6-[ 18 f]fluoro-l-dopa: a well-established neurotracer with...

Review Article6-[18F]Fluoro-L-DOPA A Well-EstablishedNeurotracer with Expanding Application Spectrum andStrongly Improved Radiosyntheses

M Pretze1 C Waumlngler2 and B Waumlngler1

1 Molecular Imaging and Radiochemistry Department of Clinical Radiology and Nuclear MedicineMedical Faculty Mannheim of Heidelberg University Theodor-Kutzer-Ufer 1-3 68167 Mannheim Germany

2 Biomedical Chemistry Department of Clinical Radiology andNuclearMedicineMedical FacultyMannheim of Heidelberg University68167 Mannheim Germany

Correspondence should be addressed to B Wangler bjoernwaenglermedmauni-heidelbergde

Received 26 February 2014 Revised 17 April 2014 Accepted 18 April 2014 Published 28 May 2014

Academic Editor Olaf Prante

Copyright copy 2014 M Pretze et alThis is an open access article distributed under theCreative CommonsAttribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Formany years themain application of [18F]F-DOPAhas been the PET imaging of neuropsychiatric diseases movement disordersand brain malignancies Recent findings however point to very favorable results of this tracer for the imaging of other malignantdiseases such as neuroendocrine tumors pheochromocytoma and pancreatic adenocarcinoma expanding its application spectrumWith the application of this tracer in neuroendocrine tumor imaging improved radiosyntheses have been developed Among thesethe no-carrier-added nucleophilic introduction of fluorine-18 especially has gained increasing attention as it gives [18F]F-DOPAin higher specific activities and shorter reaction times by less intricate synthesis protocols The nucleophilic syntheses which weredeveloped recently are able to provide [18F]F-DOPA by automated syntheses in very high specific activities radiochemical yieldsand enantiomeric purities This review summarizes the developments in the field of [18F]F-DOPA syntheses using electrophilicsynthesis pathways as well as recent developments of nucleophilic syntheses of [18F]F-DOPA and compares the different synthesisstrategies regarding the accessibility and applicability of the products for human in vivo PET tumor imaging

1 Introduction

The 18F-radiolabeled nonproteinogenic amino acid 34-dihydroxy-6-[18F]fluoro-l-phenylalanine ([18F]F-DOPA)(Figure 1) has been used for over 30 years to image thepresynaptic dopaminergic system in the human brain inorder to investigate a number of CNS disorders in particularschizophrenia [1 2] and Parkinsonrsquos disease with positronemission tomography (PET) [3 4] As DOPA is the precur-sor of the neurotransmitter dopamine the extent of accumu-lation of [18F]F-DOPA in the brain reflects the functionalintegrity of the presynaptic dopaminergic synthesis [5] andvisualizes the activity of aromatic amino acid decarboxylase(AADC) which converts [18F]F-DOPA to 18F-dopamineLikewise the [18F]F-DOPA uptake can also be relevantfor determining the effects of treatment of the underlyingpathophysiology For example its uptake in the striatum

is increased during dopamine replacement therapies inParkinsonrsquos disease [6] and modulated by administrationof dopamine D

2receptor antagonist-based antipsychotic

compounds [7 8] As a diagnostic tool for the investigationof the neuronal dopaminergic metabolism a high specificactivity (SA) of [18F]F-DOPA is not mandatory

Incidental findings in a patient undergoing a movementdisorder diagnosis resulted in a coincidental discovery of amalignant glioma indicating the potential applicability of[18F]F-DOPA also for glioma imaging [9] In the followingnumerous studies were conducted establishing [18F]F-DOPAas the main diagnostic tool for brain tumor imaging giv-ing more favorable diagnostic results than [18F]FDG [10](Figure 1) due to a significantly lower background accumula-tion Also other alternatives based on amino acids weredeveloped for the imaging of brain malignancies such

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 674063 12 pageshttpdxdoiorg1011552014674063

2 BioMed Research International

NHOH

OH

OH

OHOH

NO

O

S

OO

O

O

O

O

HO

HO

HO

HO

HO18F

18F

18F18F

[ ]FDG

NH2NH2

NH2

[ ]FET[ ]FLT

[ ]F-DOPA [11C]CH3-MET

H311C

18F18F

18F

18F

Figure 1 Selected radiotracers applicable in (brain-)tumor imaging

as [11C]methyl-l-methionine ([11C]CH3-MET) [11ndash13]

31015840-deoxy-31015840-l-[18F]fluorothymidine ([18F]FLT) [14 15] or[18F]fluoroethyl-l-tyrosine ([18F]FET) [16ndash19] (Figure 1)which also exhibit the advantage to show a low physiologicalaccumulation in normal cerebral tissue and inflamed lesionscompared to [18F]FDG thus giving more favorable resultsin brain tumor imaging Among these tracers used forneurooncologic imaging [18F]F-DOPA shows a high uptakein the malignant tissues thus allowing a very sensitive tumordetection via PET imaging

Beyond glioma imaging recent studies have also shownthe increasing importance of [18F]F-DOPA for the visual-ization of various peripheral tumor entities via PET [20]which can be attributed to the upregulation of amino acidtransporters in malignant tissues due to an often increasedproliferation [21 22] [18F]F-DOPA which is transportedvia the dopamine transporter (DAT) into cells has thusshown diagnostic advantages in the imaging of high- andlow-grade malignancies like neuroendocrine tumors [23ndash27] pheochromocytoma [28 29] and pancreatic adenocarci-noma [30ndash32] regarding diagnostic efficiency and sensitivity[18F]FDG on the contrary is taken up by the glucose trans-porter not only by malignant tissues but also by inflamedand healthy tissues exhibiting a high glucose metabolismresulting in low tumor-to-background ratios [10] in CNSmalignanciesThe proliferationmarker [18F]FLTwhich accu-mulates in malignant tissues due to an enhanced activity ofTK1 however often shows relatively low tumor uptakes [15]favoring [18F]F-DOPA for the PET imaging of malignancies

Due to its increasing importance for human tumor imag-ing the synthesis of [18F]F-DOPAbecomes a criticalmeasureregarding its dissemination in clinical routine Ideally theradiotracer should be easily accessible in high radiochemicalyields (RCYs) and specific activities (SAs) as well as in shortsynthesis times by an automated process Furthermore asit was demonstrated that d-amino acids lack a permeabilitythrough the blood-brain barrier an enantioselective synthe-sis for [18F]F-DOPA is mandatory [33]

The following review outlines the developments inthe field of [18F]F-DOPA radiosyntheses via electrophilic

synthesis routes and themore recent synthesis improvementsvia nucleophilic syntheses The main focus of this work isto compare the radiochemical yields (RCYs) radiochemicalpurities (RCPs) enantiomeric excess (ee) synthesis timesreliability and a potential for automation of the differentradiosynthesis pathways

2 Synthesis Routes for the Production of[18F]F-DOPA

21 First Attempts to Synthesize [18F]F-DOPA One of the firstfluorine-18-labeled DOPA derivatives was 5-[18F]F-DOPA[18F]4 synthesized via isotopic exchange by Firnau et alin 1973 [34] (Figure 2) In a swimming pool reactor 6Li(1198994He)3H and 16O(3H 119899)18F nuclear reactions were utilized toproduce fluorine-18 in a mixture of Li

2CO3in H2SO4and

H2O The resulting [18F]fluoride was subsequently distilled

twice and the diazonium fluoroborate precursor 1 was addedto this solution After the isotopic exchange reaction hasoccurred the water was removed and the residue was driedover P

2O5 The dried residue [18F]2 was redissolved in

dioxane filtered and heated to 80∘C After adding xylene thesolution was further heated to 132∘C for the pyrolysis of thediazonium[18F]fluoroborate [18F]2 for 30min After solventevaporation HBr (48) was added to hydrolyze [18F]3 to thefinal product 5-[18F]F-DOPA

The resulting product [18F]4 was obtained in high radio-chemical purities of gt95 but very low specific activitiesbetween 22 and 22 kBq120583mol (02ndash20 120583Cimg) Further-more the enantiomeric purity of the product was notdetermined limiting the applicability of this cumbersomesynthesis route

A significant limitation for the use of 5-[18F]F-DOPA forin vivo imaging purposes is the accelerated O-methylationof 5-[18F]F-DOPA in contrast to 6-[18F]F-DOPA ([18F]7Figure 3) This increased O-methylation rate is caused by thefluorine atom in position 5 in direct vicinity to the hydroxylgroup in position 4 [35] and results in a significantly lowerin vivo stability of 5-[18F]F-DOPA ([18F]4 Figure 2) Thesame group presented the reaction of [18F]F

2and l-DOPA

BioMed Research International 3

O

O

O O

O OO

O

O

O O

O O

OO

OOO

O

OO OH

NH

HO

HO

NH

NH

N2BF41

[18F]fluoride

N2BF318F

H2O (pH 4)

18F18F

Dioxane xylene30min 132∘C

NH2-HBr HBr (48)H2g

45min 146ndash148∘C

(1) 30min 50∘C(2) P2O5 15min [18F

18F

]2

[ ]3[18F]4

Figure 2 Isotopic exchange reaction pathway for the synthesis of 5-[18F]F-DOPA [34]

(A)

(B)

(C)

8 [18F]9

10 [18F]11

O

O

OO

O

OO

O

O

OO

O

O

O

OO

OO

O

OO

OO

O

O

N N

Si

Sn

R R

5a R=H5a R=NO2

[18F]F2

CCl4 Freon-11

18F

18F

18F

18F

[18F]6aR=H[18F]6bR=NO2

HBr 48)

35min 135∘C10min dry ice

HN

HN

HN

H

HO

HO

OH

N

CF3 CF3

HgOCOCF3

[18F]AcOFAcOH

5min rt

HI(55)

10min 130∘C

NH2

[18F]F-DOPA([18F]7)

BocO

BocO BocO

BocO

[18F]F2

CDCl3

5min 5∘C

HCI 6M)

5min 80∘C8min 130∘C

(

(

Figure 3 Examples for different demetallation synthesis routes for production of carrier-added [18F]F-DOPA ([18F]7) via desilylation (A)[42] demercuration (B) [44] and destannylation (C) [95]

in liquid hydrogen fluoride in 1984 yielding a mixture of 2-5- and 6-[18F]F-DOPA in low radiochemical yields 37 GBq[18F]F

2was produced from a Ne-target by a tandem Van

de Graaff accelerator to give 111MBq (3) 6-[18F]F-DOPAlimiting the applicability of this synthesis pathway for aroutine production [36]

22 Electrophilic Syntheses Twenty years ago the main routeto produce [18F]F

2for electrophilic fluorination reactions

was to utilize the nuclear reaction 20Ne(119889 120572)18F and a F2-

passivated Ni-target [37] However this reaction was limitedto facilities with a deuterium accelerator and was thusmostly replaced by the 18O(119901 119899)18F nuclear reaction using


O

O

F O

O

O

O

O

O

O

O

OO

O

O

NN

NN

NN

OH OH OH OHOH

OH

12

TBA[18F]FDMF

8min 110∘C

18F18F18F

mCPBACHCl3

20min 60∘C

HBr (48)

30min 150∘C

[18F]13 [18F]14 [18F]7

NH2

Figure 4 Isotopic exchange reaction for the synthesis of carrier-added [18F]F-DOPA [59]

a respective 18O gas target as this latter method enables theproduction of higher 18F activities [37ndash39]

To overcome the problem with regioselectivity [40 41]and the low radiochemical yields obtained by isotopicexchange reactions radiodemetallation reactions were pro-posed by several groups Thus desilylation [42] and demer-curation [43ndash46] as well as destannylation [47ndash52] reactionswere developed (Figure 3) of which demercuration anddestannylation gave the best results and were also adoptedto the automated routine production of [18F]F-DOPA [53]Table 1 compares some of the most promising approachesMultiple purification steps utilizing cartridges HPLC andsterile membrane filters were used to remove traces of toxicmetal contaminations in the final product solutions to obtainthe radiolabeled products in acceptable purities Neverthe-less using demetallation reactions in a clinical radiotracerproduction the final quality control has to include a test formetal contaminants

Utilizing the carrier-added electrophilic introductionof fluorine-18 the main route to synthesize [18F]F-DOPA([18F]7) is by using commercially available and enantiomer-ically pure mercury or stannyl precursors such as 8 or 10(Figure 3) in combination with automated synthesis modules[53 54] The main advantages are a high enantiomericpurity (ee gt99) short reaction times (about 50min) anda simplified synthesis setup [54] However remaining limita-tions are the achievable radiochemical yields (25 plusmn 3 06ndash26GBq due to the low production yields of [18F]F

2from

the cyclotron and the substantial loss of at least 50 ofactivity) and specific activities (4ndash25MBq120583mol) As [18F]F

2

can normally be obtained in specific activities of up to350ndash600MBq120583mol [55] the [18F]F-DOPA production isnot possible in high specific activities by the electrophilicmethod Another limitation is the cumbersome transport ofgaseous [18F]F

2 Further the preparation of the precursor

compounds is expensive and the radiofluorination of thestannyl precursors gives many side products In order toobtain [18F]F-DOPA in higher SAs and RCYs it was thusmandatory to develop another synthesis approach The mostpromising one is the nucleophilic labeling using no-carrier-added [18F]fluoride as it can be obtained in very high specificactivities of up to 314ndash43000GBq120583mol [56]

3 Nucleophilic Synthesis Strategies for theProduction of [18F]F-DOPA

As a tracer for the amino acid metabolism in brain malig-nancies a high specific activity is not mandatory for [18F]F-DOPA However the increasing importance of [18F]F-DOPAfor peripheral oncologic diagnosis and the need to producethe radiotracer in higher radiochemical yields and specificactivities (as too low SAs of [18F]F-DOPAwere shown to pro-duce pharmacologic effects such as carcinoid crisis by localconversion in tumor tissue of [18F]F-DOPA to noradrenalineinduced by the enzymes aromatic acid decarboxylase anddopamine 120573-hydroxylase [57]) resulted in efforts to developno-carrier-added nucleophilic labeling methods

31 Isotopic Exchange In 2001 Tierling et al presentedthe first utilization of an isotopic exchange reaction forthe synthesis of [18F]F-DOPA [58] This approach yielded[18F]F-DOPA in RCYs of 8ndash10 (n d c) and an ee ofgt85 within 70min Based on these results Wagner etal described the utilization of the isotopic exchange reac-tion for the radiofluorination of a 19F-precursor 12 withtetrabutylammonium[18F]fluoride to produce [18F]F-DOPAin high specific activities (Figure 4) [59] Specific activitiesin the range of 15ndash25GBq120583mol and RCYs of 22 werecalculated to be achievable from a theoretical starting activityof 100GBq [18F]fluoride [60] and 19F-precursor amounts of23 120583mol However as the reaction was only shown for astarting activity of 370MBq [18F]fluoride and 57 120583mol 19F-precursor and no further isotopic exchange experiments withhigher starting activities were demonstrated the calculatedachievable yields of up to 25GBq120583mol remain to be shown

In 2013 Martin et al implemented themethod ofWagneret al to a GE TRACERlab MXFDG In preliminary experi-ments the automated synthesis of [18F]F-DOPA resulted inreproducible RCYs of 10ndash15 (n d c) RCPs of gt95 andee of gt98 without giving other synthesis details such asreaction times and starting activities [61]

32 Nucleophilic Syntheses and Aspects of Automation Innucleophilic substitution reactions on aromatic rings using[18F]fluoride the standard leaving groups are mainly nitro-


Table 1 Selected synthesis details from electrophilic fluorination reactions for the synthesis of [18F]F-DOPA

Radiolabeling method Time [min] RCY []a Impurities in product SA [MBq120583mol] ee [] Citation

Desilylation 60 8b n d 252 100 Diksic andFarrokhzad rsquo85 [42]

L-DOPA + BF3 120 18 n d n d 100 Chirakal et al rsquo86 [92]

Demercuration 65 12 lt10 ppb Hg n d 97 Adam and Jivan rsquo88[43]

Demercuration 50 11 lt20 ppb Hg 26 gt99 Luxen et al rsquo90 [44]

Destannylation 60 25 lt15 ppb Sn n d gt99 Namavari et al rsquo92[47]

O-Pivaloyl ester of L-DOPA 60 17 plusmn 19 n d 17 plusmn 25 100 Ishiwata et al rsquo93 [93]Demercuration 45ndash50 14b lt005 120583gmL Hg 17ndash19 gt98 Chaly et al rsquo93 [94]Destannylation 45ndash50 26 15ndash25 ppm Sn 44 gt99 Dolle et al rsquo98 [48]

Destannylation 50 25 plusmn 3 lt1 120583gmL CDCl3 30 plusmn 2 96 plusmn 1 Fuchtner et al rsquo08[95]

aUnless otherwise stated RCYs are given decay corrected (d c) and bnondecay corrected (n d c)

O

O

O

O

O

OO

O

O

15 16 17NO2NO2 N

SO3CF3

Nitroveratraldehyde Nitropiperonal Trimethylammoniumveratraldehyde

Figure 5 Most common precursors for no-carrier-added nucleophilic radiofluorination reactions producing [18F]F-DOPA

N

NO

Br

18

Figure 6 Chiral phase-transfer catalyst O-ally-N-9-anthracenylmethyl-cinchonidinium bromide 18

or trimethylammonium moieties (Figure 5) in combinationwith electron withdrawing groups such as ndashCO ndashCN andndashNO2

to enable an efficient reaction Further halogenexchange reactions with substituted veratraldehyde (ndashClndashBr and ndashF) were evaluated [62] The first nucleophilicapproaches for the synthesis of [18F]F-DOPA gave racematesof d- and l-isomers of the tracerwhichwere purified by chiralHPLC resulting in a significant loss of activity [63 64]

To overcome these problems new radiosyntheses weredeveloped based on enantiomerically pure chiral precursorsor chiral auxiliaries [65ndash70] The radiolabeling reactionsusing these precursors provide the product in moderateto good RCYs accompanied by a high enantiomeric excessof gt96 The most promising approach was published byLemaire et al giving [18F]F-DOPA in a RCY of 17ndash29 (d c)and a SAofgt37GBq120583mol [66] In Table 2 selected synthesesusing different enantiomerically pure chiral precursors orchiral auxiliaries are compared

In addition asymmetric synthesis routes were developedfor the radiosynthesis of [18F]F-DOPA with higher enan-tiomeric selectivity and higher RCYs comprising approacheswith the precursors depicted in Figure 5 and enantioselectivereactions utilizing different chiral phase-transfer catalysts(cPTC) The results from these asymmetric approaches areshown in Table 3

A very promising approach for the nucleophilic synthesisof [18F]F-DOPA yielding the product in high enantiomericpurities was the utilization of the chiral phase-transfercatalystO-ally-N-9-anthracenylmethyl-cinchonidiniumbro-mide (18 Figure 6) described by Corey et al in 1997 [71]Based on the preliminary results of Lemaire et al in 1999[72] and Guillouet et al in 2001 [73] Zhang et al adoptedthe method in 2002 [74] and presented a promising synthesisroute utilizing this cPTC 18 for the enantioselective radiosyn-thesis of [18F]F-DOPA in RCYs of 7ndash15 radiochemicalpurities of gt99 and an ee of 90 within 80ndash85min syn-thesis time However special care has to be taken concerningthe trimethylammonium veratraldehyde precursor 17 whichexhibits a limited stability upon storage of the precursor formore than six months at 0ndash4∘C resulting in a decreasingRCY for the radiofluorination of 17 from 40 to lt10[75]

A limitation for this synthesis route is the achievableenantiomeric purities as according to the European Phar-macopoeia monograph the limit of the D-enantiomer in thefinal solution is 2 (ee 96) [76] Thus the synthesis had tobe further improved to comply with this limit A promising


Table 2 Selected synthesis parameters using chiral auxiliaries or precursors

Precursor Time [min] RCY [] 18F-label RCY [] overalla SA [GBq120583mol] ee [] Citation16 100ndash110 51 12b n d n d Ding et al rsquo90 [63]15 or 16 120 n d 5ndash10 n d 50 (rac) Lemaire et al rsquo91 [65]15 110 n d 5ndash10b n d 83ndash96 Lemaire et al rsquo93 [67]15 or 16 120 20ndash35 sim50 3ndash5b n d gt99 Reddy et al rsquo93 [68]15 90 45 plusmn 5 17ndash29 gt37 gt96 Lemaire et al rsquo94 [66]15 or 16 125 n d 4-5b gt74 98 Horti et al rsquo95 [69]15 85 sim50 6ndash13b gt74 98 Najafi rsquo95 [70]aUnless otherwise stated RCYs are given decay corrected (d c) and bnondecay corrected (n d c)

O

O

O

O

O

O

O

O

O

NO2

HO

HOHO

HO

OH

K[18F]FK222K2CO3DMSO

RhCl[P(C6H5)3]3

dioxane

20min 145∘C 20min 150∘C

[18F]1915 [18F]20

[18F]21[18F]7

18F

18F

18F

18F

NH2

HI (57)20min reflux

120573-TyrosinaseNH3 pyruvate

5min 45∘C

pyridoxal 5998400-phosphate ascorbateTris-HCl (pH 9)

Figure 7 Synthesis pathway for the enzymatic preparation of [18F]F-DOPA according to Kaneko et al [77]

approach was presented by Kaneko et al in 1999 (Figure 7)[77]The enzymatic reaction step was evaluated carefully andprovided a conversion rate of 58 from [18F]fluorocatechol([18F]21) to [18F]F-DOPA ([18F]7) under optimized condi-tions Despite the efficient enzymatic conversion of [18F]F-catechol to the product the overall RCY of [18F]F-DOPA thatcould be obtainedwas only 20but resulted in the formationof the product in high SAs of gt200GBq120583mol within 150minsynthesis time The enantiomeric excess was assumed to be100 due to the enzymatic character of the reaction althoughbeing not confirmed

The automation of radiotracer syntheses is mandatory fortheir wide clinical distribution as an automated process givesthe product in reproducible quality and limits the radiationexposure to the operating personnel enabling high startingactivities and thus the possibility to synthesize several patientdoses in one radiosynthesis

Therefore Lemaire et al optimized the enantioselectivereaction using the chiral phase-transfer catalysts 18 and wereable to obtain enantiomeric excesses of about 96 whenperforming the reaction in toluene at 0∘C [78] However thisreaction setup is difficult to realize in automated processesdue to cooling and heating steps in the same synthesisprocess Thus an optimized synthesis route was developedpreventing the use of diiodosilane Aldehyde [18F]19 and itsprecursor 17 (Figure 5) were trapped on a C18 cartridge the

precursor 17 was removed with water from the solid supportand [18F]19was reduced by aqueousNaBH

4and subsequently

halogenated by HBr or HI on solid support resulting in asynthesis setup that could be transferred to an automatedsynthesis module Recently this reaction setup was appliedfor the radiosynthesis and online conversion from aldehyde[18F]19 to different benzyl halides [79]

Another very promising approach was presented in2004 by Krasikova et al [80] An automated enantios-elective radiosynthesis utilizing a novel substratecatalystpair namely NiPBPGly 25 and (S)-NOBIN 26 (Figure 8)was developed In the key alkylation step the electrophilicbromide [18F]2 reacts with the nickel complex 25 in thepresence of (S)-NOBIN to form the (S)-complex [18F]27This enantioselective reaction step was accomplished at roomtemperature which is favorable in terms of automationSubsequently the alkylation was quenched by HI or aceticacid before the solvent was removed in order to preventracemization of the (S)-complex Different purification stepswere optimized to remove any potentially toxic substancespresent during the synthesis (Ni Br P or B) which wasconfirmed by ICP-MS analysis of the final product Usingthis method [18F]F-DOPA was synthesized in an ee of 96and RCYs of 16 plusmn 5 [80] in a total synthesis time of 110ndash120min Although this approach seems to be promising ithas not found a widespread application so far which may


Table 3 Selected synthesis parameters utilizing chiral phase-transfer catalysts (cPTC) or asymmetric synthesis routes

Precursor Method Time [min] RCY []18F-label

RCY []overalla SA [GBq120583mol] ee [] Citation

15 Enzymatic 150 27 2 gt200 gt99 Kaneko et al rsquo99 [77]17 cPTC 18c 110 n d 10ndash15b 74ndash185 95 Guillouet et al rsquo01 [73]17 cPTC 18 80ndash85 10ndash40 7ndash15 n d 90 Zhang et al rsquo02 [74]16 Catalyst 25d 120 53 16 plusmn 5 n d 96 Krasikova et al rsquo04 [80]17 cPTC 18 100 40ndash50 25ndash30 n d 96 Lemaire et al rsquo04 [78]15 cPTC 18 120 71 20 plusmn 4 gt50 ge95 Shen et al rsquo09 [83]17 cPTC 31e 63 50 36 plusmn 3 gt750 gt97 Libert et al rsquo13 [86]aUnless otherwise stated RCYs are given decay corrected (d c) and bnondecay corrected (n d c) csee Figure 6 dsee Figure 8 esee Figure 10

O

O

O

O

O

O

O

O O

O

O

O

OO

OO

O

O

O N

N

N

N

Ni

NiOH

OH

H

H

H

OH

HO

HO

NO2

K[18F]FK222

18F 18F 18F

18F

18F

K2CO3DMSO

5min 180∘C

NaBH4

2min rt

Ph3PBr2

5min rt

Br

[18F]22

[18F]7

[18F]23

[18F]27

[18F]2416

26

25NH2

NH2

HI (57)

10min 170∘C (S)-NOBIN 26CH2Cl2NaOH 5min rt

Figure 8 Schematic depiction of the synthesis pathway utilizing NiPBPGly 25 and (S)-NOBIN 26 as a novel substratecatalyst pair for theenantioselective radiosynthesis of [18F]F-DOPA by Krasikova et al [80]

be due to the laborious synthesis of the catalyst pair [8182] and the challenging purification procedures required forthe synthesis which include self-made columnscartridges inorder to remove intermediate reagents and side products

The optimization efforts towards an automation forthe routine production of [18F]F-DOPA finally resulted inpromising synthesis approaches recently In 2009 Shen etal presented a method for the fully automated synthesisfor [18F]F-DOPA [83] utilizing the cPTC 18 which can beperformed at ambient temperature (Figure 9) combining themethods described by Zhang et al [74] and Lemaire et al[78] By optimization of the amounts of reagents during thealkylation process they were able to obtain [18F]F-DOPA inRCYs of 20plusmn4 SAs ofsim50GBq120583mol and ee ofge95within120min synthesis time In order to obtain higher RCYs itis important to radiolabel the nitro precursor 15 in DMFinstead of DMSO due to oxidation processes of the aldehyde15 occurring in DMSO [84 85] Furthermore the utilizationof HBr in combination with KI in the deprotection stepresulted in higher RCYs compared to HI alone However asnoncharacterized substances precipitate during the synthesis

a limitation of this method is the cumbersome maintenanceof the synthesismodule after each synthesis To overcome thisobstacle the use of a cassette module would be favorable asthis approach would not require the elaborate purification ofthe module after each use

Libert and coworkers investigated different cPTC regard-ing their potential to produce [18F]F-DOPA in the highestenantiomeric excesses and high enantiomeric purities ofgt97 could be obtained under mild reaction conditionswithin short reaction times [86] Together with the use of astructurally optimized chiral phase-transfer catalyst (31) [7187] (Figure 10) amuch simplified synthesis setup for automa-tion was enabled With this optimization the group of Libertand Lemaire was able to establish a fast automated synthesisand reported product amounts of gt45 GBq obtained in RCYsof 24 (n d c) and specific activities of gt750GBq120583mol [86]within 63 minutes (Figure 10) Furthermore utilizing cPTC31 as the catalyst an ee of gt97 could be achieved

33 Miscellaneous In this chapter some unconventionalapproaches for the production of [18F]F-DOPAare described


K[18F]FK222

K2CO3DMF

10min 140∘C

O

O

HO

HO

O OO

O

O I

O

ON

OO

O

O

OH

NO2

NH2

[18F]7 [18F]29

[18F]1915 [18F]28

18F 18F

18F 18F

Diiodosilanein situ

10min rt

10min 150∘C

HBr (48) KI

Ph2C=NCH2CO2t-BucPTC 18

CH2Cl2CsOH

10min rt

Figure 9 Automated radiosynthesis procedure for [18F]F-DOPA using the chiral phase transfer catalyst 18 [83]

O

O

HO

HO

OO

O

OO

O O

O

OON N

N

N

Br

OO

O

O

OH

OH


10min 140∘C

15min 180∘C

[18F]19

31

17 [18F]30 [18F]28

[18F]29[18F]7

18F 18F 18F

18F18F

2min rt2min rt

HI (57)

HI (57)NaBH4 I

NH2

Ph2C=NCH2CO2t-Bu tolueneKOH 9M 5min rt

SO3CF3

Figure 10 Schematic depiction of the automated synthesis pathway using the chiral phase-transfer catalyst 31 [86]

In 2008 Forsback et al presented an electrophilic labelingapproach for the production of [18F]F-DOPA in RCYs of64 plusmn 17 (d c) and SAs of 37 plusmn 09GBq120583mol [88] Thekey step was the synthesis of [18F]F

2in an electrical discharge

chamber by a 18F19F-exchange reaction The 18F-source was[18F]fluoromethane which was mixed with a low amount(1 120583mol) of carrier fluorine in neon (Ne05 F

2) inside the

discharge chamber [18F]Fluoromethane was produced frommethyliodide by a nucleophilic substitution reaction withK[18F]FK222 in acetonitrile Deuterated solvents for thesynthesis of [18F]F-DOPA like CDCl

3 CD2Cl2 and C

3D6O

were also investigated providing significantly higher yieldsthan Freon-11 [89]

In 2012 Lee et al presented a very fast oxidative fluori-nation approach for 18F-aryl compounds utilizing a nickel-complex 32 and [18F]fluoride (Figure 11) Nickel complex 32(1mg) a hypervalent iodine oxidant 33 (1 eq) an aqueous

solution of [18F]fluoride (2minus5 120583L 37minus185MBq) and K222(20mg) in acetonitrile (200minus500120583L) at 23∘C yielded a Boc-protected [18F]F-DOPA-analogue [18F]34 in RCYs of 15plusmn7(n d c) in less than 1 minute [90]This might be also a usefulapproach for a very fast synthesis of [18F]F-DOPA

In 2013 Stenhagen et al presented an Ag-mediatedelectrophilic [18F]fluorination of an enantiomerically pureprecursor The protected arylboronic ester was transformedto a 6-Ag-DOPA derivative with silver triflate Next[18F]selectfluor bis(triflate) in acetone-d

6was added [18F]F-

DOPAwas obtained after 20min reaction at ambient temper-ature and 5min deprotection in RCYs of 19plusmn 12 and SAs of26 plusmn 03GBq120583mol [91] These results are comparable withthe best known electrophilic approaches and could also servefor an automated synthesis

In summary radiosynthesis procedures for [18F]F-DOPAwere developed which can give the radiotracer in high RCYs


O2N

O2S

N

N

N

2

2

NI

O O

OO

N

Ni

32

33O

O

OTf

OBocOBoc

OBocOBoc

NHBoc NHBocK[18F]FK222CH3CN

lt1min 23∘C

18F

[18F]34

Figure 11 Schematic depiction of an oxidative fluorination approach using the nickel complex 32 and a hypervalent iodine oxidant 33 givingthe Boc-protected [18F]F-DOPA-analogue [18F]34 [90]

SAs and enantiomeric excesses in short reaction timesFuture efforts to even further improve these results couldinclude the utilization of nonoxidizing solvents and micro-wave conditions in order to achieve even higher [18F]fluorideincorporation rates Up to now automated systems based onthe radiochemistry described by for example Wagner et al[59] Martin et al [61] and Libert et al [86] are commerciallyavailable

4 Conclusion

In over 30 years the radiosynthesis of [18F]F-DOPA was per-formed via electrophilic and isotopic exchange routes whenthe tracer was mainly applied for the in vivo PET imagingof central motor disorders and metabolism imaging pur-poses However the main production route with [18F]F

2and

commercially available stannyl precursors provides [18F]F-DOPA in relatively low RCYs and SAs limiting the use of thispromising radiotracer to the imaging of neuronal functionand brain malignancies which is still its main application

With the discovery of the potential of [18F]F-DOPA asradiotracer for the imaging of peripheral malignancies suchas neuroendocrine tumors new radiosynthesis approachesbased on nucleophilic substitution reactions were developedyielding [18F]F-DOPA in higher RCYs and SAs as well asshorter synthesis times Here two main approaches werefollowed one comprises the introduction of nucleophilic[18F]fluoride into complex chiral precursors followed bydeprotection and purification and the other approach startswith introduction of [18F]fluoride into simple precursorsfollowed by the utilization of chiral phase-transfer catalystsfor an enantioselective synthesis of the product These pro-cesses can also be transferred to automated synthesismodulesallowing for a broader dissemination of this favorable radio-tracer extending the palette of radiotracers towards a patient-individualized precision medicine

Conflict of Interests

The authors declare no conflict of interests

Acknowledgment

The funding from ldquoPerspektivforderung desMinisteriums furWissenschaft und Kunst Baden-Wurttembergrdquo is gratefullyacknowledged

References

[1] O D Howes A J Montgomery M-C Asselin R MMurray PM Grasby and P KMcguire ldquoMolecular imaging studies of thestriatal dopaminergic system in psychosis and predictions forthe prodromal phase of psychosisrdquo British Journal of Psychiatryvol 191 no 51 supplement pp S13ndashS18 2007

[2] S K Bose F E Turkheimer O D Howes et al ldquoClassificationof schizophrenic patients and healthy controls using [18F]fluorodopa PET imagingrdquo Schizophrenia Research vol 106 no2-3 pp 148ndash155 2008

[3] D J Brooks ldquoPET studies on the function of dopamine in healthand Parkinsonrsquos diseaserdquo Annals of the New York Academy ofSciences vol 991 pp 22ndash35 2003

[4] D J Brooks K A Frey K LMarek et al ldquoAssessment of neuro-imaging techniques as biomarkers of the progression of Parkin-sonrsquos diseaserdquo Experimental Neurology vol 184 no 1 pp S68ndashS79 2003

[5] P Cumming P Deep O Rousset A Evans and A GjeddeldquoOn the rate of decarboxylation of Dopa to Dopamine in livingmammalian brainrdquoAnnals of the New York Academy of Sciencesvol 835 pp 274ndash308 1997

[6] T Nakamura V Dhawan T Chaly et al ldquoBlinded positronemission tomography study of dopamine cell implantation forParkinsonrsquos diseaserdquo Annals of Neurology vol 50 no 2 pp 181ndash187 2001

[7] J Tedroff R Torstenson P Hartvig et al ldquoEffects of thesubstituted (S)-3-phenylpiperidine (minus)-OSU6162 on PET mea-surements in subhuman primates evidence for tone-dependentnormalization of striatal dopaminergic activityrdquo Synapse vol28 pp 280ndash287 1998

[8] R Torstenson P Hartvig B Langstrom S Bastami G Antoniand J Tedroff ldquoEffect of apomorphine infusion on dopaminesynthesis rate relates to dopaminergic tonerdquo Neuropharmacol-ogy vol 37 no 8 pp 989ndash995 1998


[9] WDHeiss KWienhard RWagner et al ldquoF-Dopa as an aminoacid tracer to detect brain tumorsrdquo Journal of Nuclear Medicinevol 37 pp 1180ndash1182 1996

[10] W Chen D H S Silverman S Delaloye et al ldquo 18F-FDOPAPET imaging of brain tumors comparison study with 18F-FDGPET and evaluation of diagnostic accuracyrdquo Journal of NuclearMedicine vol 47 no 6 pp 904ndash911 2006

[11] S Oka H Okudaira M Ono et al ldquoDifferences in transportmechanisms of trans-1-amino-3-[18F]fluorocyclobutanecar-boxylic acid in inflammation prostate cancer and glioma cellscomparison with L-[Methyl-11C]methionine and 2-deoxy-2-[18F]fluoro-D-glucoserdquo Molecular Imaging and Biology vol 16no 3 pp 322ndash329 2013

[12] Y Okochi T Nihashi M Fujii et al ldquoClinical use of 11C-methionine and 18F-FDG-PET for germinoma in central ner-vous systemrdquo Annals of Nuclear Medicine vol 28 no 2 pp 94ndash102 2013

[13] S Takenaka Y Asano J Shinoda et al ldquoComparison of 11C-methionine 11C-chlorine and 18F-fluorodeoxyglucose-PET fordistinguishing glioma recurrence from radiation necrosisrdquoNeurologia Medico-Chirurgica vol 54 no 4 pp 280ndash289 2014

[14] W Chen T Cloughesy N Kamdar et al ldquoImaging proliferationin brain tumors with 18F-FLT PET comparison with 18F-FDGrdquoJournal of Nuclear Medicine vol 46 no 6 pp 945ndash952 2005

[15] L B Been A J H Suurmeijer D C P Cobben P L Jager H JHoekstra and P H Elsinga ldquo[18F]FLT-PET in oncology cur-rent status and opportunitiesrdquo European Journal of NuclearMedicine and Molecular Imaging vol 31 no 12 pp 1659ndash16722004

[16] N Galldiks G Stoffels M I Ruge et al ldquoRole of O-(2-18F-fluoroethyl)-L-tyrosine PET as a diagnostic tool for detectionof malignant progression in patients with low-grade gliomardquoJournal of NuclearMedicine vol 54 no 12 pp 2046ndash2054 2013

[17] M D Piroth J Prasath A Willuweit et al ldquoUptake of O-(2-[18F]fluoroethyl)-L-tyrosine in reactive astrocytosis in thevicinity of cerebral gliomasrdquo Nuclear Medicine and Biology vol40 pp 795ndash800 2013

[18] K K Sai C Huang L Yuan et al ldquo 18F-AFETP 18F-FET and18F-FDG imaging of mouse DBT gliomasrdquo Journal of NuclearMedicine vol 54 no 7 pp 1120ndash1126 2013

[19] K Zhang K J Langen I Neuner et al ldquoRelationship ofregional cerebral blood flow and kinetic behaviour of O-(2-18F-fluoroethyl)-L-tyrosine uptake in cerebral gliomasrdquoNuclearMedicine Communications vol 35 no 3 pp 245ndash251 2014

[20] J P Seibyl W Chen and D H S Silverman ldquo34-dihydroxy-6-[18F]-fluoro-L-phenylalanine positron emission tomography inpatients with central motor disorders and in evaluation of brainand other tumorsrdquo Seminars in Nuclear Medicine vol 37 no 6pp 440ndash450 2007

[21] K J Isselbacher ldquoSugar and amino acid transport by cells inculture differences between normal and malignant cellsrdquo TheNew England Journal of Medicine vol 286 no 17 pp 929ndash9331972

[22] H Busch J R Davis G R Honig D C Anderson P V Nairand W L Nyhan ldquoThe uptake of a variety of amino acids intonuclear proteins of tumorsrdquo Cancer Research vol 19 pp 1030ndash1039 1959

[23] O C Neels K P Koopmans P L Jager et al ldquoManipulation of[11C]-5-hydroxytryptophan and 6-[18F]fluoro-34-dihydroxy-L-phenylalanine accumulation in neuroendocrine tumor cellsrdquoCancer Research vol 68 no 17 pp 7183ndash7190 2008

[24] H Minn S Kauhanen M Seppanen and P Nuutila ldquo18F-FDOPA a multiple-target moleculerdquo Journal of NuclearMedicine vol 50 no 12 pp 1915ndash1918 2009

[25] P L Jager R Chirakal C J Marriott A H BrouwersK P Koopmans and K Y Gulenchyn ldquo6-L-18F-fluorodihydroxyphenylalanine pet in neuroendocrine tumorsbasic aspects and emerging clinical applicationsrdquo Journal ofNuclear Medicine vol 49 no 4 pp 573ndash586 2008

[26] S Balogova J-N Talbot V Nataf et al ldquo18F-Fluorodihydrox-yphenylalanine vs other radiopharmaceuticals for imaging neu-roendocrine tumours according to their typerdquoEuropean Journalof Nuclear Medicine and Molecular Imaging vol 40 no 6 pp943ndash966 2013

[27] S Chondrogiannis G Grassetto M C Marzola et al ldquo18F-DOPA PETCT biodistribution consideration in 107 consecu-tive patients with neuroendocrine tumoursrdquo Nuclear MedicineCommunications vol 33 no 2 pp 179ndash184 2012

[28] L Martiniova S Cleary E W Lai et al ldquoUsefulness of [18F]-DA and [18F]-DOPA for PET imaging in a mouse model ofpheochromocytomardquoNuclear Medicine and Biology vol 39 no2 pp 215ndash226 2012

[29] H C Rischke M R Benz D Wild et al ldquoCorrelation ofthe genotype of paragangliomas and pheochromocytomas withtheir metabolic phenotype on 34-dihydroxy-6-18F-fluoro-L-phenylalanin PETrdquo Journal of Nuclear Medicine vol 53 no 9pp 1352ndash1358 2012

[30] J Tuomela S Forsback L Haavisto et al ldquoEnzyme inhibitionof dopaminemetabolism alters 6-[18F]FDOPA uptake in ortho-topic pancreatic adenocarcinomardquo EJNMMI Research vol 3no 1 article 18 pp 1ndash10 2013

[31] H Jadvar ldquoHepatocellular carcinoma and gastroenteropan-creatic neuroendocrine tumors potential role of other positronemission tomography radiotracersrdquo Seminars in NuclearMedicine vol 42 no 4 pp 247ndash254 2012

[32] K P Koopmans O C Neels I P Kema et al ldquoImprovedstaging of patients with carcinoid and islet cell tumors with18F-dihydroxy-phenyl-alanine and 11C-5-hydroxy-tryptophanpositron emission tomographyrdquo Journal of Clinical Oncologyvol 26 no 9 pp 1489ndash1495 2008

[33] W H Oldendorf ldquoStereospecificity of blood-brain barrier per-meability to amino acidsrdquo The American Journal of Physiologyvol 224 no 4 pp 967ndash969 1973

[34] G Firnau C Nahmias and S Garnett ldquoThe preparation of[18F]5-fluoro-DOPA with reactor-produced fluorine-18 rdquo TheInternational Journal of Applied Radiation and Isotopes vol 24no 3 pp 182ndash184 1973

[35] G Firnau S Sood R Pantel and S Garnett ldquoPhenol ionizationin dopa determines the site of methylation by catechol-O-methyltransferaserdquo Molecular Pharmacology vol 19 no 1 pp130ndash133 1981

[36] G Firnau R Chirakal and E S Garnett ldquoAromatic radiofluori-nation with [18F]fluorine gas 6-[18F]fluoro-L-dopardquo Journal ofNuclear Medicine vol 25 no 11 pp 1228ndash1233 1984

[37] R J Nickles M E Daube and T J Ruth ldquoAn 18O2target

for the production of [18F]F2rdquo International Journal of Applied

Radiation and Isotopes vol 35 no 2 pp 117ndash122 1984[38] A D Roberts T R Oakes and R J Nickles ldquoDevelopment of

an improved target for [18F]F2productionrdquo Applied Radiation

and Isotopes vol 46 no 2 pp 87ndash91 1995[39] E Hess S Sichler A Kluge and H H Coenen ldquoSynthesis of 2-

[18F]fluoro-L-tyrosine via regiospecific fluoro-de-stannylationrdquoApplied Radiation and Isotopes vol 57 no 2 pp 185ndash191 2002


[40] K Hatano K Ishiwata and T Yanagisawa ldquoCo productionof 2 6-[18F]difluoroDOPA during electrophilic synthesis of 6-[18F]fluoro-L-DOPArdquoNuclearMedicine and Biology vol 23 pp101ndash103 1996

[41] H H Coenen K Franken P Kling and G Stocklin ldquoDirectelectrophilic radiofluorination of phenylalanine tyrosine anddopardquo Applied Radiation and Isotopes vol 39 no 12 pp 1243ndash1250 1988

[42] M Diksic and S Farrokhzad ldquoNew synthesis of fluorine-18-labeled 6-fluoro-L-dopa by cleaving the carbon-silicon bondwith fluorinerdquo Journal of Nuclear Medicine vol 26 no 11 pp1314ndash1318 1985

[43] M J Adam and S Jivan ldquoSynthesis and purification of L-6-[18F]fluorodopardquo Applied Radiation and Isotopes vol 39 no 12pp 1203ndash1206 1988

[44] A Luxen M Perlmutter G T Bida et al ldquoRemote semiauto-mated production of 6-[18F]fluoro-L-dopa for human studieswith PETrdquoApplied Radiation and Isotopes vol 41 no 3 pp 275ndash281 1990

[45] A Bishop N Satyamurthy G Bida and J R Barrio ldquoChemicalreactivity of the 18F electrophilic reagents from the 18O(p n)18Fgas target systemsrdquoNuclear Medicine and Biology vol 23 no 5pp 559ndash565 1996

[46] T Chaly D Bandyopadhyay R Matacchieri et al ldquoA dis-posable synthetic unit for the preparation of 3-O-methyl-6-[18F]fluorodopa using a regioselective fluorodemercurationreactionrdquo Applied Radiation and Isotopes vol 45 no 1 pp 25ndash30 1994

[47] M Namavari A Bishop N Satyamurthy G Bida and J RBarrio ldquoRegioselective radiofluorodestannylation with [18F]F

2

and [18F]CH3COOF a high yield synthesis of 6-[18F]fluoro-L-

dopardquo Applied Radiation and Isotopes vol 43 no 8 pp 989ndash996 1992

[48] F Dolle S Demphel F Hinnen D Fournier F Vaufrey and CCrouzel ldquo6-[18F]fluoro-L-DOPA by radiofluorodestannylationa short and simple synthesis of a new labelling precursorrdquoJournal of Labelled Compounds and Radiopharmaceuticals vol41 no 2 pp 105ndash114 1998

[49] F Fuchtner P Angelberger H Kvaternik F HammerschmidtB P Simovc and J Steinbach ldquoAspects of 6-[18F]fluoro-L-DOPA preparation precursor synthesis preparative HPLCpurification and determination of radiochemical purityrdquoNuclear Medicine and Biology vol 29 no 4 pp 477ndash481 2002

[50] F Fuchtner and J Steinbach ldquoEfficient synthesis of the 18F-labelled 3-O-methyl-6-[18F]fluoro-L-DOPArdquo Applied Radia-tion and Isotopes vol 58 no 5 pp 575ndash578 2003

[51] CWChangH EWangHM Lin C S Chtsai J B Chen andR-S Liu ldquoRobotic synthesis of 6-[18F]fluoro-L-dopardquo NuclearMedicine Communications vol 21 no 9 pp 799ndash802 2000

[52] M J Adam J Lu and S Jivan ldquoStereoselective synthesis of 3-O-methyl-6-[18F]fluorodopa via fluorodestannylationrdquo Journalof Labelled Compounds and Radiopharmaceuticals vol 34 no6 pp 565ndash570 1994

[53] E F J de Vries G Luurtsema M Brussermann P H Elsingaand W Vaalburg ldquoFully automated synthesis module forthe high yield one-pot preparation of 6-[18F]fluoro-L-DOPArdquoApplied Radiation and Isotopes vol 51 no 4 pp 389ndash394 1999

[54] A Luxen M Guillaume W P Melega V W Pike O Solinand R Wagner ldquoProduction of 6-[18F]fluoro-L-DOPA and itsmetabolism in vivo a critical reviewrdquo Nuclear Medicine andBiology vol 19 no 2 pp 149ndash158 1992

[55] E Hess G Blessing H H Coenen and S M Qaim ldquoImprovedtarget system for production of high purity [18F]fluorine via the18O(pn)18F reactionrdquo Applied Radiation and Isotopes vol 52no 6 pp 1431ndash1440 2000

[56] F Fuchtner S Preusche P Mading J Zessin and J SteinbachldquoFactors affecting the specific activity of [18F]fluoride from a[18O]water targetrdquo Nuklearmedizin vol 47 no 3 pp 116ndash1192008

[57] K P Koopmans A H Brouwers M N De Hooge et al ldquoCar-cinoid crisis after injection of 6-18F- fluorodihydroxyphenylala-nine in a patient with metastatic carcinoidrdquo Journal of NuclearMedicine vol 46 no 7 pp 1240ndash1243 2005

[58] T Tierling K Hamacher and H H Coenen ldquoA new nucle-ophilic asymmetric synthesis of 6-[18F]fluoro-dopardquo Journal ofLabelled Compounds and Radiopharmaceuticals vol 44 sup-plement pp S146ndashS147 2001

[59] 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

[60] F M Wagner Zur Synthese radiofluorierter aromatischerAminosauren mittels Isotopenaustausch am Beispiel von 6-[18F]Fluor-L-DOPA rdquo [PhD thesis] Forschungszentrum JulichUniversitat zu Koln 2007

[61] R Martin D Baumgart S Hubner et al ldquoAutomated nucle-ophilic one-pot synthesis of 18F-L-DOPA with high specificactivity using the GE TRACERlabMXFDGrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 56 supplementS126 2013

[62] A Al-Labadi K-P Zeller and H-J Machulla ldquoSynthesis of6-[18F]fluoroveratraldehyde by nucleophilic halogen exchangeat electron-rich precursorsrdquo Journal of Radioanalytical andNuclear Chemistry vol 270 no 2 pp 313ndash318 2006

[63] Y-S Ding C-Y Shiue J S Fowler A P Wolf and APlenevaux ldquoNo-carrier-added (NCA) aryl [18F]fluorides via thenucleophilic aromatic substitution of electron-rich aromaticringsrdquo Journal of Fluorine Chemistry vol 48 no 2 pp 189ndash2061990

[64] C Lemaire M Guillaume R Cantineau and L ChristiaensldquoNo-carrier-added regioselective preparation of 6-[18F]fluoro-L-dopardquo Journal of NuclearMedicine vol 31 no 7 pp 1247ndash12511990

[65] C Lemaire M Guillaume R Cantineau A Plenevaux and LChristiaens ldquoAn approach to the asymmetric synthesis of L-6-[18F]fluorodopa via NCA nucleophilic fluorinationrdquo AppliedRadiation and Isotopes vol 42 no 7 pp 629ndash635 1991

[66] C Lemaire P Damhaut A Plenevaux and D ComarldquoEnantioselective synthesis of 6-[fluorine-18]-fluoro-L-dopafrom no-carrier-added fluorine-18-fluoriderdquo Journal of NuclearMedicine vol 35 no 12 pp 1996ndash2002 1994

[67] C Lemaire A Plenevaux RCantineau L ChristiaensMGuil-laume and D Comar ldquoNucleophilic enantioselective synthesisof 6-[18F]fluoro-L-dopa via two chiral auxiliariesrdquo AppliedRadiation and Isotopes vol 44 no 4 pp 737ndash744 1993

[68] G N Reddy M Haeberli H-F Beer and A P Schubiger ldquoAnimproved synthesis of no-carrier-added (NCA) 6-[18F]fluoro-L-DOPA and its remote routine production for PET investiga-tions of dopaminergic systemsrdquoApplied Radiation and Isotopesvol 44 no 4 pp 645ndash649 1993


[69] A Horti D E Redmond Jr and R Soufer ldquoNo-carrier-added(NCA) synthesis of 6-[18F]fluoro-L-DOPA using 356788a-hexahydro-778a-trimethyl-[6S-(6120572 8120572 8120572120573)]-68-methano-2H-14-benzoxazin-2-onerdquo Journal of Labelled Compounds andRadiopharmaceuticals vol 36 no 5 pp 409ndash423 1995

[70] A Najafi ldquoMeasures and pitfalls for successful preparation ofldquono carrier addedrdquo asymmetric 6-[18F]fluor-L-dopa from 18F-fluoride ionrdquo Nuclear Medicine and Biology vol 22 no 3 pp395ndash397 1995

[71] E J Corey F Xu and M C Noe ldquoA rational approach tocatalytic enantioselective enolate alkylation using a structurallyrigidified and defined chiral quaternary ammonium salt underphase transfer conditionsrdquo Journal of the American ChemicalSociety vol 119 no 50 pp 12414ndash12415 1997

[72] C Lemaire S Guillouet A Plenevaux C Brihaye J Aerts andA Luxen ldquoThe synthesis of 6-[18F]fluoro-L-dopa by chiral cat-alytic phase-transfer alkylationrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 42 supplement 1 pp S113ndashS1151999

[73] S Guillouet C Lemaire G Bonmarchand L Zimmer andD le Bars ldquoLarge scale production of 6-[18F]fluoro-L-DOPAin a semi-automated systemrdquo Journal of Labelled Compoundsand Radiopharmaceuticals vol 44 supplement pp S868ndashS8702001

[74] L Zhang G Tang D Yin X Tang and Y Wang ldquoEnantios-elective synthesis of no-carrier-added (NCA) 6-[18F]fluoro-L-DOPArdquo Applied Radiation and Isotopes vol 57 no 2 pp 145ndash151 2002

[75] D Yin L Zhang G Tang X Tang and Y Wang ldquoEnantios-elective synthesis of no-carrier added (NCA) 6-[18F]Fluoro-L-Dopardquo Journal of Radioanalytical and Nuclear Chemistry vol257 no 1 pp 179ndash185 2003

[76] ldquoFluorodopa (18F) (prepared by electrophilic substitution)injectionrdquo European Pharmacopoeia vol 6 pp 990ndash992 2008

[77] S Kaneko K Ishiwata K Hatano H Omura K Ito and MSenda ldquoEnzymatic synthesis of no-carrier-added 6-[18F]fluoro-L-dopa with 120573- tyrosinaserdquo Applied Radiation and Isotopes vol50 no 6 pp 1025ndash1032 1999

[78] C Lemaire S Gillet S Guillouet A Plenevaux J Aerts and ALuxen ldquoHighly enantioselective synthesis of no-carrier-added6-[18F]fluoro-L-dopa by chiral phase-transfer alkylationrdquo Euro-pean Journal of Organic Chemistry no 13 pp 2899ndash2904 2004

[79] C Lemaire L Libert A Plenevaux J Aerts X Franci andA Luxen ldquoFast and reliable method for the preparation ofortho- and para-[18F]fluorobenzyl halide derivatives key inter-mediates for the preparation of no-carrier-added PET aromaticradiopharmaceuticalsrdquo Journal of Fluorine Chemistry vol 138pp 48ndash55 2012

[80] R N Krasikova V V Zaitsev S M Ametamey et al ldquoCatalyticenantioselective synthesis of 18F-fluorinated 120572-amino acidsunder phase-transfer conditions using (S)-NOBINrdquo NuclearMedicine and Biology vol 31 no 5 pp 597ndash603 2004

[81] Y N Belokon K A Kochetkov T D Churkina et al ldquoHighlyefficient catalytic synthesis of alpha-amino acids under phase-transfer conditions with a novel catalystsubstrate pairrdquo Ange-wandte Chemie International Edition vol 40 pp 1948ndash19512001

[82] M Smrcina J Polakova S Vyskocil and P Kocovsky ldquoSynthe-sis of enantiomerically pure binaphthyl derivatives Mechanismof the enantioselective oxidative coupling of naphthols anddesigning a catalytic cyclerdquo Journal of Organic Chemistry vol58 no 17 pp 4534ndash4538 1993

[83] B Shen W Ehrlichmann M Uebele H-J Machulla andG Reischl ldquoAutomated synthesis of nca [18F]FDOPA vianucleophilic aromatic substitution with [18F]fluoriderdquo AppliedRadiation and Isotopes vol 67 no 9 pp 1650ndash1653 2009

[84] B Shen D Loffler G Reischl H-J Machulla and K-P ZellerldquoNucleophilic [18F]Fluorination and subsequent decarbony-lation of methoxy-substituted nitro- and halogen-benzenesactivated by one or two formyl groupsrdquo Journal of LabelledCompounds and Radiopharmaceuticals vol 53 no 3 pp 113ndash119 2010

[85] B Shen D Loffler K-P Zeller M Ubele G Reischl and H-J Machulla ldquoEffect of aldehyde and methoxy substituents onnucleophilic aromatic substitution by [18F]fluoriderdquo Journal ofFluorine Chemistry vol 128 no 12 pp 1461ndash1468 2007

[86] L C Libert X Franci A R Plenevaux et al ldquoProduction at theCurie level of no-carrier-added 6-18F-fluoro-L-dopardquo Journal ofNuclear Medicine vol 54 no 7 pp 1154ndash1161 2013

[87] S-S Jew and H-G Park ldquoCinchona-based phase-transfercatalysts for asymmetric synthesisrdquo Chemical Communicationsno 46 pp 7090ndash7103 2009

[88] S ForsbackO EskolaMHaaparanta J Bergman andO SolinldquoElectrophilic synthesis of 6-[18F]fluoro-L-DOPA using post-target produced [18F]F2rdquo Radiochimica Acta vol 96 no 12 pp845ndash848 2008

[89] S Forsback O Eskola J Bergman M Haaparanta and OSolin ldquoAlternative solvents for electrophilic synthesis of 6-[18F] fluoro-L-DOPArdquo Journal of Labelled Compounds andRadiopharmaceuticals vol 52 no 7 pp 286ndash288 2009

[90] 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

[91] I S R Stenhagen A K Kirjavainen S J Forsback et al ldquoFluo-rination of an arylboronic ester using [18F]selectfluor bis(tri-flate) application to 6-[18F]fluoro-l-DOPArdquo Chemical Commu-nications vol 49 no 14 pp 1386ndash1388 2013

[92] R Chirakal G Firnau and E S Garnett ldquoHigh yield synthesisof 6-[18F]fluoro-L-dopardquo Journal of Nuclear Medicine vol 27no 3 pp 417ndash421 1986

[93] K Ishiwata S Ishii M Senda Y Tsuchiya and K TomimotoldquoElectrophilic synthesis of 6-[18F]fluoro-L-DOPA use of 4-O-pivaloyl-L-DOPA as a suitable precursor for routine produc-tionrdquoApplied Radiation and Isotopes vol 44 no 4 pp 755ndash7591993

[94] T Chaly J R Dahl R Matacchieri et al ldquoSynthesis of 6-[18F]fluorodopaminewith a synthetic unitmade up of primarilysterile disposable components and operated by a master slavemanipulatorrdquo Applied Radiation and Isotopes vol 44 no 5 pp869ndash873 1993

[95] F Fuchtner J Zessin P Mading and F Wust ldquoAspects of 6-[18F]fluoro-L-DOPA preparationrdquo Nuklearmedizin vol 47 pp62ndash64 2008

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



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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


NHOH

OH

OH

OHOH

NO

O

S

OO

O

O

O

O

HO

HO

HO

HO

HO18F

18F

18F18F

[ ]FDG

NH2NH2

NH2

[ ]FET[ ]FLT

[ ]F-DOPA [11C]CH3-MET

H311C

18F18F

18F

18F

Figure 1 Selected radiotracers applicable in (brain-)tumor imaging

as [11C]methyl-l-methionine ([11C]CH3-MET) [11ndash13]

31015840-deoxy-31015840-l-[18F]fluorothymidine ([18F]FLT) [14 15] or[18F]fluoroethyl-l-tyrosine ([18F]FET) [16ndash19] (Figure 1)which also exhibit the advantage to show a low physiologicalaccumulation in normal cerebral tissue and inflamed lesionscompared to [18F]FDG thus giving more favorable resultsin brain tumor imaging Among these tracers used forneurooncologic imaging [18F]F-DOPA shows a high uptakein the malignant tissues thus allowing a very sensitive tumordetection via PET imaging

Beyond glioma imaging recent studies have also shownthe increasing importance of [18F]F-DOPA for the visual-ization of various peripheral tumor entities via PET [20]which can be attributed to the upregulation of amino acidtransporters in malignant tissues due to an often increasedproliferation [21 22] [18F]F-DOPA which is transportedvia the dopamine transporter (DAT) into cells has thusshown diagnostic advantages in the imaging of high- andlow-grade malignancies like neuroendocrine tumors [23ndash27] pheochromocytoma [28 29] and pancreatic adenocarci-noma [30ndash32] regarding diagnostic efficiency and sensitivity[18F]FDG on the contrary is taken up by the glucose trans-porter not only by malignant tissues but also by inflamedand healthy tissues exhibiting a high glucose metabolismresulting in low tumor-to-background ratios [10] in CNSmalignanciesThe proliferationmarker [18F]FLTwhich accu-mulates in malignant tissues due to an enhanced activity ofTK1 however often shows relatively low tumor uptakes [15]favoring [18F]F-DOPA for the PET imaging of malignancies

Due to its increasing importance for human tumor imag-ing the synthesis of [18F]F-DOPAbecomes a criticalmeasureregarding its dissemination in clinical routine Ideally theradiotracer should be easily accessible in high radiochemicalyields (RCYs) and specific activities (SAs) as well as in shortsynthesis times by an automated process Furthermore asit was demonstrated that d-amino acids lack a permeabilitythrough the blood-brain barrier an enantioselective synthe-sis for [18F]F-DOPA is mandatory [33]

The following review outlines the developments inthe field of [18F]F-DOPA radiosyntheses via electrophilic

synthesis routes and themore recent synthesis improvementsvia nucleophilic syntheses The main focus of this work isto compare the radiochemical yields (RCYs) radiochemicalpurities (RCPs) enantiomeric excess (ee) synthesis timesreliability and a potential for automation of the differentradiosynthesis pathways

2 Synthesis Routes for the Production of[18F]F-DOPA

21 First Attempts to Synthesize [18F]F-DOPA One of the firstfluorine-18-labeled DOPA derivatives was 5-[18F]F-DOPA[18F]4 synthesized via isotopic exchange by Firnau et alin 1973 [34] (Figure 2) In a swimming pool reactor 6Li(1198994He)3H and 16O(3H 119899)18F nuclear reactions were utilized toproduce fluorine-18 in a mixture of Li

2CO3in H2SO4and

H2O The resulting [18F]fluoride was subsequently distilled

twice and the diazonium fluoroborate precursor 1 was addedto this solution After the isotopic exchange reaction hasoccurred the water was removed and the residue was driedover P

2O5 The dried residue [18F]2 was redissolved in

dioxane filtered and heated to 80∘C After adding xylene thesolution was further heated to 132∘C for the pyrolysis of thediazonium[18F]fluoroborate [18F]2 for 30min After solventevaporation HBr (48) was added to hydrolyze [18F]3 to thefinal product 5-[18F]F-DOPA

The resulting product [18F]4 was obtained in high radio-chemical purities of gt95 but very low specific activitiesbetween 22 and 22 kBq120583mol (02ndash20 120583Cimg) Further-more the enantiomeric purity of the product was notdetermined limiting the applicability of this cumbersomesynthesis route

A significant limitation for the use of 5-[18F]F-DOPA forin vivo imaging purposes is the accelerated O-methylationof 5-[18F]F-DOPA in contrast to 6-[18F]F-DOPA ([18F]7Figure 3) This increased O-methylation rate is caused by thefluorine atom in position 5 in direct vicinity to the hydroxylgroup in position 4 [35] and results in a significantly lowerin vivo stability of 5-[18F]F-DOPA ([18F]4 Figure 2) Thesame group presented the reaction of [18F]F

2and l-DOPA


O

O

O O

O OO

O

O

O O

O O

OO

OOO

O

OO OH

NH

HO

HO

NH

NH

N2BF41

[18F]fluoride

N2BF318F

H2O (pH 4)

18F18F


NH2-HBr HBr (48)H2g


(1) 30min 50∘C(2) P2O5 15min [18F

18F

]2

[ ]3[18F]4


(A)

(B)

(C)

8 [18F]9

10 [18F]11

O

O

OO

O

OO

O

O

OO

O

O

O

OO

OO

O

OO

OO

O

O

N N

Si

Sn

R R

5a R=H5a R=NO2

[18F]F2

CCl4 Freon-11

18F

18F

18F

18F


HBr 48)


HN

HN

HN

H

HO

HO

OH

N

CF3 CF3

HgOCOCF3

[18F]AcOFAcOH

5min rt

HI(55)

10min 130∘C

NH2

[18F]F-DOPA([18F]7)

BocO

BocO BocO

BocO

[18F]F2

CDCl3

5min 5∘C

HCI 6M)


(

(










O

O

F O

O

O

O

O

O

O

O

OO

O

O

NN

NN

NN

OH OH OH OHOH

OH

12

TBA[18F]FDMF

8min 110∘C

18F18F18F

mCPBACHCl3

20min 60∘C

HBr (48)

30min 150∘C

[18F]13 [18F]14 [18F]7

NH2





2from


2




















O

O

O

O

O

OO

O

O

15 16 17NO2NO2 N

SO3CF3



N

NO

Br

18











O

O

O

O

O

O

O

O

O

NO2

HO

HOHO

HO

OH


RhCl[P(C6H5)3]3

dioxane

20min 145∘C 20min 150∘C

[18F]1915 [18F]20

[18F]21[18F]7

18F

18F

18F

18F

NH2

HI (57)20min reflux


5min 45∘C







4and subsequently








O

O

O

O

O

O

O

O O

O

O

O

OO

OO

O

O

O N

N

N

N

Ni

NiOH

OH

H

H

H

OH

HO

HO

NO2

K[18F]FK222

18F 18F 18F

18F

18F

K2CO3DMSO

5min 180∘C

NaBH4

2min rt

Ph3PBr2

5min rt

Br

[18F]22

[18F]7

[18F]23

[18F]27

[18F]2416

26

25NH2

NH2

HI (57)









K[18F]FK222

K2CO3DMF

10min 140∘C

O

O

HO

HO

O OO

O

O I

O

ON

OO

O

O

OH

NO2

NH2

[18F]7 [18F]29

[18F]1915 [18F]28

18F 18F

18F 18F

Diiodosilanein situ

10min rt

10min 150∘C

HBr (48) KI


CH2Cl2CsOH

10min rt


O

O

HO

HO

OO

O

OO

O O

O

OON N

N

N

Br

OO

O

O

OH

OH


10min 140∘C

15min 180∘C

[18F]19

31

17 [18F]30 [18F]28

[18F]29[18F]7

18F 18F 18F

18F18F

2min rt2min rt

HI (57)

HI (57)NaBH4 I

NH2


SO3CF3





2) inside the


3 CD2Cl2 and C

3D6O





6was added [18F]F-




O2N

O2S

N

N

N

2

2

NI

O O

OO

N

Ni

32

33O

O

OTf

OBocOBoc

OBocOBoc


lt1min 23∘C

18F

[18F]34



4 Conclusion


2and





Acknowledgment


References





















































2

























































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Disease Markers



OncologyJournal of





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Journal of

ObesityJournal of

















O

O

O O

O OO

O

O

O O

O O

OO

OOO

O

OO OH

NH

HO

HO

NH

NH

N2BF41

[18F]fluoride

N2BF318F

H2O (pH 4)

18F18F


NH2-HBr HBr (48)H2g


(1) 30min 50∘C(2) P2O5 15min [18F

18F

]2

[ ]3[18F]4


(A)

(B)

(C)

8 [18F]9

10 [18F]11

O

O

OO

O

OO

O

O

OO

O

O

O

OO

OO

O

OO

OO

O

O

N N

Si

Sn

R R

5a R=H5a R=NO2

[18F]F2

CCl4 Freon-11

18F

18F

18F

18F


HBr 48)


HN

HN

HN

H

HO

HO

OH

N

CF3 CF3

HgOCOCF3

[18F]AcOFAcOH

5min rt

HI(55)

10min 130∘C

NH2

[18F]F-DOPA([18F]7)

BocO

BocO BocO

BocO

[18F]F2

CDCl3

5min 5∘C

HCI 6M)


(

(










O

O

F O

O

O

O

O

O

O

O

OO

O

O

NN

NN

NN

OH OH OH OHOH

OH

12

TBA[18F]FDMF

8min 110∘C

18F18F18F

mCPBACHCl3

20min 60∘C

HBr (48)

30min 150∘C

[18F]13 [18F]14 [18F]7

NH2





2from


2




















O

O

O

O

O

OO

O

O

15 16 17NO2NO2 N

SO3CF3



N

NO

Br

18











O

O

O

O

O

O

O

O

O

NO2

HO

HOHO

HO

OH


RhCl[P(C6H5)3]3

dioxane

20min 145∘C 20min 150∘C

[18F]1915 [18F]20

[18F]21[18F]7

18F

18F

18F

18F

NH2

HI (57)20min reflux


5min 45∘C







4and subsequently








O

O

O

O

O

O

O

O O

O

O

O

OO

OO

O

O

O N

N

N

N

Ni

NiOH

OH

H

H

H

OH

HO

HO

NO2

K[18F]FK222

18F 18F 18F

18F

18F

K2CO3DMSO

5min 180∘C

NaBH4

2min rt

Ph3PBr2

5min rt

Br

[18F]22

[18F]7

[18F]23

[18F]27

[18F]2416

26

25NH2

NH2

HI (57)









K[18F]FK222

K2CO3DMF

10min 140∘C

O

O

HO

HO

O OO

O

O I

O

ON

OO

O

O

OH

NO2

NH2

[18F]7 [18F]29

[18F]1915 [18F]28

18F 18F

18F 18F

Diiodosilanein situ

10min rt

10min 150∘C

HBr (48) KI


CH2Cl2CsOH

10min rt


O

O

HO

HO

OO

O

OO

O O

O

OON N

N

N

Br

OO

O

O

OH

OH


10min 140∘C

15min 180∘C

[18F]19

31

17 [18F]30 [18F]28

[18F]29[18F]7

18F 18F 18F

18F18F

2min rt2min rt

HI (57)

HI (57)NaBH4 I

NH2


SO3CF3





2) inside the


3 CD2Cl2 and C

3D6O





6was added [18F]F-




O2N

O2S

N

N

N

2

2

NI

O O

OO

N

Ni

32

33O

O

OTf

OBocOBoc

OBocOBoc


lt1min 23∘C

18F

[18F]34



4 Conclusion


2and





Acknowledgment


References





















































2

























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















O

O

F O

O

O

O

O

O

O

O

OO

O

O

NN

NN

NN

OH OH OH OHOH

OH

12

TBA[18F]FDMF

8min 110∘C

18F18F18F

mCPBACHCl3

20min 60∘C

HBr (48)

30min 150∘C

[18F]13 [18F]14 [18F]7

NH2





2from


2




















O

O

O

O

O

OO

O

O

15 16 17NO2NO2 N

SO3CF3



N

NO

Br

18











O

O

O

O

O

O

O

O

O

NO2

HO

HOHO

HO

OH


RhCl[P(C6H5)3]3

dioxane

20min 145∘C 20min 150∘C

[18F]1915 [18F]20

[18F]21[18F]7

18F

18F

18F

18F

NH2

HI (57)20min reflux


5min 45∘C







4and subsequently








O

O

O

O

O

O

O

O O

O

O

O

OO

OO

O

O

O N

N

N

N

Ni

NiOH

OH

H

H

H

OH

HO

HO

NO2

K[18F]FK222

18F 18F 18F

18F

18F

K2CO3DMSO

5min 180∘C

NaBH4

2min rt

Ph3PBr2

5min rt

Br

[18F]22

[18F]7

[18F]23

[18F]27

[18F]2416

26

25NH2

NH2

HI (57)









K[18F]FK222

K2CO3DMF

10min 140∘C

O

O

HO

HO

O OO

O

O I

O

ON

OO

O

O

OH

NO2

NH2

[18F]7 [18F]29

[18F]1915 [18F]28

18F 18F

18F 18F

Diiodosilanein situ

10min rt

10min 150∘C

HBr (48) KI


CH2Cl2CsOH

10min rt


O

O

HO

HO

OO

O

OO

O O

O

OON N

N

N

Br

OO

O

O

OH

OH


10min 140∘C

15min 180∘C

[18F]19

31

17 [18F]30 [18F]28

[18F]29[18F]7

18F 18F 18F

18F18F

2min rt2min rt

HI (57)

HI (57)NaBH4 I

NH2


SO3CF3





2) inside the


3 CD2Cl2 and C

3D6O





6was added [18F]F-




O2N

O2S

N

N

N

2

2

NI

O O

OO

N

Ni

32

33O

O

OTf

OBocOBoc

OBocOBoc


lt1min 23∘C

18F

[18F]34



4 Conclusion


2and





Acknowledgment


References





















































2

























































of






Disease Markers



OncologyJournal of





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Journal of

ObesityJournal of



























O

O

O

O

O

OO

O

O

15 16 17NO2NO2 N

SO3CF3



N

NO

Br

18











O

O

O

O

O

O

O

O

O

NO2

HO

HOHO

HO

OH


RhCl[P(C6H5)3]3

dioxane

20min 145∘C 20min 150∘C

[18F]1915 [18F]20

[18F]21[18F]7

18F

18F

18F

18F

NH2

HI (57)20min reflux


5min 45∘C







4and subsequently








O

O

O

O

O

O

O

O O

O

O

O

OO

OO

O

O

O N

N

N

N

Ni

NiOH

OH

H

H

H

OH

HO

HO

NO2

K[18F]FK222

18F 18F 18F

18F

18F

K2CO3DMSO

5min 180∘C

NaBH4

2min rt

Ph3PBr2

5min rt

Br

[18F]22

[18F]7

[18F]23

[18F]27

[18F]2416

26

25NH2

NH2

HI (57)









K[18F]FK222

K2CO3DMF

10min 140∘C

O

O

HO

HO

O OO

O

O I

O

ON

OO

O

O

OH

NO2

NH2

[18F]7 [18F]29

[18F]1915 [18F]28

18F 18F

18F 18F

Diiodosilanein situ

10min rt

10min 150∘C

HBr (48) KI


CH2Cl2CsOH

10min rt


O

O

HO

HO

OO

O

OO

O O

O

OON N

N

N

Br

OO

O

O

OH

OH


10min 140∘C

15min 180∘C

[18F]19

31

17 [18F]30 [18F]28

[18F]29[18F]7

18F 18F 18F

18F18F

2min rt2min rt

HI (57)

HI (57)NaBH4 I

NH2


SO3CF3





2) inside the


3 CD2Cl2 and C

3D6O





6was added [18F]F-




O2N

O2S

N

N

N

2

2

NI

O O

OO

N

Ni

32

33O

O

OTf

OBocOBoc

OBocOBoc


lt1min 23∘C

18F

[18F]34



4 Conclusion


2and





Acknowledgment


References





















































2

























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















O

O

O

O

O

O

O

O

O

NO2

HO

HOHO

HO

OH


RhCl[P(C6H5)3]3

dioxane

20min 145∘C 20min 150∘C

[18F]1915 [18F]20

[18F]21[18F]7

18F

18F

18F

18F

NH2

HI (57)20min reflux


5min 45∘C







4and subsequently








O

O

O

O

O

O

O

O O

O

O

O

OO

OO

O

O

O N

N

N

N

Ni

NiOH

OH

H

H

H

OH

HO

HO

NO2

K[18F]FK222

18F 18F 18F

18F

18F

K2CO3DMSO

5min 180∘C

NaBH4

2min rt

Ph3PBr2

5min rt

Br

[18F]22

[18F]7

[18F]23

[18F]27

[18F]2416

26

25NH2

NH2

HI (57)









K[18F]FK222

K2CO3DMF

10min 140∘C

O

O

HO

HO

O OO

O

O I

O

ON

OO

O

O

OH

NO2

NH2

[18F]7 [18F]29

[18F]1915 [18F]28

18F 18F

18F 18F

Diiodosilanein situ

10min rt

10min 150∘C

HBr (48) KI


CH2Cl2CsOH

10min rt


O

O

HO

HO

OO

O

OO

O O

O

OON N

N

N

Br

OO

O

O

OH

OH


10min 140∘C

15min 180∘C

[18F]19

31

17 [18F]30 [18F]28

[18F]29[18F]7

18F 18F 18F

18F18F

2min rt2min rt

HI (57)

HI (57)NaBH4 I

NH2


SO3CF3





2) inside the


3 CD2Cl2 and C

3D6O





6was added [18F]F-




O2N

O2S

N

N

N

2

2

NI

O O

OO

N

Ni

32

33O

O

OTf

OBocOBoc

OBocOBoc


lt1min 23∘C

18F

[18F]34



4 Conclusion


2and





Acknowledgment


References





















































2

























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















O

O

O

O

O

O

O

O O

O

O

O

OO

OO

O

O

O N

N

N

N

Ni

NiOH

OH

H

H

H

OH

HO

HO

NO2

K[18F]FK222

18F 18F 18F

18F

18F

K2CO3DMSO

5min 180∘C

NaBH4

2min rt

Ph3PBr2

5min rt

Br

[18F]22

[18F]7

[18F]23

[18F]27

[18F]2416

26

25NH2

NH2

HI (57)









K[18F]FK222

K2CO3DMF

10min 140∘C

O

O

HO

HO

O OO

O

O I

O

ON

OO

O

O

OH

NO2

NH2

[18F]7 [18F]29

[18F]1915 [18F]28

18F 18F

18F 18F

Diiodosilanein situ

10min rt

10min 150∘C

HBr (48) KI


CH2Cl2CsOH

10min rt


O

O

HO

HO

OO

O

OO

O O

O

OON N

N

N

Br

OO

O

O

OH

OH


10min 140∘C

15min 180∘C

[18F]19

31

17 [18F]30 [18F]28

[18F]29[18F]7

18F 18F 18F

18F18F

2min rt2min rt

HI (57)

HI (57)NaBH4 I

NH2


SO3CF3





2) inside the


3 CD2Cl2 and C

3D6O





6was added [18F]F-




O2N

O2S

N

N

N

2

2

NI

O O

OO

N

Ni

32

33O

O

OTf

OBocOBoc

OBocOBoc


lt1min 23∘C

18F

[18F]34



4 Conclusion


2and





Acknowledgment


References





















































2

























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















K[18F]FK222

K2CO3DMF

10min 140∘C

O

O

HO

HO

O OO

O

O I

O

ON

OO

O

O

OH

NO2

NH2

[18F]7 [18F]29

[18F]1915 [18F]28

18F 18F

18F 18F

Diiodosilanein situ

10min rt

10min 150∘C

HBr (48) KI


CH2Cl2CsOH

10min rt


O

O

HO

HO

OO

O

OO

O O

O

OON N

N

N

Br

OO

O

O

OH

OH


10min 140∘C

15min 180∘C

[18F]19

31

17 [18F]30 [18F]28

[18F]29[18F]7

18F 18F 18F

18F18F

2min rt2min rt

HI (57)

HI (57)NaBH4 I

NH2


SO3CF3





2) inside the


3 CD2Cl2 and C

3D6O





6was added [18F]F-




O2N

O2S

N

N

N

2

2

NI

O O

OO

N

Ni

32

33O

O

OTf

OBocOBoc

OBocOBoc


lt1min 23∘C

18F

[18F]34



4 Conclusion


2and





Acknowledgment


References





















































2

























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















O2N

O2S

N

N

N

2

2

NI

O O

OO

N

Ni

32

33O

O

OTf

OBocOBoc

OBocOBoc


lt1min 23∘C

18F

[18F]34



4 Conclusion


2and





Acknowledgment


References





















































2

























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























































2

























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















6-[ 18 f]fluoro-l-dopa: a well-established neurotracer with...

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