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Review
. 2021 Sep 25;6(1):33.
doi: 10.1186/s41181-021-00143-y.

Closing the gap between 19F and 18F chemistry

Javier Ajenjo #  1 , Gianluca Destro #  1   2 , Bart Cornelissen  1 , Véronique Gouverneur  3
Affiliations
Review

Closing the gap between 19F and 18F chemistry

Javier Ajenjo et al. EJNMMI Radiopharm Chem. .

Erratum in

Abstract

Positron emission tomography (PET) has become an invaluable tool for drug discovery and diagnosis. The positron-emitting radionuclide fluorine-18 is frequently used in PET radiopharmaceuticals due to its advantageous characteristics; hence, methods streamlining access to 18F-labelled radiotracers can make a direct impact in medicine. For many years, access to 18F-labelled radiotracers was limited by the paucity of methodologies available, and the poor diversity of precursors amenable to 18F-incorporation. During the last two decades, 18F-radiochemistry has progressed at a fast pace with the appearance of numerous methodologies for late-stage 18F-incorporation onto complex molecules from a range of readily available precursors including those that do not require pre-functionalisation. Key to these advances is the inclusion of new activation modes to facilitate 18F-incorporation. Specifically, new advances in late-stage 19F-fluorination under transition metal catalysis, photoredox catalysis, and organocatalysis combined with the availability of novel 18F-labelled fluorination reagents have enabled the invention of novel processes for 18F-incorporation onto complex (bio)molecules. This review describes these major breakthroughs with a focus on methodologies for C-18F bond formation. This reinvigorated interest in 18F-radiochemistry that we have witnessed in recent years has made a direct impact on 19F-chemistry with many laboratories refocusing their efforts on the development of methods using nucleophilic fluoride instead of fluorination reagents derived from molecular fluorine gas.

Keywords: Fluoride; Fluorine; Positron emission tomography; Radiochemistry; Radiofluorination.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
A Production of [18F]F2 and fluorination reagents derived from [18F]F2. B Radiosynthesis of [18F]FDG from [18F]F2. C Radiolabelling of aminoacids and peptides with [18F]NFSI. D Radiosynthesis of [18F]FDOPA. E Radiofluorination of [PdII]-sydnone complex. MTBE = methyl tert-butyl ether. NaDT = sodium decatungstate. Bnep = boronate neopentylglycol ester. BCN = bicyclo[6.1.0]nonyne
Fig. 2
Fig. 2
Timeline for (hetero)aryl–19F/18F bond formation from [18F]fluoride. FG = functional group. R = EWG or EDG. EWG = electron-withdrawing group. EDG = electron-donating group. X = counter-anion. LG = leaving group
Fig. 3
Fig. 3
A Balz-Schiemann reaction. B Nucleophilic aromatic substitution with [18F]F−. C Microwave-assisted radiofluorination of m-substituted arene precursors. D Radiofluorination of sydnones. E Reactions of [18F]F− with diaryliodonium salts affording electron-rich aryl [18F]fluoride. F Reactions of [18F]F− with diaryliodonium salts bearing 2-thienyl group. G Radiofluorination of spirocyclic hypervalent iodine(III) precursors for non-activated and hindered arenes. EWG = electron-withdrawing group. EDG = electron-donating group. LG = leaving group
Fig. 4
Fig. 4
A Concerted nucleophilic aromatic substitution (CSNAr) of phenols with [18F]F−. B CSNAr via aryl fluorosulfonate intermediates. C Dibenzothiophene sulfoniums as leaving groups for aromatic 18F-fluorination. D Electrochemical radiofluorination. E Aryl umpolung strategy with the use of external oxidant. F Photoredox radiofluorination. EWG = electron-withdrawing group. EDG = electron-donating group. NCS = N-Chlorosuccinimide. DBTO = dibenzothiophene S-oxide. TFAA = trifluoroacetic anhydride. TfOH = triflic acid. PIDA = phenyliodine diacetate. PC = photocatalyst
Fig. 5
Fig. 5
A Csp2–F bond formation through Pd0/PdII and PdII/PdIV catalytic cycles and application to radiofluorination. B Use of Ni-complex for radiofluorination. C CuIII–F C–F reductive elimination and application to radiofluorination. D Titanium-mediated radiofluorination of aryl and alkyl tosylate derivatives. NHC = N-heterocycle carbene. EWG = electron-withdrawing group. EDG = electron-donating group
Fig. 6
Fig. 6
A [18F]FDG radiosynthesis from [18F]fluoride. B Radiosynthesis of [18F]Pyfluor. C Allylic radiofluorination. D Ring opening of epoxides by [18F]fluoride. E Groves Csp3–H radiofluorination and 18F-fluorodecarboxylation. F Radiofluorination of α-diazocarbonyl compound. G Oxidative 18F-fluorocyclization. H Photo-mediated decarboxylative radiofluorination of activated esters. I Electrochemical radiofluorination. EWG = electron-withdrawing group. EDG = electron-donating group. PhthH = N-Hydroxyphthalimide
Fig. 7
Fig. 7
A Halogen exchange strategy for [18F]CF3 construction. B Silver-mediated halogen exchange for -CF3, -OCF3, -SCF3, -CF2H, -OCF2H 18F-radiofluorination. C Radiosynthesis of [18F]TFMISO. D 18F-Functionalization of fluoroalkenes, E Radiofluorination of trifluoroacetamides. F Oxidative 18F-fluorodesulfurisation. G Radiosynthesis of [18F]EF5 from [18F]F2. H Decarboxylative radiofluorination for the synthesis of [18F]CF3. I Ar–[18F]CF3 disconnection: 18F-Trifluoromethylation of aryl iodides and aryl boronic acids. J [18F]Trifluoroethanol for cross-coupling reaction. K Manganese-mediated [18F]CF3 construction. L Radiosynthesis of the [18F]Me3SiCF3 ([18F]Ruppert-Prakash reagent. M New disconnection: Aliphatic 18F-trifluoromethylation from C–18F reductive elimination from AuIII center. EWG = electron-withdrawing group. EDG = electron-donating group
Fig. 8
Fig. 8
A Radiosynthesis of [18F]difluoromethylarenes via oxidative decarboxylation with Selectfluor bis(triflate). B Radiosynthesis of [18F]difluoromethylarenes via halogen exchange. C Two-step approach from aryl (pseudo) halides. D Two-step approach from benzyl bromides. E Two-step approach from aryl boronic acids. F New disconnection: late-stage radical 18F-difluoromethylation with Hu-type [18F]reagent. EWG = electron-withdrawing group. EDG = electron-donating group
Fig. 9
Fig. 9
A Radiosynthesis of [18F]ArOCF3, [18F]ArOCF2H, and [18F]ArSCF3 by Ag-mediated halogen exchange with [18F]fluoride. B [18F]trifluoromethylthiolation with difluorocarbene precursors and [18F]fluoride. C Radiosynthesis of [18F]ArSCF3 from aryl boronic esters. D Radiosynthesis of [18F]ArSCHF2 from aryl boronic acids. E Synthesis of N-CF3 and N-CF2H. EWG = electron-withdrawing group, EDG = electron-donating group
Fig. 10
Fig. 10
A Use of prosthetic groups for indirect radiofluorination of peptides. B Direct 18F-incorporation on modified peptides. C Ru-mediated deoxyfluorination of peptidic tyrosine. D [18F]Umemoto reagent for radiofluorination of peptidic cysteine. E C–H 18F-Trifluoromethylation of peptidic tryptophan and tyrosine with the [18F]Langlois reagent. F Radiofluorination with fluorinase enzyme. DMG = dimethylguanidine. TFA = trifluoroacetic acid. DTT = DL-dithiothreitol
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