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Facile 18F labeling of non-activated arenes via a spirocyclic iodonium(III) ylide method and its application in the synthesis of the mGluR5 PET radiopharmaceutical [18F]FPEB

Abstract

Non-activated (electron-rich and/or sterically hindered) arenes are prevalent chemical scaffolds in pharmaceuticals and positron emission tomography (PET) diagnostics. Despite substantial efforts to develop a general method to introduce 18F into these moieties for molecular imaging by PET, there is an urgent and unmet need for novel radiofluorination strategies that result in sufficiently labeled tracers to enable human imaging. Herein, we describe an efficient method that relies on spirocyclic iodonium ylide (SCIDY) precursors for one-step and regioselective radiofluorination, as well as proof-of-concept translation to the radiosynthesis of a clinically useful PET tracer, 3-[18F]fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ([18F]FPEB). The protocol begins with the preparation of a SCIDY precursor for FPEB, followed by radiosynthesis of [18F]FPEB, by either manual operation or an automated synthesis module. [18F]FPEB can be obtained in quantities >7.4 GBq (200 mCi), ready for injection (20 ± 5%, non–decay corrected), and has excellent chemical and radiochemical purity (>98%) as well as high molar activity (666 ± 51.8 GBq/μmol; 18 ± 1.4 Ci/μmol). The total time for the synthesis and purification of the corresponding labeling SCIDY precursor is 10 h. The subsequent radionuclide production, experimental setup, 18F labeling, and formulation of a product that is ready for injection require 2 h.

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Fig. 1
Fig. 2: Preparation of SCIDY precursor (16) and radiosynthesis of [18F]FPEB (10).
Fig. 3: Schematic of the GE TRACERlab FXFN radiosynthesis module automated synthesis manifold for [18F]FPEB.
Fig. 4: Semi-preparative HPLC traces of a typical radiosynthesis of [18F]FPEB.
Fig. 5: Analytical radioactive (top) and UV (bottom) HPLC traces for [18F]FPEB.

References

  1. Ametamey, S. M., Honer, M. & Schubiger, P. A. Molecular imaging with PET. Chem. Rev. 108, 1501–1516 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Miller, P. W., Long, N. J., Vilar, R. & Gee, A. D. Synthesis of 11C, 18F, 15O, and 13N radiolabels for positron emission tomography. Angew. Chem. Int. Ed. Engl. 47, 8998–9033 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Phelps, M. E. Positron emission tomography provides molecular imaging of biological processes. Proc. Natl. Acad. Sci. USA 97, 9226–9233 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Brooks, A. F., Topczewski, J. J., Ichiishi, N., Sanford, M. S. & Scott, P. J. Late-stage [18F]fluorination: new solutions to old problems. Chem. Sci. 5, 4545–4553 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cole, E. L., Stewart, M. N., Littich, R., Hoareau, R. & Scott, P. J. Radiosyntheses using fluorine-18: the art and science of late stage fluorination. Curr. Top. Med. Chem. 14, 875–900 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Campbell, M. G. & Ritter, T. Modern carbon-fluorine bond forming reactions for aryl fluoride synthesis. Chem. Rev. 115, 612–633 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Liang, S. H. & Vasdev, N. Total radiosynthesis: thinking outside “the box”. Aust. J. Chem. 68, 1319–1328 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Preshlock, S., Tredwell, M. & Gouverneur, V. 18F-labeling of arenes and heteroarenes for applications in positron emission tomography. Chem. Rev. 116, 719–766 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Di Raddo, P., Diksic, M. & Jolly, D. The 18F radiofluorination of arylsilanes. J. Chem. Soc. Chem. Commun. 1984, 159–160 (1984).

    Article  Google Scholar 

  10. Chirakal, R., Coates, G., Firnau, G., Schrobilgen, G. J. & Nahmias, C. Direct radiofluorination of dopamine: 18F-labeled 6-fluorodopamine for imaging cardiac sympathetic innervation in humans using positron emission tomography. Nucl. Med. Biol. 23, 41–45 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Firnau, G., Chirakal, R. & Garnett, E. S. Aromatic radiofluorination with [18F]fluorine gas: 6-[18F]fluoro-l-dopa. J. Nucl. Med. 25, 1228–1233 (1984).

    CAS  PubMed  Google Scholar 

  12. Balz, G. & Schiemann, G. Über aromatische Fluorverbindungen, I.: Ein neues Verfahren zu ihrer Darstellung. Eur. J. Inorg. Chem. 60, 1186–1190 (1927).

    Google Scholar 

  13. Wallach, O. Ueber das verhalten einiger diazo und diazoamidoverbindungen. Eur. J. Org. Chem. 235, 233–255 (1886).

    Google Scholar 

  14. Linjing, M. et al. 18F‐radiolabeling of aromatic compounds using triarylsulfonium salts. Eur. J. Org. Chem. 2012, 889–892 (2012).

    Article  Google Scholar 

  15. Sander, K. et al. Sulfonium salts as leaving groups for aromatic labelling of drug-like small molecules with fluorine-18. Sci. Rep. 5, 9941 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chun, J. H., Morse, C. L., Chin, F. T. & Pike, V. W. No-carrier-added [18F]fluoroarenes from the radiofluorination of diaryl sulfoxides. Chem. Commun. 49, 2151–2153 (2013).

    Article  CAS  Google Scholar 

  17. Wagner, F. M., Ermert, J. & Coenen, H. H. Three-step, “one-pot” radiosynthesis of 6-fluoro-3,4-dihydroxy-l-phenylalanine by isotopic exchange. J. Nucl. Med. 50, 1724–1729 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Gao, Z. et al. Metal-free oxidative fluorination of phenols with [18F]fluoride. Angew. Chem. Int. Ed. Engl. 51, 6733–6737 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Neumann, C. N., Hooker, J. M. & Ritter, T. Corrigendum: Concerted nucleophilic aromatic substitution with 19Fand 18F. Nature 538, 274 (2016).

    Article  CAS  PubMed  Google Scholar 

  20. Lee, E. et al. A fluoride-derived electrophilic late-stage fluorination reagent for PET imaging. Science 334, 639–642 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lee, E., Hooker, J. M. & Ritter, T. Nickel-mediated oxidative fluorination for PET with aqueous [18F] fluoride. J Am Chem Soc 134, 17456–17458 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hoover, A. J. et al. A transmetalation reaction enables the synthesis of [18F]5-fluorouracil from [18F]fluoride for human PET imaging. Organometallics 35, 1008–1014 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Beyzavi, M. H. et al. 18F-deoxyfluorination of phenols via ru pi-complexes. ACS Cent. Sci. 3, 944–948 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tredwell, M. et al. A general copper-mediated nucleophilic 18F fluorination of arenes. Angew. Chem. Int. Ed. Engl. 53, 7751–7755 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Ichiishi, N. et al. Copper-catalyzed [18F]fluorination of (mesityl)(aryl)iodonium salts. Org. Lett. 16, 3224–3227 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pike, V. W. & Aigbirhio, F. I. 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, 2215–2216 (1995).

    Article  Google Scholar 

  27. Ross, T. L., Ermert, J., Hocke, C. & Coenen, H. H. Nucleophilic 18F-fluorination of heteroaromatic iodonium salts with no-carrier-added [18F]fluoride. J. Am. Chem. Soc. 129, 8018–8025 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Hu, B. et al. A practical, automated synthesis of meta-[18F]fluorobenzylguanidine for clinical use. ACS Chem. Neurosci. 6, 1870–1879 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Qin, L. et al. A mild and general one-pot synthesis of densely functionalized diaryliodonium salts. Eur. J. Org. Chem. 2015, 5919–5924 (2015).

    Article  CAS  Google Scholar 

  30. Haskali, M. B. et al. An investigation of (diacetoxyiodo)arenes as precursors for preparing no-carrier-added [18F]fluoroarenes from cyclotron-produced [18F]fluoride ion. J. Org. Chem. 81, 297–302 (2016).

    Article  CAS  PubMed  Google Scholar 

  31. Neumann, K. D. et al. Efficient automated syntheses of high specific activity 6-[18F]fluorodopamine using a diaryliodonium salt precursor. J. Labelled Comp. Radiopharm. 59, 30–34 (2016).

    Article  CAS  PubMed  Google Scholar 

  32. Chun, J. H., Lu, S., Lee, Y. S. & Pike, V. W. Fast and high-yield microreactor syntheses of ortho-substituted [18F]fluoroarenes from reactions of [18F]fluoride ion with diaryliodonium salts. J. Org. Chem. 75, 3332–3338 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Moon, B. S. et al. Facile aromatic radiofluorination of [18F]flumazenil from diaryliodonium salts with evaluation of their stability and selectivity. Org. Biomol. Chem. 9, 8346–8355 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Kuik, W. J. 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. 56, 106–112 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Wang, B., Cerny, R. L., Uppaluri, S., Kempinger, J. J. & Dimagno, S. G. Fluoride-promoted ligand exchange in diaryliodonium salts. J. Fluor. Chem. 131, 1113–1121 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rotstein, B. H., Stephenson, N. A., Vasdev, N. & Liang, S. H. Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non-activated and hindered aromatics. Nat. Commun. 5, 4365 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Rotstein, B. H. et al. Mechanistic studies and radiofluorination of structurally diverse pharmaceuticals with spirocyclic iodonium(III) ylides. Chem. Sci. 7, 4407–4417 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cardinale, J., Ermert, J., Humpert, S. & Coenen, H. H. 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. 4, 17293–17299 (2014).

    Article  CAS  Google Scholar 

  39. Kugler, F., Ermert, J., Kaufholz, P. & Coenen, H. H. 4-[18F]Fluorophenylpiperazines by improved Hartwig–Buchwald N-arylation of 4-[18F]fluoroiodobenzene, formed via hypervalent lambda3-iodane precursors: application to build-up of the dopamine D4 ligand [18F]FAUC 316. Molecules 20, 470–486 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Nymann, P. I., Langgaard, K. J. & Manfred, H. M. Nucleophilic 18F‐labeling of spirocyclic iodonium ylide or boronic pinacol ester precursors: advantages and disadvantages. Eur. J. Org. Chem. 2017, 453–458 (2017).

    Article  Google Scholar 

  41. Jacobson, O. et al. 18F-labeled single-stranded DNA aptamer for PET imaging of protein tyrosine kinase-7 expression. J. Nucl. Med. 56, 1780–1785 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang, L. et al. Ortho-stabilized 18F-azido click agents and their application in PET imaging with single-stranded DNA aptamers. Angew. Chem. Int. Ed. Engl. 54, 12777–12781 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cai, Z. et al. Fluorine-18-labeled antagonist for PET imaging of kappa opioid receptors. ACS Chem. Neurosci. 8, 12–16 (2017).

    Article  CAS  PubMed  Google Scholar 

  44. Wang, L. et al. A facile radiolabeling of [18F]FDPA via spirocyclic iodonium ylides: preliminary PET imaging studies in preclinical models of neuroinflammation. J. Med. Chem. 60, 5222–5227 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Collier, T. L. et al. Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib. Nat. Commun. 8, 15761 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Stephenson, N. A. et al. Iodonium ylide-mediated radiofluorination of 18F-FPEB and validation for human use. J. Nucl. Med. 56, 489–492 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Murray, R. W. & Singh, M. Synthesis of epoxides using dimethyldioxirane: trans-stilbene oxide. Org. Syn. 74, 91–97 (1997).

    Article  CAS  Google Scholar 

  48. Ye, C., Twamley, B. & Shreeve, J. M. Straightforward syntheses of hypervalent iodine(III) reagents mediated by Selectfluor. Org. Lett. 7, 3961–3964 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Linlin, Q. et al. A mild and general one‐pot synthesis of densely functionalized diaryliodonium salts. Eur. J. Org. Chem. 2015, 5919–5924 (2015).

    Article  Google Scholar 

  50. Niswender, C. M. & Conn, P. J. Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu. Rev. Pharmacol. Toxicol. 50, 295–322 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hamill, T. G. et al. Synthesis, characterization, and first successful monkey imaging studies of metabotropic glutamate receptor subtype 5 (mGluR5) PET radiotracers. Synapse 56, 205–216 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Wang, J. Q., Tueckmantel, W., Zhu, A., Pellegrino, D. & Brownell, A. L. Synthesis and preliminary biological evaluation of 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile as a PET radiotracer for imaging metabotropic glutamate receptor subtype 5. Synapse 61, 951–961 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Lim, K., Labaree, D., Li, S. & Huang, Y. Preparation of the metabotropic glutamate receptor 5 (mGluR5) PET tracer [18F]FPEB for human use: an automated radiosynthesis and a novel one-pot synthesis of its radiolabeling precursor. Appl. Radiat. Isot. 94, 349–354 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Liang, S. H. et al. Microfluidic continuous-flow radiosynthesis of [18F]FPEB suitable for human PET imaging. Medchemcomm 5, 432–435 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. Mossine, A. V. et al. Synthesis of [18F]arenes via the copper-mediated [18F]fluorination of boronic acids. Org. Lett. 17, 5780–5783 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Preshlock, S. et al. Enhanced copper-mediated 18F-fluorination of aryl boronic esters provides eight radiotracers for PET applications. Chem. Commun. 52, 8361–8364 (2016).

    Article  CAS  Google Scholar 

  57. Makaravage, K. J., Brooks, A. F., Mossine, A. V., Sanford, M. S. & Scott, P. J. Copper-mediated radiofluorination of arylstannanes with [18F]KF. Org. Lett. 18, 5440–5443 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Alagille, D. et al. Potent mGluR5 antagonists: pyridyl and thiazolyl-ethynyl-3,5-disubstituted-phenyl series. Bioorg. Med. Chem. Lett. 21, 3243–3247 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Schlyer, D. J., Firouzbakht, M. L. & Wolf, A. P. Impurities in the [18O]water target and their effect on the yield of an aromatic displacement reaction with [18F]fluoride. Appl. Radiat. Isot. 44, 1459–1465 (1993).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank X. Zhang and Z. Chen for technical support and members of the staff in the radiochemistry and radiopharmaceutical development program at MGH for helpful discussions.

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S.H.L., L.W., N.A.S., and B.H.R. performed the experimental work. S.H.L. and N.V. oversaw the radiopharmaceutical production. All authors wrote the manuscript.

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Correspondence to Steven H. Liang.

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Key references using this protocol

Rotstein, B.H., Stephenson, N.A., Vasdev, N. & Liang, S.H. Nat. Commun. 5, 4365 (2014): https://www.nature.com/articles/ncomms5365

Rotstein, B.H. et al. Chem. Sci. 7, 4407–4417 (2016): https://pubs.rsc.org/en/content/articlelanding/2016/sc/c6sc00197a#!divAbstract

Stephenson, N.A. et al. J. Nucl. Med. 56, 489–492 (2015): http://jnm.snmjournals.org/content/56/3/489.long

Wang, L. et al. J. Med. Chem. 60, 5222–5227 (2017): https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00432

Key data used in this protocol

Rotstein, B.H., Stephenson, N.A., Vasdev, N. & Liang, S.H. Nat. Commun. 5, 4365 (2014): https://www.nature.com/articles/ncomms5365

Stephenson, N.A. et al. J. Nucl. Med. 56, 489–492 (2015): http://jnm.snmjournals.org/content/56/3/489.long

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Liang, S.H., Wang, L., Stephenson, N.A. et al. Facile 18F labeling of non-activated arenes via a spirocyclic iodonium(III) ylide method and its application in the synthesis of the mGluR5 PET radiopharmaceutical [18F]FPEB. Nat Protoc 14, 1530–1545 (2019). https://doi.org/10.1038/s41596-019-0149-3

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