29] , all prepared using aromatic nucleophilic

F - ﬂ uorination as

the ﬁ rst synthetic step. The single drawback to this approach is that all of these small

molecules are themselves synthesized using multiple steps and some puriﬁ cation is needed

before they are usable in the ﬁ nal desired reaction to label the target molecule.

Nucleophilic aromatic substitution of aryl rings followed by removal of the ring -

activating electron - withdrawing group offers a more lengthy but feasible route to the

F -

labeling of aromatic rings bearing no activating groups or, even more challenging, bearing

electron - donating groups that normally inhibit aromatic nucleophilic substitution reactions

[23, 30] . Although useful ﬂ uorine - 18 radiopharmaceuticals have been prepared using these

methods [31, 32] , a certain loss of overall radiochemical yield is expected due to radio-

nuclide decay during these required extra steps after

F - ﬂ uorination. As an alternative

there are more direct methods for radioﬂ uorination of electron - rich aryl rings, as discussed

in the next section.

14.3.4

F - Labeling of Electron - Rich Aryl Rings

As not all biological molecules or drug candidates present a suitable activated aryl ring

for simple nucleophilic aromatic substitutions, the direct

F - labeling of electron - rich aro-

matic rings represent a signiﬁ cant challenge in the synthesis of radiolabeled pharmaceuti-

cals. Electrophilic reagents such as: [

F]F

and acetyl [

F]hypoﬂ uorite (AcOF), have been

used to label electron - rich aromatics [28] . These electrophilic reagents are generally pro-

duced via carrier - added methods and thus provide ﬁ nal products with low to at best mod-

erate speciﬁ c activity. This has limited the use of electrophilic

F - ﬂ uorination reactions

to the production of radiopharmaceuticals for which there is no need for high speciﬁ c

activity and where the chemical species are not toxic [5] . In addition, these reagents are

very reactive and non - regioselective, often leading to a mixture of

F - labeled products

and a requirement for careful separation and puriﬁ cation. This reduces the radiochemical

yield of any single desired product.

Recently, a few improved methods of direct

F - ﬂ uorination on electron - rich aromat-

ics have been reported, using nucleophilic substitution [33 – 36] or electrophilic substitution

[37 – 39] . These improved methods are encouraging solutions to the complex problem of

F - ﬂ uorination of electron - rich aryl rings.

14.3.4.1 Nucleophilic

F - Fluorinations Using Iodonium Salts

For years, diaryliodonium salts have been used for the direct

F - ﬂ uorinations in nucleo-

philic substitution reaction on aromatic rings [34, 35, 40, 41] . The introduction of no -

carrier - added [

F]ﬂ uoride into an aryl substituent of diaryliodonium salt results in a

[

F]ﬂ uorinated arene and a corresponding iodoarene (Figure 14.4 ).

The nucleophilic attack by [

F]ﬂ uoride ion on the diaryliodonium salt occurs prefer-

ably at the more electron - deﬁ cient ring [42] . Therefore, a more electron - rich ring such as

370 Fluorine in Medicinal Chemistry and Chemical Biology

a heteroaromatic moiety in the iodonium salt should allow the direct nucleophilic

F -

labeling of a second aryl group that is comparatively less but still electron - rich [36] . It has

been reported by Ross et al. using the 2 - thienyl group as a highly electron - rich heteroaro-

matic ring to direct the nucleophilic

F - ﬂ uorination to the second, less electron - rich aryl

ring [34] . This heteroaromatic system provides a regiospeciﬁ c single radioactive product

and yields of the corresponding aryl substituents via this method are shown in Table 14.2 .

As expected, the radiochemical yields were generally high with a decrease of the electron

density, except for the ortho - methoxy derivative (61%). The huge difference between

ortho - and para - substituted rings is not explainable by the regular character of the aromatic

nucleophilic substitution reaction mechanism, and the meta - derivative shows a slightly

higher initial reaction rate than the ortho - and para - derivatives but ends in a lower

Figure 14.4 Reaction of [

F]ﬂ uoride ion with diaryliodonium salts. Proportions of the four

possible products ([

F]ﬂ uoroarenes vs. iodoarenes) is dependent on the ring substituents.

Table 14.2 Radiochemical yields ( RCY ) for nucleophilic

F - ﬂ uorination of

aryl(2 - thienyl)iodonium bromides

R RCY (%)

4 - OBn

36 ± 3

4 - OMe

29 ± 3

4 - Me

32 ± 2

64 ± 4

3 - OMe

20 ± 3

4 - Cl

62 ± 4

4 - Br

70 ± 5

4 - I

60 ± 8

2 - OMe

61 ± 5

Fluorine-18 Radiopharmaceuticals 371

radiochemical yield. These might be due to a so - called Meisenheimer complex formed as

an intermediate in this reaction, which is stabilized by resonance structures [34] .

14.3.5 Prosthetic Groups: Fluoroalkyl and Fluoroacyl Substituents

In the design of radiopharmaceuticals labeled with ﬂ uorine - 18, it has become fashionable

to simply alter the structure of a known parent drug or biochemical substrate by the sub-

stitution of a ﬂ uoroalkyl group for a methyl group. This often provides minimal disruption

to the physiochemical properties of a molecule (lipophilicity, molecular weight, p K

)

and has been found in many cases to provide molecules with equivalent or even

enhanced biological activity in vivo . Although in many cases appropriate precursors can

be prepared with leaving groups pre - positioned at the end of short alkyl chains (see

[

F]ﬂ uoropropyl - DTBZ, above), the development of simple

F - ﬂ uoroalkylating [43] and

F - ﬂ uoroacylating agents [44, 45] also allows the application of this approach to families

of compounds without the need to synthesize for each one an appropriate precursor for a

single - step nucleophilic ﬂ uorination. Most useful radiotracers have incorporated

[

F]ﬂ uoromethyl, [

F]ﬂ uoroethyl or [

F]ﬂ uoropropyl alkyl groups, or [

F]ﬂ uoroacetyl

and [

F]ﬂ uoropropionyl acyl groups: larger groups begin to introduce considerable size

and lipophilicity to the original molecule.

14.4 Electrophilic

F - ﬂ uorination: General Aspects

Although the majority of radiopharmaceuticals labeled with ﬂ uorine - 18 have been

prepared using nucleophilic ﬂ uorination reactions, in a few instances the application

of electrophilic ﬂ uorination reactions has proved quite suitable. The most signiﬁ cant

limitation of electrophilic

F - ﬂ uorinations is the relatively low speciﬁ c activities (less than

10 Ci/mmol) commonly obtained for ﬁ nal products. This is a result of the fact that

electrophilic

F - ﬂ uorination reagents (perchloryl ﬂ uoride, acetyl hypoﬂ uorite, xenon

diﬂ uoride, N - ﬂ uoro - N - alkylsulfonamides, diethylaminosulfur triﬂ uoride) are prepared in

low speciﬁ c activity from

F - labeled ﬂ uorine gas, which in itself produced in a carrier -

added fashion. A second drawback of electrophilic ﬂ uorination is that the maximum

radiochemical yield obtainable is 50%, as only one of the two ﬂ uorine atoms in ﬂ uorine

gas can end up in the product (or, for preparation of electrophilic reagents such as acetyl

[

F]hypoﬂ uorite, the maximum yield of preparing the reagent from [

F]F

is 50%).

Production of [

F]F

, from which numerous subsequent electrophilic ﬂ uorination

reagents have been prepared, can be accomplished in two fashions. The ﬁ rst is the irradia-

tion of cyclotron targets containing small amounts of carrier ﬂ uorine gas in neon [46] ;

ﬂ uorine - 18 is produced by the nuclear reaction

Ne(d, α )

F, with essentially exchange of

the ﬂ uorine - 18 and ﬂ uorine - 19 atoms to produce carrier - added [

F]F

. As an alternative

to direct production of ﬂ uorine - 18 gas in a neon target, it is also possible to form [

F]F

using a two - step procedure of ﬁ rst irradiation of oxygen - 18 (the high - yield method for

ﬂ uorine - 18 production), followed by a second irradiation of a gas mixture containing

carrier ﬂ uorine gas to initiate exchange of the ﬂ uorine atoms, producing carrier - added

ﬂ uorine gas [47, 48] .

372 Fluorine in Medicinal Chemistry and Chemical Biology

Despite the low speciﬁ c activity obtained with electrophilic

F - ﬂ uorination reagents,

important radiopharmaceuticals have been prepared in this fashion.

14.4.1 [

F ]Fluoro DOPA : One - step Electrophilic Fluorination

l - 3,4 - dihydroxy - 6 - [

F]ﬂ uorophenylalanine ([

F]FDOPA) is a amino acid derivative pri-

marily utilized to follow the biosynthesis of dopamine in the brain, as it is taken up by

dopaminergic neurons and decarboxylated to 6 - [

F]ﬂ uorodopamine and stored in vesicles

alongside endogenous dopamine. It was one of the ﬁ rst ﬂ uorine - 18 radiopharmaceuticals

developed for clinical investigations of movement disorders (e.g., Parkinson ’ s disease) and

its synthesis has drawn much attention and been discussed numerous times [4, 49] . The

synthesis of [

F]FDOPA can be achieved using both electrophilic and nucleophilic routes,

and provides a good example of how these different methods each have advantages and

drawbacks. The synthesis of FDOPA is also a general example of methods for preparation

F - labeled aromatic amino acids and derivatives, and thus has been extended to desired

molecules such as ﬂ uorinated phenylalanines and ﬂ uorotyrosines.

The initial syntheses of [

F]FDOPA were done using direct electrophilic ﬂ uorination

of DOPA [49] , which was soon replaced with methods for regioselective

F - ﬂ uorination

of DOPA using organomercuric [50] or organostannane precursors [51] (Figure 14.5 ).

Figure 14.5 Electrophilic

F - ﬂ uorination of an organomercurial derivative of dihydroxyphe-

nylalanine as a route to synthesis of 6 - [

F]ﬂ uoro - 3,4 - dihydroxyphenylalanine (6 - [

F]ﬂ uoroDOPA,

FDOPA). Reaction is stereospeciﬁ c and regioselective but requires a step for deprotection of

functional groups.

Fluorine-18 Radiopharmaceuticals 373

The methods using organometallics are relatively simple and can provide enantiomerically

pure [

F]FDOPA in yields as high as 25% (decay - corrected). These methods have even

been automated [51] . The use of the organometallic approach exempliﬁ es a simpliﬁ cation

of the radiochemistry, which, however, complicates the quality control analysis, as in

addition to the normal requirements for a radiopharmaceutical (radiochemical purity,

radionuclidic purity, chemical purity), there is also the need to develop and implement

sensitive analytical techniques to ensure that there are no residual amounts of the metals

(mercury or tin) in the ﬁ nal product. The advantage of the electrophilic approach to

[

F]FDOPA is that the product is obtained in two steps in enantiomerically pure form; the

disadvantages are the limited radiochemical yield, the low speciﬁ c activity inherent in

electrophilic reactions, and the need for extensive quality control analysis. Fortunately,

[

F]FDOPA is one of the radiochemicals for which high speciﬁ c activity is not required,

as the transporters and enzymes involved in [

F]FDOPA uptake and retention in neurons

are not saturated by the chemical amounts of FDOPA associated with the radiochemical

product, and it has also been demonstrated there is no toxicity associated with the

chemical. Efforts continue for improvement and simpliﬁ cation of methods for electrophilic

ﬂ uorination to yield FDOPA [52] .

In contrast to the electrophilic approach, the nucleophilic methods [53 – 55] for syn-

thesis of [

F]FDOPA involve four synthetic steps (Figure 14.6 ) starting with [

F]ﬂ uoride

ion, require a signiﬁ cantly longer total synthesis time, and in the end probably do not result

Figure 14.6 Nucleophilic approach to synthesis of 6 - [

F]ﬂ uoroDOPA. The multistep synthe-

sis introduces ﬂ uorine - 18 in an initial nucleophilic aromatic substitution reaction.

374 Fluorine in Medicinal Chemistry and Chemical Biology

in a much higher yield than that obtained by electrophilic routes. The syntheses require

the use of chiral auxiliaries or chiral phase - transfer reagents to produce [

F]FDOPA in

appropriate enantiomeric purity [54] ; otherwise a chiral column chromatography step is

necessary to separate the two isomers formed in the alkylation of a simple glycine synthon,

which of course results in loss of some product as the wrong isomer. Use of the nucleo-

philic route does produce higher speciﬁ c activities, but this is not a clear advantage for a

radiopharmaceutical that does not require such. In contrast, [

F]ﬂ uorodopamine serves as

an excellent example where the choice of a synthetic strategy is very important; the syn-

thesis via nucleophilic aromatic

F - ﬂ uorination [56] provides a high speciﬁ c activity

product without in vivo hemodynamic effects, whereas the same compound made by an

electrophilic route [57] yields a carrier - added radiopharmaceutical that is not suitable for

radiotracer studies of in vivo biochemistry.

14.4.2 Fluoro - destannylation

Trimethyltin substituents are known to react with [

F]ﬂ uorine in a regioselective manner

[58] . Several important radiopharmaceuticals such as [

F]ﬂ uoro - l - DOPA [39] [

F]ﬂ uoro -

l - tyrosine [37] , and [

F]ﬂ uorometaraminol [59] have been synthesized using this method.

The limitation of this method is again the low speciﬁ c activity from [

F]ﬂ uorine gas.

Hopefully, with development of advanced technology, a better electrophilic [

F]ﬂ uorine

source might be available. Another concern of this method is the residue of potentially

toxic metals, but tin has less toxicity than mercury. Recently, resin - bonded aryltin precur-

sors have been reported for

125

I - labeling by destannylation [60, 61] . The desired radioactive

product will only be released from resin via destannylation, while unreacted precursor and

tin - containing side - product remains bonded to the resin which is easily removed by ﬁ ltra-

tion. This method may have great potential for use in

F - ﬂ uorination in a similar

fashion.

14.5 New Directions in

F - labeling

Labeling of biologically active molecules with ﬂ uorine - 18 has taken great strides in the

last two decades, largely due to the successful application of well - known reaction methods

– nucleophilic and electrophilic ﬂ uorinations – to an increasingly diverse assortment of

chemical structures. Two recent developments, the application of “ click ” chemistry and

the use of protic solvents in nucleophilic ﬂ uorinations, deserve mention here as new

directions in

F - labeling that have the potential to signiﬁ cantly impact both the types of

compounds labeled and the yields obtained.

14.5.1 Application of “ Click ” Chemistry to

F - labeling

“ Click ” chemistry is a generic term that describes chemical reactions that are easy to

perform and work up, are high yielding, and are insensitive to oxygen or water [62, 63] .

However, there has arisen one particular reaction that has become the leader of the ﬁ eld

Fluorine-18 Radiopharmaceuticals 375

and that is the Huisgen 1,3 - dipolar cycloaddition of terminal alkynes with azides to give

1,2,3 - triazoles (Figure 14.7 ) [64] .

Prior to the use of copper(I), the cycloaddition required elevated temperatures for

prolonged periods. Typically, reactions required reﬂ uxing in toluene or carbon tetrachlo-

ride for 10 – 48 h. Under these conditions, the cycloaddition was non - regiospeciﬁ c with two

possible regioisomers (1,4 and 1,5) formed. Some control of regiospeciﬁ city was obtain-

able when electron - withdrawing groups were substituted on the alkyne, favoring produc-

tion of 1,4 - regioisomer. Meanwhile, the addition of electron - withdrawing groups to the

azide favors production of the 1,5 - regioisomer. In practice, the cycloaddition yielded

mixtures of product and exclusive production of one regioisomer remained elusive [65] .

Thus, the cycloaddition under these conditions failed to fulﬁ ll the requirement of a “ click ”

chemistry [64] .

The utility of the Huisgen 1,3 - dipolar cycloaddition was discovered when it was

realized that copper(I) not only catalyzes the reaction but also promotes the regiospeciﬁ c-

ity, with exclusive production of the 1,4 - triazole regioisomer (Figure 14.8 ) [64] . The ﬁ rst

publication by Meldal et al. , in 2002, outlined the use of copper(I) in the cycloaddition

reaction for triazole synthesis on a solid phase [66] . This was an organic - solvent - based

Figure 14.7 The 1,3 - cycloaddition of an azide and a terminal alkene to form a 1,2,3 - triazole.

The thermal reaction produces both the possible regioisomers, whereas the copper - catalyzed

reaction yields the single 1,4 - regioisomer.

Figure 14.8 Use of the copper(I) - mediated alkene - azide 1,3 - cycloaddition ( “ click ” chemis-

try) in both organic solvent and aqueous solvent systems. The aqueous system, with in situ

generation of copper(I) from copper(II), is less sensitive to oxygen.

376 Fluorine in Medicinal Chemistry and Chemical Biology

procedure that used copper(I) iodide with N,N - diisopropylethylamine (DIPEA) in

various solvent such as acetonitrile, dichloromethane, tetrahydrofuran, toluene, or N,N -

dimethylformamide, with the terminal alkyne immobilized on a swollen solid support.

This was closely followed by the report of Folkin and Sharpless and colleagues showing

that the reaction could be carried out in water using copper sulfate and sodium ascorbate

[67] . Both methods have recently become very popular and have made the Huisgen 1,3 -

dipolar cycloaddition the essential “ click ” chemistry.

The facility of this water - based method earned it many applications. The azide and

terminal alkyne are mixed in a mixture of tert - butanol and water (1:1 or 2:1). Then sodium

ascorbate (5 – 10% mol) is added followed by a copper(II) sulfate solution (1 – 5% mol),

and the ﬂ ask is sealed and stirred vigorously at ambient temperature [56] . Copper(I) is

generated in situ by reduction of the copper(II) with an excess of sodium ascorbate and

under these condition the normally oxygen - sensitive copper(I) survives. These reactions

are typically run overnight, but a mild thermal or microwave - assisted heating shortens

reaction time to 10 – 15 minutes [68] . A number of modiﬁ ed reaction conditions have been

reported, using copper(I) species directly, as CuI, CuOTf · C

or [Cu(CH

CN)

], with

a nitrogen base such as triethylamine or pyridine [69 – 71] . The reaction mechanism is still

under investigation and appears quite complex [53, 64 72] . A recent analysis suggests that

both azide and alkyne are activated by copper, possibly within a multinuclear copper -

acetylide species, supporting earlier reports of two copper centers participating in the

catalysis [72, 73] .

Organic solvent - based procedures have been used in situations when the reactants

are not soluble in aqueous media. Copper(I) is supplied directly to the reaction in form of

CuI with DIPEA, and co - solvents such as acetonitrile, dichloromethane, tetrahydrofuran,

toluene, or N,N - dimethylformamide are used. Some alternative protocols, using THF with

Cu(PPh

)Br and DIPEA, or CuBr in DMF with bipyridine, have also been reported

[74, 76] .

The simplicity and efﬁ ciency of the “ click ” chemistry is attractive to ﬂ uorine - 18

chemistry, where time plays an important role in synthesis due to the relative short half -

life of ﬂ uorine - 18. This one - pot reaction provides a versatile tool for coupling drug - like

fragments in high yield and under mild conditions. The product 1,2,3 - triazole formed from

cycloaddition is biologically stable with polarity and size similar to an amide group that

is a common functional group in many radiopharmaceuticals [77] .

F - labeled peptides are a rapidly emerging ﬁ eld for targeted PET imaging probes.

Although a variety of

F - labeled prosthetic groups have been developed in the past decade,

only a limited number of chemical reactions have been utilized to incorporate the pros-

thetic groups into peptides, including acylation [78 – 83] , alkylation [84] , and oxime forma-

tion [85, 86] . Acylation is the most commonly used approach and requires multistep

protection and deprotection of other functional groups within the peptide sequence, which

otherwise would be acylated. For both the alkylation and oxime formation reactions, the

reagents used have potential to react with other functional groups within the peptides as

well. The products formed by acylation, alkylation and oxidation are often species that

are susceptible to hydrolysis or oxidation. Therefore the “ click ” chemistry of azides and

terminal alkynes is expected to be a superior method for the preparation of

F - labeled

peptides because of the following advantages: (i) the reaction can be performed in an

aqueous media using readily accessible reagents and without exclusion of atmospheric

Fluorine-18 Radiopharmaceuticals 377

oxygen; (ii) the relatively mild reaction conditions are tolerant of peptide bonds, and neu-

tralization of the reaction media is not required before or after reaction; (iii) since the

reaction between alkyne and azide is orthogonal to any functional groups [87 – 91] it is not

necessary to protect other functional groups within the peptide sequence; (iv) the reaction

is highly regioselective, leading to 1,4 - disubstituted 1,2,3 - triazole in high yield with simple

work - up and puriﬁ cation; and (v) the product is relatively stable. The large dipole moment

and the nitrogen atoms in positions 2 and 3 of the triazole serve as weak hydrogen bond

acceptors and improve the solubility of the product in water [63] .

The ﬁ rst application of copper(I) - catalyzed 1,3 - dipolar cycloaddition in preparation

of [

F]ﬂ uoropeptides was reported by Marik and Sutcliffe in 2006 (Figure 14.9 ) [92] .

Three [

F]ﬂ uoroalkynes ( n = 1, 2, and 3) were prepared in yields ranging from 36% to

80% by nucleophilic substitution of a p - toluenesulfonyl moiety with [

F]ﬂ uoride ion.

Reaction of these [

F]ﬂ uoroalkynes with various peptides (previously derivatized with

3 - azidopropionic acid) via the Cu(I) - mediated 1,3 - dipolar cycloaddition provided the

desired

F - labeled peptides in 10 minutes at room temperature with yields of 54 – 99% and

great radiochemical purity (81 – 99%) [82] .

The kinetically driven copper(I) - catalyzed cycloaddition of azides and alkynes

requires hours of reaction time to obtain quantitative yields [63] . However, in the case of

no - carrier added radiochemical synthesis the ratio of reactants and catalysts differs con-

siderably from that in traditional chemistry. In particular, the azide component and catalyst

are in huge excess compared with the [

F]ﬂ uoroalkyne. The quantitative incorporation of

[

F]ﬂ uoroalkyne could be achieved in 10 minutes when an optimized catalytic system

was used [81] . Reversed - phase HPLC analysis of all

F - labeled peptides showed only

a single product, indicating that the reaction proceeded regioselectively to yield 1,4 -

disubstituted 1,2,3 - triazoles as previously reported [64] .

In another study, coupling of [

F]ﬂ uoroethylazide with various alkyne substrates that

included a peptide to form the corresponding 2 - [

F]ﬂ uoroethyl - 1, 2, 3 - triazoles has been

recently reported by Glaser and Arstad (Figure 14.10 ) [93] .

After nucleophilic ﬂ uorination of 2 - azidoethyl - 4 - tolunenesulfonate, 2 -

[

F]ﬂ uoroethylazide was reacted with a small library of terminal alkynes in the presence

of excess Cu(II) or copper powder (method A or B). The radiochemical yields were

Figure 14.9 Use of “ click ” chemistry of 1,3 - dipolar cycloadditions of [

F]ﬂ uoroalkynes to

radiolabel N - (3 - azidopropionyl)peptides.

378 Fluorine in Medicinal Chemistry and Chemical Biology

measured by analytical HPLC 15 minutes post reaction at ambient temperature and also

after subsequent heating to 80 ° C for 15 minutes (Table 14.3 ) [93, 94] . At ambient tem-

perature, the degree of incorporation of 2 - [

F]ﬂ uoroethylazide varied from no product to

greater than 98% yield of product, depending on the alkyne substrate and the catalytic

system. Following heating to 80 ° C for 15 minutes, nearly complete conversions of

2 - [

F]ﬂ uoroethylazide to corresponding 1,2,3 - triazoles were observed for a majority of

the substrates. It should be noted that the “ click ” reaction has a high tolerance for other

functional groups in the terminal alkynes, including N - and C - terminal amides, which is

very attractive for labeling of peptides. With a suitable match of catalytic system and

alkyne substrate, high product yields can be obtained within a short reaction time under

mild conditions, which opens up the possibility of labeling fragile biomolecules that

otherwise cannot be labeled with ﬂ uorine - 18 [95] .

The “ click ” chemistry has been rapidly adopted by radiochemists in

F - labeling.

There is a wide selection of

F - labeled prosthetic alkynes and azides, as well as com-

mercially available alkynes and azides, providing numerous possible combinations of this

azide – alkyne cycloaddition to form various

F - labeled biomolecules with numerous func-

tional groups. In addition to the continuously growing

F - labeled peptide synthesis [24,

81 – 84] ,

F - labeled folic acid, folates [96, 97] , glucose analogues [98] , oligonucleotides

[99] , and lipids [99] have been prepared using “ click ” chemistry. In all cases, 1,2,3 - triazole

formation was completed in less than 30 minutes at room temperature in aqueous media

in good yields. The products could be puriﬁ ed using simple HPLC or solid - phase extrac-

tion with no multistep puriﬁ cation method needed.

In conclusion, the Huisgen 1,3 - dipolar cycloaddition of terminal alkynes with azides

to form 1,2,3 - triazoles, referred to as “ click ” chemistry, provides a simple, ﬂ exible, and

highly efﬁ cient method for

F - labeling. This powerful linking reaction opens numerous

possibilities for combining alkynes with azides, forming all varieties of

F - labeled, highly

functionalized biomolecules. The improvement of peptide and lipid labeling using “ click ”

chemistry will further beneﬁ t the

F - labeling of a variety of possible drug carries such as

dendrimers, micelles, microbubbles, liposomes, and cells. Nuclear medicine imaging will

be able to take advantages of the novel

F - labeling methodologies, where ﬂ uorine - 18

could be simply clicked on these multifunctional vehicles without damaging other

Figure 14.10 Application of “ click ” chemistry of 1,3 - dipolar cycloaddition of [

F]ﬂ uroethylazide

to a terminal alkene as a route to one - step radiolabeling of larger molecules.