18 f-labelled intermediates for radiosynthesis by modular...

Review Article18F-Labelled Intermediates for Radiosynthesis byModular Build-Up Reactions Newer Developments

Johannes Ermert

Institut fur Neurowissenschaften und Medizin INM-5 Nuklearchemie Forschungszentrum Julich 52425 Julich Germany

Correspondence should be addressed to Johannes Ermert jermertfz-juelichde

Received 27 March 2014 Accepted 12 May 2014 Published 23 June 2014

Academic Editor Patrick Riss

Copyright copy 2014 Johannes Ermert This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

This brief review gives an overview of newer developments in 18F-chemistry with the focus on small 18F-labelled moleculesas intermediates for modular build-up syntheses The short half-life (lt2 h) of the radionuclide requires efficient syntheses ofthese intermediates considering that multistep syntheses are often time consuming and characterized by a loss of yield in eachreaction step Recent examples of improved synthesis of 18F-labelled intermediates show new possibilities for no-carrier-addedring-fluorinated arenes novel intermediates for tri[18F]fluoromethylation reactions and 18F-fluorovinylation methods

1 Introduction

Thepositron emitter fluorine-18 is a commonly used radionu-clide in molecular imaging with positron emission tomo-graphy (PET) due to its advantageous nuclear propertiesThus it finds wide application as noninvasive quantitativeand versatile modality in medical diagnosis research anddrug development [1] Fluorine-18 has a short half-life of1097min which only allows time-limited syntheses andstudy protocols The methods for introducing this short-lived radionuclide into organic molecules thus require fastchemistry and it is desirable to introduce the 18F-label duringthe last possible synthetic step

A further aspect is the stoichiometry of 18F-chemistrythat differs from ldquocoldrdquo fluorinations The radionuclide isproduced in low (nano- to picomolar) amounts and itsconcentration in reaction mixtures is several orders of mag-nitude lower than the precursor concentration Furthermorethe syntheses of the radiotracers have to be performed inclosed lead-shielded hot cells which necessitates an easilyapplicable and remote-controlled process Thus besides thedevelopment of more efficient and flexible 18F-labellingmethods new technological approaches have been examinedespecially in the field of microfluidic chemistry [2ndash10] Thedevelopment of a reliable 18F-labelling technique togetherwith an automatic synthesis module is a major prerequisite of

routine production of 18F-labelled PET radiopharmaceuticals[11ndash13]

Methods for the introduction of [18F]fluorine intoorganic molecules can be divided into two groups namelydirect and indirectThe direct method entails introduction of[18F]fluorine without changing the carbon skeleton structureof the molecule However in many cases this necessitates theprotection of functional groups or requires other transforma-tions like reduction or oxidation of functional groups afterintroduction of radiofluorine [14]

The indirect method involves build-up syntheses thatis changing the carbon skeleton structure and startingfrom small molecules which themselves can be easily 18F-fluorinated by nucleophilic substitution Such small 18F-labelled alkyl [15] or aryl [16] groups bear typically reactivefunctional groups for further transformation reactionsThoseintermediates are used to synthesizemore complex biologicalmolecules which cannot be labelled with fluorine-18 due tomechanistic reasons or are not stable enough to tolerate direct18F-fluorination conditions

In the case of 18F-labelling of macromolecules like pep-tides proteins and antibodies these small 18F-labelled inter-mediates are commonly called ldquoprosthetic groupsrdquo In the lastdecade progress has been made regarding the 18F-labelling ofmacromolecules [17 18] Besides the use of prosthetic groups

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 812973 15 pageshttpdxdoiorg1011552014812973

2 BioMed Research International

several alternative methods have also been introduced capa-ble of using even mild and aqueous conditions for examplechelated aluminum [19ndash21] boron- [22] andor silicon-based[18F]fluoride acceptor groups [23ndash26] The latter methodswere also used for the synthesis of small molecules [27]

This review focuses on new developments regarding theuse of small 18F-labelled intermediates for build-up synthe-ses of biologically active compounds The 18F-labelling ofmacromolecules and the click chemistry approach are notconsideredThose special topics of 18F-labelling can be foundin other contributions to this issue [28ndash30]

2 18F-Fluorinating Agents

As starting material for all chemical syntheses either aqueous[18F]fluoride or gaseous [18F]F

2is used both of which are

generally produced at a cyclotron via the 18O(pn)18F nuclearreaction [31]The nucleophilic [18F]fluoride ion is available inno-carrier-added (nca) form which allows the synthesis ofradiotracers with high specific activity In contrast in-targetproduced [18F]F

2is available only in carrier-added (ca) form

which leads to radiotracers with low specific activityHistorically for important radiopharmaceuticals like

2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and 6-[18F]fluoro-L-dopa only electrophilic 18F-fluorination was avail-able Today this method is rarely used because of the need ofcarrier for [18F]F

2production Thus the use of electrophilic

18F-fluorination is limited to nontoxic compounds as wellas to those that can be applied with a low specific activityAlso since [18F]F

2is very reactive and 18F-labelled side prod-

ucts are formed less reactive electrophilic 18F-agents weredeveloped [32]More recently the synthesis of N-[18F]fluoro-benzenesulfonimide (NFSi) was described which is a highlystable reactive and selective electrophilic 18F-labelling agentand allows the synthesis of 18F-labelled allylic fluorides and120572-fluorinated ketones from allylsilanes and silyl enol ethersrespectively [33]

An alternative method using a ldquoposttargetrdquo synthesis of[18F]F

2leads to moderate specific activity of up to 247GBq

120583mol starting from nca [18F]fluoride [34] It wasrecently revisited for the radiosynthesis of [18F]selectfluorbis(triflate) the 18F-labelled form of (1-chloromethyl-4-flu-orodiazonia-bicyclo[222]-octane bis-(tetra-fluoroborate))an easy to handle and stable electrophilic fluorinating reagent(cf Figure 1) [35] This reagent could successfully be usedfor the silver(I)-mediated 18F-fluorination of electron-richarylstannane models and intermediates as well as for thepreparation of 6-[18F]fluoro-L-DOPA [36] albeit all withlimited specific activity of 37 plusmn 09GBq120583mol

3 Aliphatic Intermediates

Aliphatic 18F-fluorination is certainly the most prominentmethod for 18F-labelling [32] and important PET-radio-tracers for clinical use are aliphatically 18F-labelled com-pounds which fulfill these requirements for example

Electrophilicsubstitutionreactions

Nucleophilicsubstitutionreactions

Cl

TfOminus

TfOminus

N+

N+

18F

18O(pn)18F [18F]Fminus

[18F]F2

Figure 1 Nuclear reactions to produce fluorine-18 and the18F-fluorinating agents [18F]fluoride [18F]fluorine gas and[18F]selectfluor bis(triflate)

[18F]FDG 31015840-deoxy-31015840-[18F]fluorothymidine ([18F]FLT)[18F]fluoro(m)ethylcholine and O-2-[18F]fluoroethyl-L-tyrosine ([18F]FET) (cf Figure 2) [15 37 38] [18F]Fluoro(m)-ethylcholine is an example for 18F-labelled endogenouscompounds whereas [18F]FDGand [18F]FLT are 18F-labelleddeoxy derivatives of the corresponding endogenous sub-stances In all cases a proton is replaced by a fluorineatom without changing the carbon skeleton of the originalcompound In contrast [18F]FET is an example of anendogenous 18F-labelled compound where the introductionof the radionuclide is performed by an 18F-fluoroalkylationreaction Here the 18F-label is introduced into the moleculeby addition of further C-atoms which means that theskeleton of the molecule is significantly changed Otherexamples of this kind of reaction are the 18F-fluoroacylationand 18F-fluoroamidation reactions which are widely usedfor labelling of macromolecules [39] most often in aqueoussolution

31 Intermediates for Nucleophilic Substitution and OtherCoupling Reactions The synthesis of intermediates for 18F-fluoroalkylation is characterized by a two- or three-step pro-cedure (cf Figure 3) [40] First [18F]fluoride is introducedinto a molecule using precursors containing a good leavinggroupThe 18F-labelled precursor is then isolated and purifiedbefore coupling with a further molecule

In the first step the [18F]fluoride has to be separated fromthe target water and activated for a nucleophilic substitutionreaction The standard conditions of these basic methods aredescribed in several reviews [11 32 41] A simplification ofthis approach was achieved by water removal on a stronganion-exchange resin [42] or by use of strong organic basesas additives replacing the inorganic bases or salts classicallyused in the resin eluent [43ndash46] Instead of trapping on anion-exchange resins nca [18F]fluoride can also be separated byelectrochemical methods which are useful to minimize thereaction volume especially for the use inmicrofluidic systems[47ndash51] The use of mixtures of nonpolar tert-alcohols withacetonitrile as a reaction medium enhanced the reactivityof cesium[18F]fluoride or tetrabutylammonium [18F]fluorideand reduced the formation of typical by-products compared

BioMed Research International 3

OH

n

+

N

NH

O O

O

O

O

H

OH

OH

HO

HO

HO18F18F

18F

18F

2-[18F]fluoro-2-deoxy-D-glucose (FDG) [18F]fluoro(m)ethylcholine (FCH)

Clminus

n = 1 2

N(CH3)2

H3C

NH2

CO2H

3998400-Deoxy-3998400 -L-thymidine (FLT) O-2-[18F]fluoroethyl-L-tyrosine (FET)-[18F]fluoro

Figure 2 Important 18F-labelled radiotracers in clinical use

BzO

Method C

Method B

Method A

Intermediates forand click reactions

R FF

XAlkyl

18F

18F

18F

18F

18F

X = Br I sulfonatesN3 acetylene

Tri[18F]fluoromethylation

Palladium iridium or manganesecatalyzed 18F-fluorination

[18F]Fminus

SN

Figure 3 Pathways for aliphatic 18F-labelling intermediates starting from nca [18F]fluoride

to those conventionally obtained only with dipolar aproticsolvents [52 53]

Bromine and iodine and several sulfonate derivativesserve generally as leaving groups for a nucleophilic aliphaticradiofluorination [15 40 54 55] Alternatively in the caseof preparation of O-[18F]fluoromethylated aliphatic and aro-matic ethers the 123-triazolium triflate group serves as avery good nucleofuge for displacement by the [18F]fluorideion [56]

The purification of 18F-fluorinating agents is performedby HPLC solid phase extraction (SPE) or distillation Themain challenge is the complete separation of the 18F-labelledintermediate from the precursor which also would act asreaction partner in the following coupling step This leadsto unwanted side reactions which could lower the radio-chemical yield (RCY) or necessitate a higher concentration

of the precursor for the subsequent coupling reaction Apurification of the 18F-fluorinating agent via HPLC (or GC) isvery effective and is often used [57ndash59] but it is more incon-venient for automatization [60 61] The use of SPE [62ndash64]or a distillation process for purification is principally easierto automate [40] For instance 1-bromo-3-(nitrobenzene-4-sulfonyloxy)-propane as starting precursor will be retained inthe reaction vessel during the distillation process of 1-bromo-3-[18F]fluoropropane due to its very high boiling point thuseliminating the risk of formation of pseudocarrier [65] In afew cases the direct coupling of the 18F-labelled intermediatewas performed without former separation and purification[66]

Another possibility for simplified workup is the useof fluorous solid phase extraction (FSPE) A nucleophilic18F-fluorination of fluorous-tagged precursors can easily be


purified by FSPE regardless of the affinity of the untaggedsubstrate for the stationary phase FSPE-purified labelledcompounds can then be used in subsequent reactions ormoreeasily purified by HPLC before administration [67 68] Asimilar approach was performed using molecular imprintedpolymers [69]

Coupling reactions of the 18F-fluorination agent with thedesired target molecule are performed either by the use of afurther leaving group by the click chemistry approach [70]by Staudinger ligation [71ndash73] or byPd(0)mediated reactions[74]

A series of arylsulfonates were prepared as nucleophileassisting leaving groups (NALG) in which the metal chelat-ing unit is attached to the aryl ring by an ether linkerUnder microwave irradiation and without the assistance ofa cryptand such as Kryptofix 222 primary substrates withselectedNALGs led to a 2-3-fold improvement in radiofluori-nation yields over traditional leaving groups [75]

32 Tri[18F]fluoromethyl Group The CF3group has an elec-

tronegativity similar to that of oxygen [76] and is character-ized by a large hydrophobic parameter as measured by therelative partition coefficient [77] The trifluoromethyl groupis an important pharmacophore present in many biologicallyactive pharmaceutical and agrochemical drugsThe increasedlipophilicity and a superior metabolic stability comparedto that of the trifluoromethyl analogues often account foran improved activity profile [78] Thus radiolabelled tri-fluoromethyl groups are of potential interest to facilitatedrug discovery Earlier attempts to synthesize an 18F-labelledtrifluoromethyl group were also characterized by low RCYand low specific activity due to decomposition of the targetmaterial [79ndash81]

The recently published developments can be divided inaliphatic and aromatic tri[18F]fluoromethylation reactions(cf Figure 3 method B)

A novel one-step method for nucleophilic radiosyn-thesis of aliphatic tri[18F]fluoromethyl groups using thenca [18F]fluoride ion under relatively mild conditions wasdeveloped by incorporation of the radiolabel by an equiv-alent nucleophilic addition of H[18F]F to the 1-tosyl-22-difluorovinyl group (cf Figure 4) The tosylate function thenserves as leaving group in a subsequent coupling step [8283] The specific activity of the tri[18F]fluoromethylether wasdetermined to be 86MBqnmol The need of a double bondto achieve the addition of the [18F]fluoride limits this reactionto aliphatic tri[18F]fluoromethylations

Aromatic tri[18F]fluoromethyl groups were formerly syn-thesized using hardly accessible aromatic-CF

2Br groups [84]

Two new approaches were published quite recently (cfFigure 5) Both methods start with an aliphatic precursorwhich is first labelledwith fluorine-18 and then coupled to thebenzene ring In a two-step procedure tri[18F]fluoromethane([18F]fluoroform) available from difluoroiodomethane and[18F]fluoride [85] is coupled in a copper(I) mediated reactionto aromatic halides using potassium tert-butoxide as base

F

F X

OTosOTosF

F X

F

F

O R18F 18F

Figure 4 New aliphatic tri[18F]fluoromethylation

HI

F

F H

F

F

Ar

FFF

ClF

O

OMe18F18F

Figure 5 Aromatic tri[18F]fluoromethylation reactions

The RCY was determined up to 65 with a specific activ-ity of up to 50GBq120583mol [86] This method has recentlybeen improved performing a one-pot synthesis in the pres-ence of copper(I)bromide NN-diisopropyl-N-ethylamineand the corresponding iodoarene without separation of the[18F]fluoroform intermediate [87] The RCYs of the desiredtri[18F]fluoroarenes were determined with up to 90 but noinformation on the specific activities was given

An alternative method is used in a one-pot processThe trifluoromethylation agent [18F]CF

3Cu generated in

situ from methyl chlorodifluoroacetate CuI TMEDA and[18F]fluoride is coupled to (hetero)aryl iodides in RCYs rang-ing from 17 to 87 [88] A drawback of this procedure is stillthe relative low specific activity of 01 GBq120583mol exemplifiedso far only for 4-tri[18F]fluoromethyl nitrobenzeneHoweverthe method enables an efficient tri-[18F]fluoromethylationof complex molecules like [18F]fluoxetine N-Boc protected[18F]fluoxetine was readily prepared in 37 RCY The subse-quentN-Boc deprotection delivered [18F]fluoxetinewith 95yield A more detailed review on the scope and limitations ofthe radiosynthesis of tri[18F]fluoromethyl groups is providedas part of this special issue [89]

33 Palladium Managnese and Iridium Catalyzed 18F-Fluor-ovinylation Transition metal catalyzed allylic substitutionis a powerful method for carbonndashcarbon and carbonndashheteroatom bond formation (cf Figure 3 above method C)These reactions encompass a wide variety of heteroatoms (NO and S) as nucleophiles [90] In the field of 18F-chemistrya palladium catalyzed allylic fluorination reaction was devel-oped and transferred to nca conditions yielding 18F-labelledcinnamyl fluoride starting from [18F]TBAF cinnamyl methylcarbonate [Pd (dba)

2] and triphenylphosphine in anhydrous

acetonitrile [91]Further a rapid allylic fluorination method utilizing

trichloroacetimidates in conjunction with an iridium catalysthas been developed The reaction is performed at roomtemperature without the need of inert gas atmosphere andrelies on the Et

3Nsdot3HF reagent to provide branched allylic

fluorides with complete regioselectivity This high-yieldingreaction can be carried out on a multigram scale and showsconsiderable functional group toleranceThe use of Kryptofix222K

2CO3allowed an incorporation of fluorine-18 within

10min [92] The RCY of allylic [18F]fluoride was determined


to be 38 A specific activity for the aforementioned reac-tions however was not reported

A new method enables the facile nca 18F-labelling ofaliphatic CndashH bonds in benzylic position using manganesesalen catalysts with RCY ranging from 20 to 72 within10min without the need for preactivation of the labellingprecursor [93]

4 Aromatic and Heteroaromatic Intermediates

41 18F-Labelled Aromatic and Heteroaromatic Intermedi-ates by Classic Approaches Historically the use of theBalz-Schiemann or Wallach reaction was the first attemptto synthesize 18F-labelled aromatic rings starting from[18F]fluoride (cf Figure 6 method A) [94 95] Howeverthe thermal decomposition of the corresponding aryl dia-zonium salts and of the aryl triazenes is characterized bylow RCY a low specific radioactivity and extensive by-product formation [95]The use of tetrachloroborate or 246-triisopropylbenzenesulfonate as counterions led to improve-ments of the Balz-Schiemann reaction which enables thesynthesis of [18F]fluoroarenes in 39 RCY at the ncalevel exemplified for 4-[18F]fluorotoluene [96] In a recentlypublished study these nucleophilic 18F-labelling methodswere reinvestigated using polymer bound aryl diazoniumsalts and aryl triazenes [97] The solid phase supported de-diazofluorination using arenediazonium cations ionicallybound to a sulfonate functionalised ion exchange resinwas however not suitable for nucleophilic 18F-labelling ofaromatic compounds whereas the solid supported triazeneyielded the 18F-labelled product in a reasonable RCY of 16

Most successful for the introduction of fluorine-18 intoaromatic rings is the conventional aromatic nucleophilicsubstitution (SNAr) reaction using the [18F]fluoride anion todisplace a suitable leaving group from an electron deficientbenzene ring As leaving groups serve halides the nitroand the trimethylammonium function The activation ofthe aromatic ring is usually achieved by suitable func-tional groups with andashM effect like the carbonyl carboxylcyano and nitro group [32] These highly activating groupsespecially enable the efficient introduction of [18F]fluorideinto aromatic rings to label small 18F-intermediates forbuild-up syntheses The activating functionality is then con-verted by reduction oxidation or hydrolysis to nucleophilicgroups for subsequent coupling reactions The nca inter-mediates 4-[18F]fluoroaniline 4-[18F]fluorobenzylamine [9899] 4-[18F]fluorobenzoic acid or 4-[18F]fluorophenol (seeSection 33) which are not directly achievable by a 18F-fluorination reaction are obtained by these strategies (cfFigure 7) [16 100] 4-[18F]Fluorobenzaldehyde is also used inmulticomponent reactions to yield 18F-radiotracers with thelabel positioned on an aryl moiety not susceptible to directnucleophilic fluorination [101]

The azocarbonyl unit is a new group for activation ofthe arene ring by an SNAr mechanism The aromatic coreof phenylazocarboxylic esters is highly activated towardsnucleophilic aromatic 18F-substitution (cf Figure 8) [102]

This kind of compounds was converted in a radical ary-lation reaction into biaryl compounds or in substitutionsat its carbonyl unit to produce azocarboxamides Becauseof the high reactivity of the aryl radical side productslike [18F]fluorobenzene and 4-[18F]fluorophenol were alsoformed

The conventional nucleophilic aromatic substitutionreaction can principally be used for the nca 18F-labellingof aromatic rings in complex molecules [14] However thedirect introduction of [18F]fluoride is often hampered by alack of activation and further functional groups especiallythose which have acidic protons In the case of free aminohydroxyl or carboxylic acid functions the use of protectinggroups is indispensable which have to be removed at the endof synthesis Generally the direct 18F-labelling of complexmolecules enables the establishment of one-pot syntheseswhich is advantageous of being better introduced in aremote controlled synthesizer In a multistep synthesis theintermediates have often to be purified (eg [103]) whichhampers the installation in a synthesismoduleThus one-potsyntheses are normally preferable over the build-up synthesisusing several reactor vesselsThere are exceptions to this rulefor example when the build-up synthesis gives substantiallyhigher RCYs [104]

In contrast to benzene some heteroarenes like pyridineefficiently support the SNAr reaction and can directly be usedto prepare 18F-labelled heteroarenes in the 2- or 4-position[105ndash107] Because of its straightforward feasibility thismethod was even applied for radiofluorination of complexstructures containing an azabenzoxazole [108] a 13-thiazole[109] a fluoropurine [110] a pyridine [111ndash118] a quinolinol[119] or a pyrimidine moiety [120]

42 New Developments on Radiofluorination of Arenes Ingeneral the examination of new methods for 18F-labellingof arene rings focuses on the late stage introduction of[18F]fluorine into complex organic molecules without theneed of any transformation reaction afterwards This prin-cipally simplifies the establishment of 18F-labelling meth-ods in fully automated remotely controlled synthesis unitsHowever these new methods are also useful for the syn-thesis of small intermediates for build-up synthesis Thenovel methods of two prominent ones [18F]fluorophenoland [18F]fluoro-halobenzene are separately described (seeSections 43 and 44)

421 Iodonium Salts (See Figure 6 Method D and Figure 9)The classical approach of nca nucleophilic aromatic 18F-substitution reactions is limited to activated arene ringsThe use of diaryliodonium salts enables the introductionof nca [18F]fluoride into aromatic rings without furtheractivation of strong electron withdrawing groups whichwas first demonstrated in 1995 [121] The reaction via anSNAr mechanism leads to nca [18F]fluoroarenes and thecorresponding iodoarenes The nucleophilic attack on thediaryliodonium salt occurs preferably at the more electron-deficient ring and a steric influence of substituents especially


R

EWG

EWG

R

R

N N N

R

R

R

R

Umpolung andelectrochemical

reactionsMethods G and H

Clas

sical

appr

oach

es

Iodonium saltsMethod D

Aromatic nucleophilic substitution

Method C

Triarylsulfonium saltsMethod E

Diaryl sulfoxidesMethod F

Wallach reactionMethod B

Balz-Schiemann reactionMethod A

ElectrophilicsubstitutionChapter 2

New

dev

elopm

ents

N

N

LG

LG

X

Y

R

SO

PhR

R

[18F]Fminus

18F 18F

18F

18F

18F

18F

18F

18F

[18F]F2

N2BF4

S+

I+

LG leaving groupEWG electron withdrawing group

Y = aryl heteroaryl ylideX = C N

Figure 6 Pathways for aromatic 18F-labelling

OR

OHO

CNO

OH

18F

18F 18F 18F18F

18F 18F

NH2NH2

N+

Ominus

Figure 7 18F-labelled aromatic small molecules available bySNAr reactions used as intermediates and further important 18F-intermediates derived therefrom

NN

O O

O

NN

O ON N N

O

OMe

18F18F

18F

N+Ominus

Figure 8 Radical arylation and substitution reactions of a 18F-labelled phenylazocarboxylic ester [102]

of ortho-substituted could be observed [95] Further studieshave recently been performed to examine the possibilities andlimitations of this reaction with a focus on the synthesis ofortho- and meta-substituted arenes and the use of microre-actors [122ndash124]

An interesting aspect here is that the reaction ofdiaryliodonium salts with [18F]fluoride is feasible in the pres-ence of water however depending on the substituents present


O

O

O

O

R

I+Cminus

(a)

RS

I+Brminus

(b)

MeO

I+minusOTs

N3

(c)

MeO

I+minusOTs

N3

(d)

NMeO X Y

X = H Y = Br ClX = Br Cl Y = H

I+minusOTs

(e)

Figure 9 Structures of several iodonium salts for 18F-labelling (a) iodonium ylide (b) aryl(thienyl) iodonium salt (c) [(azidomethyl)phenyl](41015840-methoxyphenyl) iodonium tosylate (d) [(azido)phenyl](41015840-methoxyphenyl) iodonium tosylates and (e) halopyridinyl-(41015840-methoxy-phenyl)iodonium tosylate

on the arene ring Iodonium salts bearing a para- or ortho-electron-withdrawing group (eg p-CN) reacted rapidly (sim3min) to give the expected major [18F]fluoroarene productin useful albeitmoderate radiochemical yields evenwhen thesolvent had awater content of up to 28 Iodonium salts bear-ing electron-withdrawing groups in metaposition (eg m-NO2) or an electron-donating substituent (p-OMe) gave low

radiochemical yields under the same conditions The findingthat [18F]fluoroarenes that having an ortho-alkyl substituentor an ortho- or a para-electron withdrawing group can besynthesized without the need to remove irradiated wateror to add a cryptand could be attractive in some radio-tracer production settings particularly as this method savestime avoids any need for automated drying of cyclotron-produced [18F]fluoride and also avoids substantial loss ofradioactivity through adsorption onto hardware surfaces[125]

In order to control the attack of the [18F]fluoride ionon the diaryliodonium salts it is important that one arenering be more electron-rich than the ring to be labelledwith fluorine-18 Here the use of symmetrically substituteddiaryliodonium salts [126] or the use of aryl(heteroaryl) iodo-nium salts [127] is an alternative to direct the 18F-labellingto the desired ring More recently the use of aryiodoniumylides became of interest for this purpose The electron-richstatus of the ylides made for example from dimedone (55-dimethylcyclohexane-13-dione) even enables the synthesisof electron-rich arenes in high RCY [128] This type ofprecursor has recently been demonstrated to be even suitablefor complex molecules [129]

Some special intermediates like azide-containing diaryl-iodonium salts bearing an azidomethyl grouponone aryl ringand with a 4-methoxy group on the second one enable thesynthesis of click-labelling synthons up to 50 RCY even inthe presence of a high fraction of water in the reaction solvent[130]

Halopyridinyl-(41015840-methoxyphenyl)iodonium tosylateswere used to rapidly produce [18F]fluorohalopyridines and

in useful RCYs including the otherwise difficult to access3-[18F]fluorohaloisomers [131]

422 Sulfur Activated Systems (See Figure 6 and Methods Eand F) Another newer method for the 18F-labelling of non-activated aromatic compoundsmakes use of triarylsulfoniumsalts The method is applicable to a wide range of substitutedaryl systems including amides [132]

A new radiosynthetic method for producing nca[18F]fluoroarenes is based on the reactions of diaryl sul-foxides bearing electron-withdrawing paragroups with the[18F]fluoride ion These reactions are relatively mild rapidand efficient However this reaction is limited to aromaticrings bearing an electron withdrawing function like the nitrocyano or trifluoromethyl group [133]

423 Umpolungs Reactions (See Figure 6 and Methods G andH) New concepts to synthesize 18F-labelled aromatic ringstry to achieve fluoride-derived electrophilic nca fluorina-tion reagents by fluoride umpolung [134 135] A preliminaryrealization of this concept was achieved by using a nca[18F]fluoride capture by a Pd(IV) complex to form an elec-trophilic 18F-fluorination reagent followed by a subsequentnca 18F-fluorination of palladium aryl complexes [136137] Another kind of palladium catalyzed fluoride activationenables the synthesis of 18F-labelled 1-[18F]fluoronaphthalenein 33 RCY but only in the presence of fluoride carrier [138]Another advanced method for a transition metal catalyzedlate-stage radiofluorination relies on a one-step oxidative 18F-fluorination using a nickel aryl complex and a strong oxida-tion agent [139]

[18F]Fluoride can also be introduced into organicmolecules by electrochemical oxidative fluorination viaan aryl cation that undergoes rearomatization by loss ofa proton Oxidation of benzene in an electrolysis cellusing Et

3Nsdot3HF and Et

3NsdotHCl in acetonitrile as the elec-

trolyte gave ca [18F]fluorobenzene in 17 RCY [140] and


OH

X

O

O

OH

S

OBn

OBnBnO

18F

I+Brminus

I+Brminus

N+Ominus

(1) [18F]Fluoride

(1) [18F]Fluoride(1) [18F]Fluoride

(1)[18F]Fluoride(2) Baeyer-Villiger reaction

RCY = up to 65(2) Deprotection

RCY = 35

RCY = 15(2) Deprotection

RCY = 52

X = aryl alkyl

Figure 10 Methods for the synthesis of nca 4-[18F]fluorophenol

[18F]fluorophenylalanine in 105 RCY with a specific activ-ity of 12 GBqmmol [141]

However the aim of all these methods is the late stage18F-fluorination of electron-neutral and electron-rich aro-matic compounds to simplify the synthesis of radiotracersRegarding the palladium and nickel reactions the precursorsynthesis is often complex has to be carefully handled underinert atmosphere and needs high synthetic experience Thismethod is far from ideal given the many reagents anddemanding reaction conditions necessary which hamper tofulfill a ldquogood manufacturing practicerdquo (GMP) pharmaceuti-cal production [142 143] Thus although principally applica-ble their limitation and complexity do notwarrant usefulnessfor the syntheses of build-up intermediates as there are moreefficient methods available for those molecules

43 Nca 4-[18F]Fluorophenol 4-[18F]Fluorophenol is a ver-satile structural unit for the synthesis of more complexradiopharmaceuticals bearing a 4-[18F]fluorophenoxy moi-ety Former syntheses of nca 4-[18F]fluorophenol weremade either by a modified Balz-Schiemann reaction or byhydrolysis of a 4-[18F]fluorobenzene diazonium salt withradiochemical yields of only 10ndash15 and 15ndash33 within35 and 60min respectively [144] These methods requiredeither the preparation of an anhydrous tetrachloroborate ora two-step synthesis from [18F]fluoroaniline and were notestablished for radiotracer production

Amore reliable preparation of nca 2- and 4-[18F]fluoro-phenol was achieved using the Baeyer-Villiger reaction on18F-labelled benzaldehyde acetophenone or benzophenonederivatives Total radiochemical yields of about 25 werereceived using m-chloroperbenzoic acid as oxidant in thepresence of trifluoroacetic acid [145] The Baeyer-Villiger

reaction of 18F-labelled benzophenone derivatives containingfurther electron withdrawing groups yielded up to 65of 4-[18F]fluorophenol within 60min with a high radio-chemical purity However a considerable disadvantage ofthis method is the somewhat cumbersome work-up of theaqueous reaction mixture in order to isolate the product forits further use [146] The formation of 18F-labelled 4-phenolderivatives by Baeyer-Villiger oxidation was for exampleapplied to the direct 18F-fluorination of 6-[18F]fluoro-L-dopa[147]

A novel radiochemical transformation by an oxidative18F-fluorination of tert-butylphenols uses the concept of anaryl umpolung (cf Figure 10) and is also applicable to otherO-unprotected phenols The reaction is performed at roomtemperature by applying a one-pot protocol and can also beperformed in a commercially available microfluidic device[148]

Furthermore aryl(thienyl) iodonium salts [149] andbis(4-benzyloxyphenyl) iodonium salts [150] have success-fully been employed for the preparation of [18F]fluorophenolin a two-step procedure Compared with the Baeyer Vil-liger method using benzophenone derivatives this path-way saves 20 to 45min of preparation time and delivers[18F]fluorophenol in an organic solution So these methodsare more useful for subsequent coupling reactions underanhydrous conditions In contrast to the aryl umpolungreaction the iodonium strategy however necessitates adeprotection step after the 18F-exchange

44 Nca 4-[18F]Fluorohalobenzene Recently the synthe-sis of 4-[18F]fluorohalobenzenes has comprehensively beendescribed [151] here a few further aspects are added


X X

X

SX

X

I

X O

O

18F

I+

I+

18Fminus

18Fminus18Fminus

18Fminus

S+Anminus

Anminus

Anminus

RCY = 65RCY = 90

RCY = 70

X = Br I

RCY = 60ndash70

Figure 11 Most efficient one-step approaches for the nca synthesis of [18F]fluoro-halobenzenes

1-Bromo-4-[18F]fluorobenzene or 4-[18F]fluoro-1-iodoben-zene serves as intermediates for CndashC coupling reactionsusing Grignard- lithium- [152] or palladium-mediated reac-tions [151 153] In Figure 11 the most efficient routes forthe synthesis of nca 4-[18F]fluorohalobenzenes are illus-trated The use of symmetrically substituted diaryliodo-nium salts enables an efficient one-step synthesis of nca1-bromo-4-[18F]fluorobenzene [154] as well as nca 4-[18F]fluoro-1-iodobenzene [155] For the latter the precur-sor synthesis is more challenging and has recently beenimproved [156] The precursor syntheses of iodophenyl-thienyliodonium bromide and 4-iodophenyliodonium-(5-[22-dimethyl-13-dioxane-46-dione]) ylide [157] are easierto perform and the latter gave up to 70 RCY of 4-[18F]fluoro-1-iodobenzene [158] The most efficient methodfor the one-step synthesis of 4-[18F]fluoro-1-iodobenzene ishowever the use of triarylsulfonium salts [132 159] whichleads to 90 RCY A challenge when using iodonium saltsas precursor for the synthesis of 4-[18F]fluorohalobenzenesis the formation of other nonradioactive halobenzene deriva-tives which are normally not separated from the 18F-labelledproduct and thus could hamper the final product separation

5 Conclusion

The lack of universally useful methods for direct ncaradiofluorination of complex molecules causes the wide useof 18F-labelled intermediates for the build-up synthesis ofradiotracers Nevertheless multistep build-up syntheses of18F-labelled radiotracers are confronted with several funda-mental challenges which often hamper a remotely controlledlarge scale production by this type of reactions Time con-suming separation steps and the use of moisture or evenair sensitive reagents complicate the automation of thesebuild-up syntheses Their application is therefore limitedto specialized laboratories with the suitable equipment andexperienced staff The use of build-up reactions then often

enables the only way to achieve the synthesis of new radio-tracers Once proven that a radiotracer has the potential tobe a useful radiopharmaceutical for molecular imaging mostoftenways can be found to establish its routine production viaan alternative simpler synthetic concept andor by optimisa-tion Here the novel developments in umpolung reactions orthe improvements in iodonium chemistry in 18F-labelling ofarenes are promising methods which might also be effectivefor the late-stage 18F-fluorination of complex precursorsHowever their suitability for daily routine GMP-productionof radiopharmaceuticals remains to be elucidated

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgment

The author wishes to thank Professor Heinz H Coenen forhis critical discussions and helpful suggestions

References

[1] S M Ametamey M Honer and P A Schubiger ldquoMolecularimaging with PETrdquo Chemical Reviews vol 108 no 5 pp 1501ndash1516 2008

[2] S Y Lu andVW Pike ldquoMicro-reactors for PET tracer labelingrdquoin PET Chemistry the Driving Force in Molecular Imaging PA Schubiger L Lehmann and M Friebe Eds vol 62 of ErnstSchering Research FoundationWorkshop pp 271ndash287 Springer Berlin Germany 2007

[3] G Pascali P Watts and P A Salvadori ldquoMicrofluidics inradiopharmaceutical chemistryrdquoNuclear Medicine and Biologyvol 40 no 6 pp 776ndash787 2013

[4] S H Liang T L Collier B H Rotstein et al ldquoRapid microflu-idic flow hydrogenation for reduction or deprotection of 18F-labeled compoundsrdquo Chemical Communications vol 49 pp8755ndash8757 2013


[5] A Lebedev R Miraghaie K Kotta et al ldquoBatch-reactormicrofluidic device first human use of a microfluidicallyproduced PET radiotracerrdquo Lab on a Chip Miniaturisation forChemistry and Biology vol 13 no 1 pp 136ndash145 2013

[6] K Dahl M Schou and C Halldin ldquoRadiofluorination andreductive amination using a microfluidic devicerdquo Journal ofLabelled Compounds and Radiopharmaceuticals vol 55 no 13pp 455ndash459 2012

[7] V Bouvet M Wuest P-H Tam M Wang and F WuestldquoMicrofluidic technology an economical and versatileapproach for the synthesis of O-(2-[18F]fluoroethyl)-l-tyrosine([18F]FET)rdquo Bioorganic and Medicinal Chemistry Letters vol22 no 6 pp 2291ndash2295 2012

[8] V R Bouvet M Wuest L I Wiebe and F Wuest ldquoSynthesisof hypoxia imaging agent 1-(5-deoxy-5-fluoro-120572-d-arabino-furanosyl)-2-nitroimidazole using microfluidic technologyrdquoNuclear Medicine and Biology vol 38 no 2 pp 235ndash245 2011

[9] C Rensch A Jackson S Lindner et al ldquoMicrofluidics agroundbreaking technology for PET tracer productionrdquoMole-cules vol 18 no 7 pp 7930ndash7956 2013

[10] B Y Yang J M Jeong Y-S Lee D S Lee J-K Chung andM C Lee ldquoFacile calculation of specific rate constants andactivation energies of 18F-fluorination reaction using combinedprocesses of coat-capture-elution and microfluidicsrdquo Tetrahe-dron vol 67 no 13 pp 2427ndash2433 2011

[11] L Cai S Lu and VW Pike ldquoChemistry with [18F]fluoride ionrdquoEuropean Journal of Organic Chemistry no 17 pp 2853ndash28732008

[12] W Wadsak L-K Mien D E Ettlinger et al ldquo 18F fluoroethy-lations different strategies for the rapid translation of 11C-methylated radiotracersrdquoNuclear Medicine and Biology vol 34no 8 pp 1019ndash1028 2007

[13] B Amaraesekera P D Marchis K P Bobinski et al ldquoHigh-pressure compact modular radiosynthesizer for production ofpositron emitting biomarkersrdquo Applied Radiation and Isotopesvol 78 pp 88ndash101 2013

[14] J Ermert and H H Coenen ldquoNucleophilic 18F-fluorination ofcomplex molecules in activated carbocyclic aromatic positionrdquoCurrent Radiopharmaceuticals vol 3 no 2 pp 109ndash126 2010

[15] D Roeda and F Dolle ldquoAliphatic nucleophilic radiofluorina-tionrdquo Current Radiopharmaceuticals vol 3 no 2 pp 81ndash1082010

[16] J Ermert and H H Coenen ldquoNo-carrier-added [18F]fluoro-benzene derivatives as intermediates for built-up radiosynthe-sesrdquo Current Radiopharmaceuticals vol 3 no 2 pp 127ndash1602010

[17] B Kuhnast and F Dolle ldquoThe challenge of labeling macro-molecules with fluorine-18 three decades of researchrdquo CurrentRadiopharmaceuticals vol 3 no 3 pp 174ndash201 2010

[18] T A D Smith ldquoFluoride labelling of macromolecules inaqueous conditions silicon and boroaryl-based [18F]fluorineacceptors [18F]FDG conjugation and Al18F chelationrdquo Journalof Labelled Compounds and Radiopharmaceuticals vol 55 no8 pp 281ndash288 2012

[19] W JMcBride RM Sharkey H Karacay et al ldquoA novel methodof 18F radiolabeling for PETrdquo Journal of Nuclear Medicine vol50 no 6 pp 991ndash998 2009

[20] P Laverman W J McBride R M Sharkey et al ldquoA novelfacile method of labeling octreotide with18F-fluorinerdquo Journalof Nuclear Medicine vol 51 no 3 pp 454ndash461 2010

[21] W J McBride C A DSouza H Karacay R M Sharkey andD M Goldenberg ldquoNew lyophilized kit for rapid radiofluori-nation of peptidesrdquo Bioconjugate Chemistry vol 23 no 3 pp538ndash547 2012

[22] Z Liu Y Li J Lozada et al ldquoStoichiometric leverage rapid 18F-aryltrifluoroborate radiosynthesis at high specific activity forclick conjugationrdquo Angewandte Chemie International Editionvol 52 no 8 pp 2303ndash2307 2013

[23] R Schirrmacher G Bradtmoller E Schirrmacher et al ldquo18F-labeling of peptides by means of an organosilicon-basedfluoride acceptorrdquo Angewandte Chemie International Editionvol 45 no 36 pp 6047ndash6050 2006

[24] L Mu P A Schubiger and S M Ametamey ldquo[18F]fluoro-silicon- and [18F]fluoroboron-based biomolecules for PETimagingrdquo Current Radiopharmaceuticals vol 3 no 3 pp 224ndash242 2010

[25] L O Dialer S V Selivanova C J Muller et al ldquoStudies towardthe development of new silicon-containing building blocksfor the direct 18F-labeling of peptidesrdquo Journal of MedicinalChemistry vol 56 pp 7552ndash7563 2013

[26] B Wangler A P Kostikov S Niedermoser et al ldquoProteinlabeling with the labeling precursor [18F]SiFA-SH for positronemission tomographyrdquo Nature Protocols vol 7 no 11 pp 1964ndash1969 2012

[27] Y Joyard R Azzouz L Bischoff et al ldquoSynthesis of new 18F-radiolabeled silicon-based nitroimidazole compoundsrdquo Bioor-ganic and Medicinal Chemistry vol 21 no 13 pp 3680ndash36882013

[28] K Kettenbach H Schieferstein and T Ross ldquo 18F-Labelingusing click cycloadditionsrdquo BioMed Research International vol2014 Article ID 361329 16 pages 2014

[29] SMaschauer andO Prante ldquoSweetening pharmaceutical radio-chemistry by fluoroglycosylation a short reviewrdquo BioMedResearch International vol 2014 Article ID 214748 16 pages2014

[30] V Bernard-Gauthier C Wangler E Schirrmacher et alldquo 18F-Labeled silicon-based fluoride acceptors-opportunitiesfor novel positron emitting radiopharmaceuticalsrdquo BioMedResearch International In press

[31] S M Qaim J C Clark C Crouzel et al ldquoPET radionuclideproductionrdquo in Radiopharmaceuticals for Positron EmissionTomographyMethodological Aspects G Stocklin andVW PikeEds pp 15ndash26 Kluwer Academic Publishers Dordrecht TheNetherlands 1993

[32] H H Coenen ldquoFluorine-18 labeling methods features andpossibilities of basic reactionsrdquo in PET Chemistry The DrivingForce in Molecular Imaging P A Schubiger L Lehmann andM Friebe Eds vol 62 of Ernst Schering Research FoundationWorkshop pp 15ndash50 Springer Berlin Germany 2007

[33] H Teare E G Robins E Arstad S K Luthra and V Gou-verneur ldquoSynthesis and reactivity of [18F]-N-fluorobenzene-sulfonimiderdquoChemical Communications no 23 pp 2330ndash23322007

[34] J Bergman P Johnstrom M Haaparanta O Solin T Duelferand S Stone-Elander ldquoRadiolabelling of 2-oxoquazepam withelectrophilic 18F prepared from [18F]fluoriderdquo Applied Radia-tion and Isotopes vol 46 no 10 pp 1027ndash1034 1995

[35] H Teare E G Robins A Kirjavainen et al ldquoRadiosynthesisand evaluation of [18F]Selectfluor bis(triflate)rdquo AngewandteChemie International Edition vol 49 no 38 pp 6821ndash68242010


[36] I S R Stenhagen A K Kirjavainen S J Forsback et alldquoFluorination of an arylboronic ester using [18F]selectfluorbis(triflate) application to 6-[18F]fluoro-l-DOPArdquo ChemicalCommunications vol 49 no 14 pp 1386ndash1388 2013

[37] H-J Wester ldquoNuclear imaging probes from bench to bedsiderdquoClinical Cancer Research vol 13 no 12 pp 3470ndash3481 2007

[38] H H Coenen P H Elsinga R Iwata et al ldquoFluorine-18radiopharmaceuticals beyond [18F]FDG for use in oncologyand neurosciencesrdquo Nuclear Medicine and Biology vol 37 no7 pp 727ndash740 2010

[39] H J Wester and M Schottelius ldquoFluorine-18 labeling ofpeptides and proteinsrdquo in PET Chemistry the Driving Force inMolecular Imaging A P Schubiger L Lehmann andM FriebeEds vol 62 of Ernst Schering Research Foundation Workshoppp 79ndash111 2007

[40] M-R Zhang and K Suzuki ldquo[18F]Fluoroalkyl agents synthesisreactivity and application for development of PET ligands inmolecular imagingrdquoCurrent Topics inMedicinal Chemistry vol7 no 18 pp 1817ndash1828 2007

[41] O Jacobson and X Chen ldquoPET designated flouride-18 produc-tion and chemistryrdquo Current Topics in Medicinal Chemistry vol10 no 11 pp 1048ndash1059 2010

[42] S H Wessmann G Henriksen and H-J Wester ldquoCryptatemediated nucleophilic 18F-fluorination without azeotropic dry-ingrdquo NuklearMedizin vol 51 no 1 pp 1ndash8 2012

[43] C F Lemaire J J Aerts S Voccia et al ldquoFast production ofhighly reactive no-carrier-added [18F] fluoride for the labelingof radiopharmaceuticalsrdquo Angewandte Chemie InternationalEdition vol 49 no 18 pp 3161ndash3164 2010

[44] J Aerts S Voccia C Lemaire et al ldquoFast production of highlyconcentrated reactive [18F] fluoride for aliphatic and aromaticnucleophilic radiolabellingrdquo Tetrahedron Letters vol 51 no 1pp 64ndash66 2010

[45] B Mathiessen A T I Jensen and F Zhuravlev ldquoHomogeneousnucleophilic radiofluorination and fluorination with phosp-hazene hydrofluoridesrdquo Chemistry vol 17 no 28 pp 7796ndash7805 2011

[46] B Mathiessen and F Zhuravlev ldquoAutomated solid-phaseradiofluorination using polymer-supported phosphazenesrdquoMolecules vol 18 pp 10531ndash10547 2013

[47] K Hamacher T Hirschfelder and H H Coenen ldquoElectro-chemical cell for separation of [18F]fluoride from irradiated18O-water and subsequent no carrier added nucleophilic fluori-nationrdquo Applied Radiation and Isotopes vol 56 no 3 pp 519ndash523 2002

[48] G ReischlW Ehrlichmann andH-JMachulla ldquoElectrochem-ical transfer of [18F] fluoride from [18O]water into organicsolvents ready for labeling reactionsrdquo Journal of Radioanalyticaland Nuclear Chemistry vol 254 no 1 pp 29ndash31 2002

[49] H Saiki R Iwata H Nakanishi et al ldquoElectrochemical con-centration of no-carrier-added [18F]fluoride from [18O]water ina disposable microfluidic cell for radiosynthesis of 18F-labeledradiopharmaceuticalsrdquo Applied Radiation and Isotopes vol 68no 9 pp 1703ndash1708 2010

[50] R Wong R Iwata H Saiki S Furumoto Y Ishikawa and EOzeki ldquoReactivity of electrochemically concentrated anhydrous[18F]fluoride for microfluidic radiosynthesis of 18F-labeledcompoundsrdquo Applied Radiation and Isotopes vol 70 no 1 pp193ndash199 2012

[51] S Sadeghi V Liang S Cheung et al ldquoReusable electrochemicalcell for rapid separation of [18F]fluoride from [18O]water for

flow-through synthesis of 18F-labeled tracersrdquo Applied Radia-tion and Isotopes vol 75 pp 85ndash94 2013

[52] W K Dong H-J Jeong T L Seok M-H Sohn J A Katzenel-lenbogen and Y C Dae ldquoFacile nucleophilic fluorinationreactions using tert-alcohols as a reactionmedium significantlyenhanced reactivity of alkali metal fluorides and improvedselectivityrdquo Journal of Organic Chemistry vol 73 no 3 pp 957ndash962 2008

[53] K Sachin H-J Jeong S T Lim M-H Sohn D Y Chi and DW Kim ldquoAn efficient synthesis of ([18F]fluoropropyl)quinoline-58-diones by rapid radiofluorination-oxidative demethylationrdquoTetrahedron vol 67 no 10 pp 1763ndash1767 2011

[54] T Priem C Bouteiller D Camporese A Romieu and P-YRenard ldquoSynthesis and reactivity of a bis-sultone cross-linkerfor peptide conjugation and [18F]-radiolabelling via unusualldquodouble clickrdquo approachrdquo Organic and Biomolecular Chemistryvol 10 no 5 pp 1068ndash1078 2012

[55] R Loser R Bergmann M Frizler et al ldquoSynthesis and radio-pharmacological characterisation of a fluorine-18-labelledazadipeptide nitrile as a potential PET tracer for invivoimaging of cysteine cathepsinsrdquo ChemMedChem vol 8 no 8pp 1330ndash1344 2013

[56] C Park B S Lee and D Y Chi ldquoHigh efficiency synthesisof F-18 fluoromethyl ethers an attractive alternative for C-11methyl groups in positron emission tomography radiopharma-ceuticalsrdquo Organic Letters vol 15 pp 4346ndash4349 2013

[57] N Jarkas R J Voll and M M Goodman ldquoSynthesis of aphenolic precursor and its efficient O-[18F]fluoroethylationwith purified no-carrier-added [18F]2-fluoroethyl brosylate asthe labeling agentrdquo Journal of Labelled Compounds and Radio-pharmaceuticals vol 56 pp 539ndash543 2013

[58] V J Majo M S Milak J Prabhakaran et al ldquoSynthesis andin vivo evaluation of [18F]2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-124-triazine-35(2H4H)-dione([18F]FECUMI-101) as an imaging probe for 5-HT1A receptoragonist in nonhuman primatesrdquo Bioorganic and MedicinalChemistry vol 21 no 17 pp 5598ndash5604 2013

[59] F Caille T J Morley A A S Tavares et al ldquoSynthesisand biological evaluation of positron emission tomographyradiotracers targeting serotonin 4 receptors in brain [18F]MNI-698 and [18F]MNI-699rdquo Bioorganic and Medicinal ChemistryLetters vol 23 pp 6243ndash6247 2013

[60] M-R Zhang A Tsuchiyama T Haradahira Y Yoshida KFurutsuka and K Suzuki ldquoDevelopment of an automated sys-tem for synthesizing 18F-labeled compounds using [18F]fluoro-ethyl bromide as a synthetic precursorrdquo Applied Radiation andIsotopes vol 57 no 3 pp 335ndash342 2002

[61] P J Riss S Hoehnemann M Piel and F Roesch ldquoTwo-stepradiosynthesis of [18F]FE-120573-CIT and [18F]PR04MZrdquo Journal ofLabelled Compounds and Radiopharmaceuticals vol 56 no 7pp 356ndash359 2013

[62] M E Rodnick A F Brooks B G Hockley B D Hendersonand P J H Scott ldquoA fully-automated one-pot synthesis of[18F]fluoromethylcholine with reduced dimethylaminoethanolcontamination via [18F]fluoromethyl tosylaterdquo Applied Radia-tion and Isotopes vol 78 pp 26ndash32 2013

[63] D Franck T Kniess J Steinbach et al ldquoInvestigations into thesynthesis radiofluorination and conjugation of a new [18F]flu-orocyclobutyl prosthetic group and its in vitro stability usinga tyrosine model systemrdquo Bioorganic and Medicinal Chemistryvol 21 no 3 pp 643ndash652 2013


[64] T Sun G Tang H Tian et al ldquoRadiosynthesis of 1-[18F]fluoro-ethyl-L-tryptophan as a novel potential amino acid PET tracerrdquoApplied Radiation and Isotopes vol 70 no 4 pp 676ndash680 2012

[65] R P Klok P J Klein J D M Herscheid and A D WindhorstldquoSynthesis of N-(3-[18F]fluoropropyl)-2120573-carbomethoxy-3120573-(4-iodophenyl)nortropane ([18F]FP-120573-CIT)rdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 49 no 2 pp 77ndash892006

[66] E M F Billaud L Rbah-Vidal A Vidal et al ldquoSynthesis radio-fluorination and in vivo evaluation of novel fluorinated andiodinated radiotracers for PET imaging and targeted radionu-clide therapy ofmelanomardquo Journal ofMedicinal Chemistry vol56 pp 8455ndash8467 2013

[67] R Bejot T Fowler L Carroll et al ldquoFluorous synthesis of 18Fradiotracers with the [18F]fluoride ion nucleophilic fluorina-tion as the detagging processrdquo Angewandte Chemie Interna-tional Edition vol 48 no 3 pp 586ndash589 2009

[68] R Bejot J Goggi S S Moonshi and E G Robins ldquoA practicalsynthesis of [18F]FtRGD an angiogenesis biomarker for PETrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol56 no 2 pp 42ndash49 2013

[69] G E Smith S Bayoudh C Perollier et al ldquoRapid purificationof fluorine-18 containing synthons usingmolecularly imprintedpolymer cartridgesrdquo Journal of Labelled Compounds and Radio-pharmaceuticals vol 56 article S119 2013

[70] M Pretze D Pietzsch and C Mamat ldquoRecent trends inbioorthogonal click-radiolabeling reactions using fluorine-18rdquoMolecules vol 18 no 7 pp 8618ndash8665 2013

[71] M Pretze F Wuest T Peppel M Kockerling and C MamatldquoThe traceless Staudinger ligation with fluorine-18 a noveland versatile labeling technique for the synthesis of PET-radiotracersrdquo Tetrahedron Letters vol 51 no 49 pp 6410ndash64142010

[72] L Carroll S Boldon R Bejot J E Moore J Declerck and VGouverneur ldquoThe traceless Staudinger ligation for indirect 18F-radiolabellingrdquo Organic and Biomolecular Chemistry vol 9 no1 pp 136ndash140 2011

[73] C Mamat M Franke T Peppel M Kockerling and JSteinbach ldquoSynthesis structure determination and (radio-)fluorination of novel functionalized phosphanes suitable forthe traceless Staudinger ligationrdquo Tetrahedron vol 67 no 25pp 4521ndash4529 2011

[74] H Doi M Goto and M Suzuki ldquoPd0-mediated rapid C-

[18F]fluoromethylation by the cross-coupling reaction of a[18F]fluoromethyl halide with an arylboronic acid ester novelmethod for the synthesis of a 18F-labeled molecular probe forpositron emission tomographyrdquo Bulletin of the Chemical Societyof Japan vol 85 no 11 pp 1233ndash1238 2012

[75] S Lu S D Lepore Y L Song et al ldquoNucleophile assistingleaving groups a strategy for aliphatic 18F-fluorinationrdquo Journalof Organic Chemistry vol 74 no 15 pp 5290ndash5296 2009

[76] J E Huheey ldquoThe electronegativity of groupsrdquo Journal ofPhysical Chemistry vol 69 no 10 pp 3284ndash3291 1965

[77] M A McClinton and D A McClinton ldquoTrifluoromethylationsand related reactions in organic chemistryrdquoTetrahedron vol 48no 32 pp 6555ndash6666 1992

[78] J-A Ma and D Cahard ldquoAsymmetric fluorination trifluo-romethylation and perfluoroalkylation reactionsrdquo ChemicalReviews vol 104 no 12 pp 6119ndash6146 2004

[79] J Prabhakaran M D Underwood R V Parsey et al ldquoSyn-thesis and in vivo evaluation of [18F]-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide as a

PET imaging probe for COX-2 expressionrdquo Bioorganic andMedicinal Chemistry vol 15 no 4 pp 1802ndash1807 2007

[80] V JMajoVArangoNR Simpson et al ldquoSynthesis and in vitroevaluation of [18F]BMS-754807 a potential PET ligand for IGF-1Rrdquo Bioorganic and Medicinal Chemistry Letters vol 23 no 14pp 4191ndash4194 2013

[81] M C Lasne C Perrio J Rouden et al ldquoChemistry of beta-emitting compounds based on fluorine-18+rdquo Topics in CurrentChemistry vol 222 pp 201ndash258 2002

[82] P J Riss and F I Aigbirhio ldquoA simple rapid procedure fornucleophilic radiosynthesis of aliphatic [18F]trifluoromethylgroupsrdquo Chemical Communications vol 47 no 43 pp 11873ndash11875 2011

[83] P J Riss V Ferrari L Brichard P Burke R Smith and F I Aig-birhio ldquoDirect nucleophilic radiosynthesis of [18F]trifluoro-alkyl tosylates improved labelling proceduresrdquo Organic andBiomolecular Chemistry vol 10 no 34 pp 6980ndash6986 2012

[84] A Hammadi and C Crouzel ldquoSynthesis of [18F]-(S)-fluoxetinea selective serotonine uptake inhibitorrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 33 no 8 pp 703ndash710 1993

[85] D Van Der Born J D M Herscheid R V A Orru andD J Vugts ldquoEfficient synthesis of [18F]trifluoromethane andits application in the synthesis of PET tracersrdquo ChemicalCommunications vol 49 no 38 pp 4018ndash4020 2013

[86] D van der Born J D M Herscheid and D J Vugts ldquoAromatictrifluoromethylation using [18F]fluoroformrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 56 article S2 2013

[87] T Ruhl W Rafique V T Lien et al ldquoCu(i)-mediated 18F-trifluoromethylation of arenes rapid synthesis of 18F-labeledtrifluoromethylarenesrdquo Chemical Communications vol 50 pp6056ndash6059 2014

[88] M Huiban M Tredwell S Mizuta et al ldquoA broadly applicable[18F]trifluoro-methylation of aryl and heteroaryl iodides forPET imagingrdquo Nature Chemistry vol 5 pp 941ndash944 2013

[89] V T Lien and P Riss ldquoRadiosynthesis of [18F]trifluoralk-ylgroups scope and limitationsrdquo BioMed Research Interna-tional In press

[90] B Sundararaju M Achard and C Bruneau ldquoTransition metalcatalyzed nucleophilic allylic substitution activation of allylicalcohols via p-allylic speciesrdquo Chemical Society Reviews vol 41pp 4467ndash4483 2012

[91] C Hollingworth A Hazari M N Hopkinson et al ldquoPalla-dium-catalyzed allylic fluorinationrdquoAngewandte Chemie Inter-national Edition vol 50 no 11 pp 2613ndash2617 2011

[92] J J Topczewski T J Tewson and H M Nguyen ldquoIridium-catalyzed allylic fluorination of trichloroacetimidatesrdquo Journalof the American Chemical Society vol 133 no 48 pp 19318ndash19321 2011

[93] X Huang W Liu H Ren et al ldquoLate stage benzylic C-Hfwith [18F]fluoride for PET imagingrdquo Journal of the AmericanChemical Society vol 136 no 19 pp 6842ndash6845 2014

[94] A J Palmer J C Clark and R W Goulding ldquoThe preparationof fluorine 18 labelled radiopharmaceuticalsrdquo InternationalJournal of Applied Radiation and Isotopes vol 28 no 1-2 pp53ndash65 1977

[95] H H Coenen and J Ermert ldquoDirect nucleophilic 18F-fluorination of electron rich arenes present limits of no-carrier-added reactionsrdquo Current Radiopharmaceuticals vol 3 no 3pp 163ndash173 2010


[96] A Knochel and O Zwernemann ldquoDevelopment of a no-carrier-added method for 18F-labelling of aromatic compoundsby fluorodediazonationrdquo Journal of Labelled Compounds andRadiopharmaceuticals vol 38 no 4 pp 325ndash336 1996

[97] P J Riss S Kuschel and F I Aigbirhio ldquoNo carrier-addednucleophilic aromatic radiofluorination using solid phase sup-ported arenediazonium sulfonates and 1-(aryldiazenyl)pipera-zinesrdquo Tetrahedron Letters vol 53 no 14 pp 1717ndash1719 2012

[98] I Koslowsky JMercer and FWuest ldquoSynthesis and applicationof 4-[18F]fluorobenzylamine a versatile building block for thepreparation of PET radiotracersrdquo Organic and BiomolecularChemistry vol 8 no 20 pp 4730ndash4735 2010

[99] J Way and F Wuest ldquoFully automated synthesis of 4-[18F]fluorobenzylamine based on borohydrideNiCl

2reduc-

tionrdquo Nuclear Medicine and Biology vol 40 no 3 pp 430ndash4362013

[100] F Wuest ldquoFluorine-18 labeling of small molecules the useof 18F-labeled aryl fluorides derived from no-carrier-added[18F]fluoride as labeling precursorsrdquo in PET Chemistry TheDriving Force in Molecular Imaging vol 64 of Ernst ScheringResearch Foundation workshop pp 51ndash78 2007

[101] L Li M N Hopkinson R L Yona R Bejot A D Gee and VGouverneur ldquoConvergent 18F radiosynthesis a new dimensionfor radiolabellingrdquo Chemical Science vol 2 no 1 pp 123ndash1312011

[102] S K Fehler S Maschauer S B Hofling et al ldquoFast andefficient 18F-labeling by [18F] fluorophenylazocarboxylic estersrdquoChemistry vol 20 pp 370ndash375 2014

[103] U Muhlhausen J Ermert and H H Coenen ldquoSynthesislabelling and first evaluation of [18F]R91150 as a serotonin 5-HT2119860

receptor antagonist for PETrdquo Journal of Labelled Com-pounds and Radiopharmaceuticals vol 52 no 1 pp 13ndash22 2009

[104] F Kugler J Ermert and H H Coenen ldquoLabeling of benzodi-oxin piperazines with fluorine-18 as prospective radioligandsfor selective imaging of dopamine D4 receptorsrdquo Journal ofLabelled Compounds and Radiopharmaceuticals vol 56 pp609ndash618 2013

[105] F Dolle ldquo[18F]Fluoropyridines from conventional radiotracersto the labeling ofmacromolecules such as proteins and oligonu-cleotidesrdquo in PET Chemistry The Driving Force in MolecularImaging P A Schubiger L Lehmann and M Friebe Eds vol62 pp 113ndash157 2007

[106] N Malik C Solbach W Voelter and H-J MacHulla ldquoNucle-ophilic aromatic substitution by [18F]fluoride at substituted 2-nitropyridinesrdquo Journal of Radioanalytical and Nuclear Chem-istry vol 283 no 3 pp 757ndash764 2010

[107] NMalikWVoelterH-JMacHulla andC Solbach ldquoRadioflu-orination of 2-fluoropyridines by isotopic exchange with[18F]fluoriderdquo Journal of Radioanalytical and Nuclear Chem-istry vol 287 no 1 pp 287ndash292 2011

[108] E D Hostetler S Sanabria-Bohorquez H Fan Z Zeng et alldquo[18F]Fluoroazabenzoxazoles as potential amyloid plaque PETtracers synthesis and in vivo evaluation in rhesus monkeyrdquoNuclear Medicine and Biology vol 38 pp 1193ndash1203 2011

[109] F G Simeon M T Wendahl and V W Pike ldquoThe [18F]2-fluoro-13-thiazolylmoiety an easily-accessible structuralmotiffor prospective molecular imaging radiotracersrdquo TetrahedronLetters vol 51 no 46 pp 6034ndash6036 2010

[110] P Marchand C Lorilleux G Gilbert et al ldquoEfficient radi-osynthesis of 2-[18F]fluoroadenosine a new route to 2-[18F]fluoropurine nucleosidesrdquo ACS Medicinal Chemistry Let-ters vol 1 no 6 pp 240ndash243 2010

[111] F Kugler W Sihver J Ermert et al ldquoEvaluation of 18F-labeledbenzodioxine piperazine-based dopamineD 4 receptor ligandslipophilicity as a determinate of nonspecific bindingrdquo Journal ofMedicinal Chemistry vol 54 no 24 pp 8343ndash8352 2011

[112] L Rbah-Vidal A Vidal S Besse et al ldquoEarly detection andlongitudinal monitoring of experimental primary and dissem-inated melanoma using [18F]ICF01006 a highly promisingmelanoma PET tracerrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 39 no 9 pp 1449ndash1461 2012

[113] S Fischer A Hiller R Smits et al ldquoRadiosynthesis of racemicand enantiomerically pure (-)-[18F]flubatine-A promising PETradiotracer for neuroimaging of 1205724Β2 nicotinic acetylcholinereceptorsrdquo Applied Radiation and Isotopes vol 74 pp 128ndash1362013

[114] J Liu L Zhu K Plossl B P Lieberman and H F KungldquoSynthesis and evaluation of novel N-fluoropyridyl derivativesof tropane as potential PET imaging agents for the dopaminetransporterrdquoBioorganic andMedicinal Chemistry Letters vol 21no 10 pp 2962ndash2965 2011

[115] B-M Swahn J Sandell D Pyring et al ldquoSynthesis andevaluation of pyridylbenzofuran pyridylbenzothiazole andpyridylbenzoxazole derivatives as18F-PET imaging agents for120573-amyloid plaquesrdquo Bioorganic and Medicinal Chemistry Lettersvol 22 no 13 pp 4332ndash4337 2012

[116] A Damont R Boisgard B Kuhnast et al ldquoSynthesis of 6-[18F]fluoro-PBR28 a novel radiotracer for imaging the TSPO18 kDa with PETrdquo Bioorganic and Medicinal Chemistry Lettersvol 21 no 16 pp 4819ndash4822 2011

[117] T G Hamill W Eng A Jennings et al ldquoThe synthesis andpreclinical evaluation in rhesus monkey of [18F]MK-6577 and[11C]CMPyPB glycine transporter 1 positron emission tomog-raphy radiotracersrdquo Synapse vol 65 no 4 pp 261ndash270 2011

[118] E D Hostetler W Eng A D Joshi et al ldquoSynthesis character-ization and monkey PET studies of [18F]MK-1312 a PET tracerfor quantification of mGluR1 receptor occupancy byMK-5435rdquoSynapse vol 65 no 2 pp 125ndash135 2011

[119] N Vasdev P Cao E M Van Oosten et al ldquoSynthesis and PETimaging studies of [18F]2-fluoroquinolin-8-ol ([18F]CABS13) intransgenic mouse models of Alzheimers diseaserdquo MedChem-Comm vol 3 no 10 pp 1228ndash1230 2012

[120] O Tietz S K Sharma J Kaur et al ldquoSynthesis of three18F-labelled cyclooxygenase-2 (COX-2) inhibitors based on apyrimidine scaffoldrdquo Organic and Biomolecular Chemistry vol11 pp 8052ndash8064 2013

[121] VW Pike and F I Aigbirhio ldquoReactions of cyclotron-produced[18F]fluoride with diaryliodonium salts a novel single-steproute to no-carrier-added [18F]fluoroarenesrdquo Journal of theChemical Society Chemical Communications no 21 pp 2215ndash2216 1995

[122] J-H Chun and VW Pike ldquoSingle-step syntheses of no-carrier-added functionalized [18F]fluoroarenes as labeling synthonsfrom diaryliodonium saltsrdquo Organic and Biomolecular Chem-istry vol 11 no 37 pp 6300ndash6306 2013

[123] J-H Chun S Lu and VW Pike ldquoRapid and efficient radiosyn-theses of meta-substituted [18F]fluoroarenes from [18F]fluorideion and diaryliodonium tosylates within a microreactorrdquo Euro-pean Journal of Organic Chemistry no 23 pp 4439ndash4447 2011

[124] J-H Chun S Lu Y-S Lee and VW Pike ldquoFast and high-yieldmicroreactor syntheses of ortho -substituted [18F]Fluoroarenesfrom reactions of [18F]Fluoride ion with diaryliodonium saltsrdquoJournal of Organic Chemistry vol 75 no 10 pp 3332ndash33382010


[125] J-H Chun S Telu S Lu and V W Pike ldquoRadiofluorination ofdiaryliodonium tosylates under aqueous-organic and cryptand-free conditionsrdquo Organic and Biomolecular Chemistry vol 11no 31 pp 5094ndash5099 2013

[126] J Ermert C Hocke T Ludwig R Gail and H H CoenenldquoComparison of pathways to the versatile synthon of no-carrier-added 1-bromo-4-[18F]fluorobenzenerdquo Journal of LabelledCom-pounds and Radiopharmaceuticals vol 47 no 7 pp 429ndash4412004

[127] T L Ross J Ermert CHocke andHHCoenen ldquoNucleophilic18F-fluorination of heteroaromatic iodonium salts with no-carrier-added [18F]fluoriderdquo Journal of the American ChemicalSociety vol 129 no 25 pp 8018ndash8025 2007

[128] N Satyamurthy and J R Barrio ldquoPreparing F-18 labeled arylderivative useful for preparation of F-18 labeled biomarkerscomprises replacing iodonium ylide group of benzene deriva-tive containing iodonium ylide group with no-carrier-added F-18 fluoride ionrdquo Patent WO2010117435-A2 2010

[129] J Cardinale J Ermert S Humpert et al ldquoIodonium ylidesfor one-step no-carrier-added radiofluorination of electronrich arenes exemplified with 4-(([18F]fluoro-phenoxy)-phenylmethyl)piperidine NET and SERT ligandsrdquo RSCAdvances vol 4 pp 17293ndash17299 2014

[130] J-H Chun and V W Pike ldquoSingle-step radiosynthesis of ldquo18F-labeled click synthonsrdquo from azide-functionalized diaryliodo-nium saltsrdquo European Journal of Organic Chemistry no 24 pp4541ndash4547 2012

[131] J-H Chun and V W Pike ldquoSelective syntheses of no-carrier-added 2- and 3-[18F] fluorohalopyridines through the radioflu-orination of halopyridinyl(41015840-methoxyphenyl)iodonium tosy-latesrdquoChemical Communications vol 48 no 79 pp 9921ndash99232012

[132] L Mu C R Fischer J P Holland et al ldquo 18F-radiolabelingof aromatic compounds using triarylsulfonium saltsrdquo EuropeanJournal of Organic Chemistry no 5 pp 889ndash892 2012

[133] J-H Chun C L Morse F T Chin and VW Pike ldquoNo-carrier-added [18F]fluoroarenes from the radiofluorination of diarylsulfoxidesrdquo Chemical Communications vol 49 no 21 pp 2151ndash2153 2013

[134] M Tredwell and V Gouverneur ldquo 18F labeling of arenesrdquoAngewandte Chemie International Edition vol 51 no 46 pp11426ndash11437 2012

[135] V Gouverneur ldquoRadiochemistry flipping fluorides reactivityrdquoNature Chemistry vol 4 no 3 pp 152ndash154 2012

[136] E Lee A S Kamlet D C Powers et al ldquoA fluoride-derivedelectrophilic late-stage fluorination reagent for PET imagingrdquoScience vol 334 no 6056 pp 639ndash642 2011

[137] J R Brandt E Lee G B Boursalian et al ldquoMechanism ofelectrophilic fluorination with Pd(IV) fluoride capture andsubsequent oxidative fluoride transferrdquoChemical Science vol 5pp 169ndash179 2014

[138] J Cardinale J Ermert F Kugler A Helfer M R Brandt andH H Coenen ldquoCarrier-effect on palladium-catalyzed nucle-ophilic 18F-fluorination of aryl triflatesrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 55 no 12 pp 450ndash453 2012

[139] E Lee J M Hooker and T Ritter ldquoNickel-mediated oxidativefluorination for PET with aqueous [18F] fluoriderdquo Journal of theAmerican Chemical Society vol 134 no 42 pp 17456ndash174582012

[140] G Reischl G J Kienzle and H-J Machulla ldquoElectrochemicalradiofluorination Part 2 Anodic monofluorination of sub-stituted benzenes using [18F]fluoriderdquo Applied Radiation andIsotopes vol 58 no 6 pp 679ndash683 2003

[141] G J Kienzle G Reischl and H-J Machulla ldquoElectrochemicalradiofluorination 3 Direct labeling of phenylalanine deriva-tives with [18F]fluoride after anodic oxidationrdquo Journal ofLabelled Compounds and Radiopharmaceuticals vol 48 no 4pp 259ndash273 2005

[142] B Langstrom and P Hartvig ldquoGMP three letters with manyinterpretations protection of patients or killing the clinical andresearch applications of PETrdquo European Journal of NuclearMedicine and Molecular Imaging vol 35 no 4 pp 693ndash6942008

[143] P H Elsinga ldquoPresent and future of PET-radiopharmaceuti-calsrdquo Nuclear Medicine Review vol 15 pp C13ndashC16 2012

[144] L Barre L Barbier and M C Lasne ldquoInvestigation of possibleroutes to no-carrier-added 4-[18F]fluorophenolrdquo Journal ofLabelled Compounds and Radiopharmaceuticals vol 35 pp167ndash168 1994

[145] I Ekaeva L Barre M-C Lasne and F Gourand ldquo2- and4-[18F]Fluorophenols from Baeyer-Villiger Oxidation of[18F]Fluorophenylketones and [18F]FluorobenzaldehydesrdquoApplied Radiation and Isotopes vol 46 no 8 pp 777ndash782 1995

[146] T Ludwig J Ermert and H H Coenen ldquo4-[18F]fluoroarylalk-ylethers via an improved synthesis of nca 4-[18F]fluoro-phenolrdquo Nuclear Medicine and Biology vol 29 no 2 pp 255ndash262 2002

[147] F M Wagner J Ermert and H H Coenen ldquoThree-step ldquoone-potrdquo radiosynthesis of 6-fluoro-34-dihydroxy-l-phenylalanineby isotopic exchangerdquo Journal of Nuclear Medicine vol 50 no10 pp 1724ndash1729 2009

[148] Z Gao Y H Lim M Tredwell et al ldquoMetal-free oxidative flu-orination of phenols with [18F]fluoriderdquo Angewandte ChemieInternational Edition vol 51 no 27 pp 6733ndash6737 2012

[149] T L Ross J Ermert and H H Coenen ldquoSynthesis of no-carrier-added 4-[18F]fluorophenol from 4-benzyloxyphenyl-(2-thienyl)iodonium bromiderdquo Molecules vol 16 no 9 pp7621ndash7626 2011

[150] A Helfer J Castillo Melean J Ermert et al ldquoBis(4-benzyloxy-phenyl)iodonium salts as effective precursors for the no-carrier-added radiosynthesis of 4-[18F]fluorophenolrdquo Applied Radia-tion and Isotopes vol 82 pp 264ndash267 2013

[151] J Way V Bouvet and F Wuest ldquoSynthesis of 4-[18F]fluoro-halobenzenes and Palladium-mediated Cross-coupling Reac-tions for the Synthesis of F-18-labeled Radiotracersrdquo CurrentOrganic Chemistry vol 17 pp 2138ndash2152 2013

[152] J Ermert T Ludwig R Gail and H H Coenen ldquo[18F]Fluoro-phenyl organometallics as intermediates of no-carrier-added18F-fluoroarylation reactionsrdquo Journal of Organometallic Chem-istry vol 692 no 19 pp 4084ndash4092 2007

[153] Z Gao V Gouverneur and B G Davis ldquoEnhanced aqueousSuzuki-Miyaura coupling allows site-specific polypeptide 18F-labelingrdquo Journal of the American Chemical Society vol 135 pp13612ndash13615 2013



[155] F R Wust and T Kniess ldquoSynthesis of 4-[18F]fluoroiodoben-zene and its application in Sonogashira cross-coupling reac-tionsrdquo Journal of Labelled Compounds and Radiopharmaceuti-cals vol 46 no 8 pp 699ndash713 2003

[156] J Cardinale J Ermert and H H Coenen ldquoConvenient prepa-ration of (4-iodophenyl)aryliodonium saltsrdquo Tetrahedron vol68 no 22 pp 4112ndash4116 2012

[157] J Cardinale and J Ermert ldquoSimplified synthesis of aryliodo-nium ylides by a one-pot procedurerdquo Tetrahedron Letters vol54 no 16 pp 2067ndash2069 2013

[158] F Kugler J Cardinale P Kaufholz et al ldquoEfficient radiosyn-theses of 18F-fluorinated aromatic amines using innovativeiodonium precursorsrdquo Journal of Nuclear Medicine MeetingAbstract vol 53 abstract 185 2012

[159] J D Way and F Wuest ldquoAutomated radiosynthesis of no-carrier-added 4-[18F]fluoroiodobenzene a versatile buildingblock in 18F radiochemistryrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 57 pp 104ndash109 2014

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


several alternative methods have also been introduced capa-ble of using even mild and aqueous conditions for examplechelated aluminum [19ndash21] boron- [22] andor silicon-based[18F]fluoride acceptor groups [23ndash26] The latter methodswere also used for the synthesis of small molecules [27]

This review focuses on new developments regarding theuse of small 18F-labelled intermediates for build-up synthe-ses of biologically active compounds The 18F-labelling ofmacromolecules and the click chemistry approach are notconsideredThose special topics of 18F-labelling can be foundin other contributions to this issue [28ndash30]

2 18F-Fluorinating Agents

As starting material for all chemical syntheses either aqueous[18F]fluoride or gaseous [18F]F

2is used both of which are

generally produced at a cyclotron via the 18O(pn)18F nuclearreaction [31]The nucleophilic [18F]fluoride ion is available inno-carrier-added (nca) form which allows the synthesis ofradiotracers with high specific activity In contrast in-targetproduced [18F]F

2is available only in carrier-added (ca) form

which leads to radiotracers with low specific activityHistorically for important radiopharmaceuticals like

2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and 6-[18F]fluoro-L-dopa only electrophilic 18F-fluorination was avail-able Today this method is rarely used because of the need ofcarrier for [18F]F

2production Thus the use of electrophilic

18F-fluorination is limited to nontoxic compounds as wellas to those that can be applied with a low specific activityAlso since [18F]F

2is very reactive and 18F-labelled side prod-

ucts are formed less reactive electrophilic 18F-agents weredeveloped [32]More recently the synthesis of N-[18F]fluoro-benzenesulfonimide (NFSi) was described which is a highlystable reactive and selective electrophilic 18F-labelling agentand allows the synthesis of 18F-labelled allylic fluorides and120572-fluorinated ketones from allylsilanes and silyl enol ethersrespectively [33]

An alternative method using a ldquoposttargetrdquo synthesis of[18F]F

2leads to moderate specific activity of up to 247GBq

120583mol starting from nca [18F]fluoride [34] It wasrecently revisited for the radiosynthesis of [18F]selectfluorbis(triflate) the 18F-labelled form of (1-chloromethyl-4-flu-orodiazonia-bicyclo[222]-octane bis-(tetra-fluoroborate))an easy to handle and stable electrophilic fluorinating reagent(cf Figure 1) [35] This reagent could successfully be usedfor the silver(I)-mediated 18F-fluorination of electron-richarylstannane models and intermediates as well as for thepreparation of 6-[18F]fluoro-L-DOPA [36] albeit all withlimited specific activity of 37 plusmn 09GBq120583mol

3 Aliphatic Intermediates

Aliphatic 18F-fluorination is certainly the most prominentmethod for 18F-labelling [32] and important PET-radio-tracers for clinical use are aliphatically 18F-labelled com-pounds which fulfill these requirements for example

Electrophilicsubstitutionreactions

Nucleophilicsubstitutionreactions

Cl

TfOminus

TfOminus

N+

N+

18F

18O(pn)18F [18F]Fminus

[18F]F2

Figure 1 Nuclear reactions to produce fluorine-18 and the18F-fluorinating agents [18F]fluoride [18F]fluorine gas and[18F]selectfluor bis(triflate)

[18F]FDG 31015840-deoxy-31015840-[18F]fluorothymidine ([18F]FLT)[18F]fluoro(m)ethylcholine and O-2-[18F]fluoroethyl-L-tyrosine ([18F]FET) (cf Figure 2) [15 37 38] [18F]Fluoro(m)-ethylcholine is an example for 18F-labelled endogenouscompounds whereas [18F]FDGand [18F]FLT are 18F-labelleddeoxy derivatives of the corresponding endogenous sub-stances In all cases a proton is replaced by a fluorineatom without changing the carbon skeleton of the originalcompound In contrast [18F]FET is an example of anendogenous 18F-labelled compound where the introductionof the radionuclide is performed by an 18F-fluoroalkylationreaction Here the 18F-label is introduced into the moleculeby addition of further C-atoms which means that theskeleton of the molecule is significantly changed Otherexamples of this kind of reaction are the 18F-fluoroacylationand 18F-fluoroamidation reactions which are widely usedfor labelling of macromolecules [39] most often in aqueoussolution

31 Intermediates for Nucleophilic Substitution and OtherCoupling Reactions The synthesis of intermediates for 18F-fluoroalkylation is characterized by a two- or three-step pro-cedure (cf Figure 3) [40] First [18F]fluoride is introducedinto a molecule using precursors containing a good leavinggroupThe 18F-labelled precursor is then isolated and purifiedbefore coupling with a further molecule

In the first step the [18F]fluoride has to be separated fromthe target water and activated for a nucleophilic substitutionreaction The standard conditions of these basic methods aredescribed in several reviews [11 32 41] A simplification ofthis approach was achieved by water removal on a stronganion-exchange resin [42] or by use of strong organic basesas additives replacing the inorganic bases or salts classicallyused in the resin eluent [43ndash46] Instead of trapping on anion-exchange resins nca [18F]fluoride can also be separated byelectrochemical methods which are useful to minimize thereaction volume especially for the use inmicrofluidic systems[47ndash51] The use of mixtures of nonpolar tert-alcohols withacetonitrile as a reaction medium enhanced the reactivityof cesium[18F]fluoride or tetrabutylammonium [18F]fluorideand reduced the formation of typical by-products compared


OH

n

+

N

NH

O O

O

O

O

H

OH

OH

HO

HO

HO18F18F

18F

18F


Clminus

n = 1 2

N(CH3)2

H3C

NH2

CO2H



BzO

Method C

Method B

Method A


R FF

XAlkyl

18F

18F

18F

18F

18F




[18F]Fminus

SN
















2Br groups [84]


F

F X

OTosOTosF

F X

F

F

O R18F 18F


HI

F

F H

F

F

Ar

FFF

ClF

O

OMe18F18F




3Cu generated in























R

EWG

EWG

R

R

N N N

R

R

R

R



Clas

sical

appr

oach

es



Method C






New

dev

elopm

ents

N

N

LG

LG

X

Y

R

SO

PhR

R

[18F]Fminus

18F 18F

18F

18F

18F

18F

18F

18F

[18F]F2

N2BF4

S+

I+




OR

OHO

CNO

OH

18F

18F 18F 18F18F

18F 18F

NH2NH2

N+

Ominus


NN

O O

O

NN

O ON N N

O

OMe

18F18F

18F

N+Ominus





O

O

O

O

R

I+Cminus

(a)

RS

I+Brminus

(b)

MeO

I+minusOTs

N3

(c)

MeO

I+minusOTs

N3

(d)

NMeO X Y


I+minusOTs

(e)












3Nsdot3HF and Et




OH

X

O

O

OH

S

OBn

OBnBnO

18F

I+Brminus

I+Brminus

N+Ominus

(1) [18F]Fluoride




RCY = 35


RCY = 52

X = aryl alkyl











X X

X

SX

X

I

X O

O

18F

I+

I+

18Fminus

18Fminus18Fminus

18Fminus

S+Anminus

Anminus

Anminus

RCY = 65RCY = 90

RCY = 70

X = Br I

RCY = 60ndash70



5 Conclusion





Acknowledgment


References











































































































2reduc-






































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















OH

n

+

N

NH

O O

O

O

O

H

OH

OH

HO

HO

HO18F18F

18F

18F


Clminus

n = 1 2

N(CH3)2

H3C

NH2

CO2H



BzO

Method C

Method B

Method A


R FF

XAlkyl

18F

18F

18F

18F

18F




[18F]Fminus

SN
















2Br groups [84]


F

F X

OTosOTosF

F X

F

F

O R18F 18F


HI

F

F H

F

F

Ar

FFF

ClF

O

OMe18F18F




3Cu generated in























R

EWG

EWG

R

R

N N N

R

R

R

R



Clas

sical

appr

oach

es



Method C






New

dev

elopm

ents

N

N

LG

LG

X

Y

R

SO

PhR

R

[18F]Fminus

18F 18F

18F

18F

18F

18F

18F

18F

[18F]F2

N2BF4

S+

I+




OR

OHO

CNO

OH

18F

18F 18F 18F18F

18F 18F

NH2NH2

N+

Ominus


NN

O O

O

NN

O ON N N

O

OMe

18F18F

18F

N+Ominus





O

O

O

O

R

I+Cminus

(a)

RS

I+Brminus

(b)

MeO

I+minusOTs

N3

(c)

MeO

I+minusOTs

N3

(d)

NMeO X Y


I+minusOTs

(e)












3Nsdot3HF and Et




OH

X

O

O

OH

S

OBn

OBnBnO

18F

I+Brminus

I+Brminus

N+Ominus

(1) [18F]Fluoride




RCY = 35


RCY = 52

X = aryl alkyl











X X

X

SX

X

I

X O

O

18F

I+

I+

18Fminus

18Fminus18Fminus

18Fminus

S+Anminus

Anminus

Anminus

RCY = 65RCY = 90

RCY = 70

X = Br I

RCY = 60ndash70



5 Conclusion





Acknowledgment


References











































































































2reduc-






































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























2Br groups [84]


F

F X

OTosOTosF

F X

F

F

O R18F 18F


HI

F

F H

F

F

Ar

FFF

ClF

O

OMe18F18F




3Cu generated in























R

EWG

EWG

R

R

N N N

R

R

R

R



Clas

sical

appr

oach

es



Method C






New

dev

elopm

ents

N

N

LG

LG

X

Y

R

SO

PhR

R

[18F]Fminus

18F 18F

18F

18F

18F

18F

18F

18F

[18F]F2

N2BF4

S+

I+




OR

OHO

CNO

OH

18F

18F 18F 18F18F

18F 18F

NH2NH2

N+

Ominus


NN

O O

O

NN

O ON N N

O

OMe

18F18F

18F

N+Ominus





O

O

O

O

R

I+Cminus

(a)

RS

I+Brminus

(b)

MeO

I+minusOTs

N3

(c)

MeO

I+minusOTs

N3

(d)

NMeO X Y


I+minusOTs

(e)












3Nsdot3HF and Et




OH

X

O

O

OH

S

OBn

OBnBnO

18F

I+Brminus

I+Brminus

N+Ominus

(1) [18F]Fluoride




RCY = 35


RCY = 52

X = aryl alkyl











X X

X

SX

X

I

X O

O

18F

I+

I+

18Fminus

18Fminus18Fminus

18Fminus

S+Anminus

Anminus

Anminus

RCY = 65RCY = 90

RCY = 70

X = Br I

RCY = 60ndash70



5 Conclusion





Acknowledgment


References











































































































2reduc-






































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























R

EWG

EWG

R

R

N N N

R

R

R

R



Clas

sical

appr

oach

es



Method C






New

dev

elopm

ents

N

N

LG

LG

X

Y

R

SO

PhR

R

[18F]Fminus

18F 18F

18F

18F

18F

18F

18F

18F

[18F]F2

N2BF4

S+

I+




OR

OHO

CNO

OH

18F

18F 18F 18F18F

18F 18F

NH2NH2

N+

Ominus


NN

O O

O

NN

O ON N N

O

OMe

18F18F

18F

N+Ominus





O

O

O

O

R

I+Cminus

(a)

RS

I+Brminus

(b)

MeO

I+minusOTs

N3

(c)

MeO

I+minusOTs

N3

(d)

NMeO X Y


I+minusOTs

(e)












3Nsdot3HF and Et




OH

X

O

O

OH

S

OBn

OBnBnO

18F

I+Brminus

I+Brminus

N+Ominus

(1) [18F]Fluoride




RCY = 35


RCY = 52

X = aryl alkyl











X X

X

SX

X

I

X O

O

18F

I+

I+

18Fminus

18Fminus18Fminus

18Fminus

S+Anminus

Anminus

Anminus

RCY = 65RCY = 90

RCY = 70

X = Br I

RCY = 60ndash70



5 Conclusion





Acknowledgment


References











































































































2reduc-






































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















O

O

O

O

R

I+Cminus

(a)

RS

I+Brminus

(b)

MeO

I+minusOTs

N3

(c)

MeO

I+minusOTs

N3

(d)

NMeO X Y


I+minusOTs

(e)












3Nsdot3HF and Et




OH

X

O

O

OH

S

OBn

OBnBnO

18F

I+Brminus

I+Brminus

N+Ominus

(1) [18F]Fluoride




RCY = 35


RCY = 52

X = aryl alkyl











X X

X

SX

X

I

X O

O

18F

I+

I+

18Fminus

18Fminus18Fminus

18Fminus

S+Anminus

Anminus

Anminus

RCY = 65RCY = 90

RCY = 70

X = Br I

RCY = 60ndash70



5 Conclusion





Acknowledgment


References











































































































2reduc-






































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















OH

X

O

O

OH

S

OBn

OBnBnO

18F

I+Brminus

I+Brminus

N+Ominus

(1) [18F]Fluoride




RCY = 35


RCY = 52

X = aryl alkyl











X X

X

SX

X

I

X O

O

18F

I+

I+

18Fminus

18Fminus18Fminus

18Fminus

S+Anminus

Anminus

Anminus

RCY = 65RCY = 90

RCY = 70

X = Br I

RCY = 60ndash70



5 Conclusion





Acknowledgment


References











































































































2reduc-






































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















X X

X

SX

X

I

X O

O

18F

I+

I+

18Fminus

18Fminus18Fminus

18Fminus

S+Anminus

Anminus

Anminus

RCY = 65RCY = 90

RCY = 70

X = Br I

RCY = 60ndash70



5 Conclusion





Acknowledgment


References











































































































2reduc-






































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















































































































2reduc-






































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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