The Radiopharmaceutical Chemistry of Fluorine-18: Nucleophilic Fluorinations

  • Johannes Ermert
  • Bernd NeumaierEmail author


The positron-emitting radionuclide fluorine-18 plays a prominent role in radiopharmaceuticals for positron emission tomography (PET) due to its favourable nuclear decay properties. Depending on the production method, 18F can be obtained in two different chemical forms: electrophilic [18F]fluorine gas and nucleophilic [18F]fluoride. Nucleophilic [18F]fluoride exhibits several advantages with respect to accessibility and chemical handling. Therefore, nucleophilic 18F-substitution reactions are of pivotal importance for the production of PET radiotracers. This chapter is devoted to this class of reactions, and in the following pages, we seek to provide a general overview of 18F itself as well as insights into nucleophilic 18F-substitution reactions. More specifically, the prerequisites for this reaction with regard to solvent, leaving groups, reactants, etc. are examined. Furthermore, several examples are discussed which demonstrate the potential of this reaction to create highly clinical relevant PET tracers. Finally, this chapter also provides practical tips and tricks for those performing this reaction in the laboratory.


Fluorine-18 [18F]fluoride Positron emission tomography (PET) Nucleophilic 18F-substitution SNSNAr Radiopharmaceuticals 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) [18F]FDOPA 


  1. 1.
    Coenen HH. Fluorine-18 labeling methods: features and possibilities of basic reactions. In: Schubiger PA, Lehmann L, Friebe M, editors. PET chemistry: The driving force in molecular imaging. Ernst Schering Research Foundation Workshop 62. Berlin/Heidelberg: Springer; 2007. p. 15–50.CrossRefGoogle Scholar
  2. 2.
    Miller PW, Long NJ, Vilar R, Gee AD. Synthesis of 11C, 18F, 15O, and 13N radiolabels for positron emission tomography. Angew Chem Int Ed Engl. 2008;47(47):8998–9033.PubMedCrossRefGoogle Scholar
  3. 3.
    Bondi AJ. van der Waals volumes and radii. J Phys Chem. 1964;68(3):441–51.CrossRefGoogle Scholar
  4. 4.
    Purser S, Moore PR, Swallow S, Gouverneur V. Fluorine in medicinal chemistry. Chem Soc Rev. 2008;37:320–30.PubMedCrossRefGoogle Scholar
  5. 5.
    Qaim SM, Clark JC, Crouzel C, Guillaume M, Helmeke HJ, Nebeling B, et al. PET radionuclide production. In: Stöcklin G, Pike VW, editors. Radiopharmaceuticals for positron emission tomography – methodological aspects. Dordrecht: Springer Netherlands; 1993. p. 1–42.Google Scholar
  6. 6.
    Wadsak W, Mitterhauser M. Basics and principles of radiopharmaceuticals for PET/CT. Eur J Radiol. 2010;73(3):461–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Bergman J, Solin O. Fluorine-18-labeled fluorine gas for synthesis of tracer molecules. Nucl Med Biol. 1997;24(7):677–83.PubMedCrossRefGoogle Scholar
  8. 8.
    Devillet F, Geets J-M, Ghyoot M, Kral E, Nactergal B, Mooij R, Vosjan M. Performance of IBA new conical shaped niobium [18O]water targets. Proceedings of the 15th international workshop on targetry and target chemistry. WTTC15 August 18-21, 2014, Prague, Czech Republic. Accessed 21 May 2018.
  9. 9.
    Ermert J, Coenen HH. Nucleophilic 18F-fluorination of complex molecules in activated carbocyclic aromatic position. Curr Radiopharm. 2010;3(2):109–26.CrossRefGoogle Scholar
  10. 10.
    van der Born D, Pees A, Poot AJ, Orru RVA, Windhorst AD, Vugts DJ. Fluorine-18 labelled building blocks for PET tracer synthesis. Chem Soc Rev. 2017;46(15):4709–73.PubMedCrossRefGoogle Scholar
  11. 11.
    Lee SJ, Oh SJ, Chi DY, Moon DH, Ryu JS. High yielding [18F]fluorination method by fine control of the base. Bull Kor Chem Soc. 2012;33(7):2177–80.CrossRefGoogle Scholar
  12. 12.
    Seo JW, Lee BS, Lee SJ, Oh SJ, Chi DY. Fast and easy drying method for the preparation of activated [18F]fluoride using polymer cartridge. Bull Kor Chem Soc. 2011;32(1):71–6.CrossRefGoogle Scholar
  13. 13.
    Wessmann SH, Henriksen G, Wester HJ. Cryptate mediated nucleophilic 18F-fluorination without azeotropic drying. Nuklearmedizin. 2012;51(1):1–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Richarz R, Krapf P, Zarrad F, Urusova EA, Neumaier B, Zlatopolskiy BD. Neither azeotropic drying, nor base nor other additives: a minimalist approach to 18F-labeling. Org Biomol Chem. 2014;12(40):8094–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Lemaire CF, Aerts JJ, Voccia S, Libert LC, Mercier F, Goblet D, et al. Fast production of highly reactive no-carrier-added [18F]fluoride for the labeling of radiopharmaceuticals. Angew Chem nt Ed Engl. 2010;49(18):3161–4.Google Scholar
  16. 16.
    Hamacher K, Coenen HH, Stöcklin G. Efficient stereospecific synthesis of no-carrier-added 2-[18F]fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution. J Nucl Med. 1986;27(2):235–8.PubMedGoogle Scholar
  17. 17.
    Suehiro M, Vallabhajosula S, Goldsmith SJ, Ballon DJ. Investigation of the role of the base in the synthesis of [18F]FLT. Appl Radiat Isot. 2007;65(12):1350–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Kim DW, Ahn DS, Oh YH, Lee S, Kil HS, Oh SJ, et al. A new class of S 2 reactions catalyzed by protic solvents: facile fluorination for isotopic labeling of diagnostic molecules. J Am Chem Soc. 2006;128(50):16394–7.Google Scholar
  19. 19.
    Kim DW, Jeong LST, Sohn MH, Katzenellenbogen JA, Chi DY. Facile nucleophilic fluorination reactions using tert-alcohols as a reaction medium: significantly enhanced reactivity of alkali metal fluorides and improved selectivity. J Org Chem. 2008;73(3):957–62.PubMedCrossRefGoogle Scholar
  20. 20.
    Lee SJ, Oh SJ, Chi DY, Kang SH, Kil HS, Kim JS, Moon DH. One-step high-radiochemical-yield synthesis of [18F]FP-CIT using a protic solvent system. Nucl Med Biol. 2007;34(4):345–51.PubMedCrossRefGoogle Scholar
  21. 21.
    Chaly T, Dhawan V, Kazumata K, Antonini A, Margouleff C, Dahl JR, et al. Radiosynthesis of [18F] N-3-fluoropropyl-2-β-carbomethoxy-3-β-(4-iodophenyl) nortropane and the first human study with positron emission tomography. Nucl Med Biol. 1996;23(8):999–1004.PubMedCrossRefGoogle Scholar
  22. 22.
    Marchand P, Ouadi A, Pellicioli M, Schuler J, Laquerriere P, Boisson F, Brasse D. Automated and efficient radiosynthesis of [18F]FLT using a low amount of precursor. Nucl Med Biol. 2016;43(8):520–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Lemaire C, Cantineau R, Guillaume M, Plenevaux A, Christiaens L. Fluorine-18-altanserin: a radioligand for the study of serotonin receptors with PET: radiolabeling and in vivo biologic behavior in rats. J Nucl Med. 1991;32(12):2266–72.PubMedGoogle Scholar
  24. 24.
    Pretze M, Wängler C, Wängler B. 6-[18F]fluoro-L-DOPA: a well-established neurotracer with expanding application spectrum and strongly improved radiosyntheses. Biomed Res Int. 2014;2014:674063.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Lemaire C, Guillaume M, Cantineau R, Christiaens L. No-carrier-added regioselective preparation of 6-[18F]fluoro-L-dopa. J Nucl Med. 1990;31(7):1247–51.Google Scholar
  26. 26.
    Lemaire C, Gillet S, Guillouet S, Plenevaux A, Aerts J, Luxen A. Highly enantioselective synthesis of no-carrier-added 6-[18F]fluoro-L-dopa by chiral phase-transfer alkylation. Eur J Org Chem. 2004;2004(13):2899–904.CrossRefGoogle Scholar
  27. 27.
    Libert LC, Franci X, Plenevaux AR, Ooi T, Maruoka K, Luxen AJ, Lemaire CF. Production at the curie level of no-carrier-added 6-18F-fluoro-L-dopa. J Nucl Med. 2013;54(7):1154–61.PubMedCrossRefGoogle Scholar
  28. 28.
    Wagner FM, Ermert J, Coenen HH. Three-step, “one-pot” radiosynthesis of 6-fluoro-3,4-dihydroxy-L-phenylalanine by isotopic exchange. J Nucl Med. 2009;50(10):1724–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Martin R, Baumgart D, Hubner S, Juttler S, Saul S, Clausnitzer A, et al. Automated nucleophilic one-pot synthesis of 18F-L-DOPA with high specific activity using the GE TRACERlab MXFDG (abstract). J Label Compd Radiopharm. 2013;56:S126.Google Scholar
  30. 30.
    Dollé F. Fluorine-18-labelled fluoropyridines: advances in radiopharmaceutical design. Curr Pharm Des. 2005;11(25):3221–35.PubMedCrossRefGoogle Scholar
  31. 31.
    Dollé F. [18F]Fluoropyridines: From conventional radiotracers to the labeling of macromolecules such as proteins and oligonucleotides. In: Schubiger PA, Lehmann L, Friebe M, editors. PET chemistry: the driving force in molecular imaging. Ernst Schering Research Foundation Workshop 62. Berlin/Heidelberg: Springer Berlin; 2007. p. 113–57.CrossRefGoogle Scholar
  32. 32.
    Preshlock S, Tredwell M, Gouverneur V. 18F-labeling of arenes and heteroarenes for applications in positron emission tomography. Chem Rev. 2016;116(2):719–66.PubMedCrossRefGoogle Scholar
  33. 33.
    Horti A, Ravert HT, London ED, Dannals RF. Synthesis of a radiotracer for studying nicotinic acetylcholine receptors: (+/−)-exo-2-(2-[18F]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane. J Label Compd Radiopharm. 1996;38(4):355–65.CrossRefGoogle Scholar
  34. 34.
    Ding YS, Liang F, Fowler JS, Kuhar MJ, Carroll FI. Synthesis of [18F]norchlorofluoroepibatidine and its N-methyl derivative: new PET ligands for mapping nicotinic acetylcholine receptors. J Label Compd Radiopharm. 1997;39(10):827–32.CrossRefGoogle Scholar
  35. 35.
    Attiná M, Cacace F, Wolf AP. Displacement of a nitro-group by [18F]fluoride ion. A new route to aryl fluorides of high specific activity. J Chem Soc Chem Commun. 1983:108–9.Google Scholar
  36. 36.
    Haka MS, Kilbourn MR, Watkins GL, Toorongian SA. Aryltrimethylammonium trifluoromethanesulfonates as precursors to aryl [18F]fluorides: improved synthesis of [18F]GBR-13119. J Label Compd Radiopharm. 1989;27(7):823–33.CrossRefGoogle Scholar
  37. 37.
    Mu L, Fischer CR, Holland JP, Becaud J, Schubiger PA, Schibli R, et al. 18F-radiolabeling of aromatic compounds using triarylsulfonium salts. Eur J Org Chem. 2012;2012(5):889–92.CrossRefGoogle Scholar
  38. 38.
    Pike VW, Aigbirhio FI. Reactions of cyclotron-produced [18F]fluoride with diaryliodonium salts – a novel single-step route to no-carrier-added [18]fluoroarenes. J Chem Soc Chem Commun. 1995:2215–6.Google Scholar
  39. 39.
    Cardinale J, Ermert J, Humpert S, Coenen HH. Iodonium ylides for one-step, no-carrier-added radiofluorination of electron rich arenes, exemplified with 4-(([18F]fluorophenoxy)-phenylmethyl) piperidine NET and SERT ligands. RSC Adv. 2014;4:17293–9.CrossRefGoogle Scholar
  40. 40.
    Rotstein BH, Stephenson NA, Vasdev N, Liang SH. Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non-activated and hindered aromatics. Nat Commun. 2014;5:4365.PubMedCrossRefGoogle Scholar
  41. 41.
    Haskali MB, Telu S, Lee Y-S, Morse CL, Lu S, Pike VW. An investigation of (diacetoxyiodo)arenes as precursors for preparing no-carrier-added [18F]fluoroarenes from cyclotron-produced [18F]fluoride ion. J Org Chem. 2016;81(1):297–302.PubMedCrossRefGoogle Scholar
  42. 42.
    Chun J-H, Morse CL, Chin FT, Pike VW. No-carrier-added [18F]fluoroarenes from the radiofluorination of diaryl sulfoxides. Chem Commun (Camb). 2013;49(21):2151–3.CrossRefGoogle Scholar
  43. 43.
    Simeon FG, Lu S, Pike VW. Diarylselenoxides as precursors to no-carrier-added [18F]fluoroarenes (abstract). J Label Compd Radiopharm. 2015;58:S149.Google Scholar
  44. 44.
    Narayanam MK, Ma G, Champagne PA, Houk KN, Murphy JM. Synthesis of [18F]fluoroarenes by nucleophilic radiofluorination of N-arylsydnones. Angew Chem Int Ed. 2017;56(42):13006–10.CrossRefGoogle Scholar
  45. 45.
    Ross TL, Ermert J, Hocke C, Coenen HH. Nucleophilic 18F-fluorination of heteroaromatic iodonium salts with no-carrier-added [18F]fluoride. J Am Chem Soc. 2007;129(25):8018–25.PubMedCrossRefGoogle Scholar
  46. 46.
    Sander K, Gendron T, Yiannaki E, Cybulska K, Kalber TL, Lythgoe MF, Arstad E. Sulfonium salts as leaving groups for aromatic labelling of drug-like small molecules with fluorine-18. Sci Rep. 2015;5:9941.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Rotstein BH, Wang L, Liu RY, Patteson J, Kwan EE, Vasdev N, Liang SH. Mechanistic studies and radiofluorination of structurally diverse pharmaceuticals with spirocyclic iodonium(III) ylides. Chem Sci. 2016;7(7):4407–17.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Coenen HH, Ermert J. Direct nucleophilic 18F-fluorination of electron rich arenes: present limits of no-carrier-added reactions. Curr Radiopharm. 2010;3(3):163–73.CrossRefGoogle Scholar
  49. 49.
    Pike VW. Hypervalent aryliodine compounds as precursors for radiofluorination. J Label Compd Radiopharm. 2018;61(3):196–227.CrossRefGoogle Scholar
  50. 50.
    Ermert J, Hocke C, Ludwig T, Gail R, Coenen H. Comparison of pathways to the versatile synthon of no-carrier-added 1-bromo-4-[18F]fluorobenzene. J Label Compd Radiopharm. 2004;47(7):429–41.CrossRefGoogle Scholar
  51. 51.
    Wüst FR, Kniess T. Synthesis of 4-[18F]fluoroiodobenzene and its application in Sonogashira cross-coupling reactions. J Label Compd Radiopharm. 2003;46(8):699–713.CrossRefGoogle Scholar
  52. 52.
    Way JD, Wuest F. Automated radiosynthesis of no-carrier-added 4-[18F]fluoroiodobenzene: a versatile building block in 18F radiochemistry. J Label Compd Radiopharm. 2014;57(2):104–9.CrossRefGoogle Scholar
  53. 53.
    Way J, Bouvet V, Wuest F. Synthesis of 4-[18F]fluorohalobenzenes and palladium-mediated cross-coupling reactions for the synthesis of 18F-labeled radiotracers. Curr Org Chem. 2013;17(19):2138–52.CrossRefGoogle Scholar
  54. 54.
    Wüst FR, Höhne A, Metz P. Synthesis of 18F-labelled cyclooxygenase-2 (COX-2) inhibitors via Stille reaction with 4-[18F]fluoroiodobenzene as radiotracers for positron emission tomography (PET). Org Biomol Chem. 2005;3:503–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Qin L, Hu B, Neumann KD, Linstad EJ, McCauley K, Veness J, et al. A mild and general one-pot synthesis of densely functionalized diaryliodonium salts. Eur J Org Chem. 2015;2015(27):5919–24.CrossRefGoogle Scholar
  56. 56.
    Kuik WJ, Kema IP, Brouwers AH, Zijlma R, Neumann KD, Dierckx RA, et al. In vivo biodistribution of no-carrier-added 6-18F-fluoro-3, 4-dihydroxy-L-phenylalanine (18F-DOPA), produced by a new nucleophilic substitution approach, compared with carrier-added 18F-DOPA, prepared by conventional electrophilic substitution. J Nucl Med. 2015;56(1):106–12.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Institute of Neuroscience and Medicine, INM-5: Nuclear ChemistryForschungszentrum Jülich GmbHJülichGermany

Personalised recommendations