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Novel electrophilic synthesis of 6-[18F]fluorodopamine and comprehensive biological evaluation

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

6-[18F]Fluorodopamine (4-(2-aminoethyl)-5-[18F]fluorobenzene-1,2-diol, 6-[18F]FDA) is a tracer for imaging sympathetically innervated tissues. Previous electrophilic labelling methods produced 6-[18F]FDA with low specific radioactivity (SA) which has limited its wider use. Our aim was to employ electrophilic labelling and increase the SA to around 15 GBq/μmol. We also sought to determine an extensive biodistribution pattern for 6-[18F]FDA in rats in order to thoroughly identify tissues with dense sympathetic innervation that were specifically labelled with 6-[18F]FDA. In addition, to investigate the safety profile of 6-[18F]FDA in larger animals, we performed in vivo studies in pigs.

Methods

6-[18F]FDA was synthesised using high SA electrophilic [18F]F2 as the labelling reagent. Biodistribution and metabolism of 6-[18F]FDA was determined ex vivo in rats, and in vivo studies were done in pigs.

Results

6-[18F]FDA was synthesised with 2.6 ± 1.1% radiochemical yield. The total amount of purified 6-[18F]FDA was 663 ± 291 MBq at the end of synthesis (EOS). SA, decay corrected to EOS, was 13.2 ± 2.7 GBq/μmol. Radiochemical purity exceeded 99.0%. Specific uptake of 6-[18F]FDA was demonstrated in heart, lung, pancreas, adrenal gland, lower large intestine (LLI), eye, thyroid gland, spleen and stomach tissue. 6-[18F]FDA in rat plasma declined rapidly, with a half-life of 2 min, indicating fast metabolism. In vivo PET studies in pigs confirmed the tracer could be used safely without pharmacological effects.

Conclusion

6-[18F]FDA was synthesised with good radiopharmaceutical quality and yields high enough for several human PET studies. The SA of 6-[18F]FDA was improved by 50- to 500-fold compared to previous electrophilic methods. Uptake of 6-[18F]FDA was specific in various peripheral organs, indicating that 6-[18F]FDA PET can be used to investigate sympathoneural functions beyond cardiac studies when higher specific uptake is achieved.

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References

  1. Raffel DM, Wieland DM. Assessment of cardiac sympathetic nerve integrity with positron emission tomography. Nucl Med Biol 2001;28:541–59.

    Article  PubMed  CAS  Google Scholar 

  2. Langer O, Halldin C. PET and SPET tracers for mapping the cardiac nervous system. Eur J Nucl Med Mol Imaging 2002;29:416–34.

    Article  PubMed  CAS  Google Scholar 

  3. Eisenhofer G, Hovevey-Sion D, Kopin IJ, Miletich R, Kirk KL, Finn R, et al. Neuronal uptake and metabolism of 2- and 6-fluorodopamine: false neurotransmitters for positron emission tomographic imaging of sympathetically innervated tissues. J Pharmacol Exp Ther 1989;248:419–27.

    PubMed  CAS  Google Scholar 

  4. Kirk KL. Photochemistry of diazonium salts. Synthesis of ring-fluorinated tyramines and dopamines. J Org Chem 1976;41:2373–6.

    Article  PubMed  CAS  Google Scholar 

  5. Goldberg LI, Kohli JD, Cantacuzene D, Kirk KI, Creveling CR. Effects of ring fluorination on the cardiovascular actions of dopamine and norepinephrine in the dog. J Pharmacol Exp Ther 1980;213:509–13.

    PubMed  CAS  Google Scholar 

  6. Goldstein DS, Chang PC, Eisenhofer G, Miletich R, Finn R, Bacher J, et al. Positron emission tomographic imaging of cardiac sympathetic innervation and function. Circulation 1990;81:1606–21.

    Article  PubMed  CAS  Google Scholar 

  7. Rufini V, Calcagni ML, Baum RP. Imaging of neuroendocrine tumors. Semin Nucl Med 2006;36:228–47.

    Article  PubMed  Google Scholar 

  8. Ilias I, Yu J, Carrasquillo JA, Chen CC, Eisenhofer G, Whatley M, et al. Superiority of 6-[18F]-fluorodopamine positron emission tomography versus [131I]-metaiodobenzylguanidine scintigraphy in the localization of metastatic pheochromocytoma. J Clin Endocrinol Metab 2003;88:4083–7.

    Article  PubMed  CAS  Google Scholar 

  9. Ilias I, Chen CC, Carrasquillo JA, Whatley M, Ling A, Lazúrova I, et al. Comparison of 6-18F-fluorodopamine PET with 123I-metaiodobenzylguanidine and 111In-pentetreotide scintigraphy in localization of nonmetastatic and metastatic pheochromocytoma. J Nucl Med 2008;49:1613–9.

    Article  PubMed  Google Scholar 

  10. Goldstein DS, Grossman E, Tamrat M, Chang PC, Eisenhofer G, Bacher J, et al. Positron emission imaging of cardiac sympathetic innervation and function using 18F-6-fluorodopamine: effects of chemical sympathectomy by 6-hydroxydopamine. J Hypertens 1991;9:417–23.

    Article  PubMed  CAS  Google Scholar 

  11. Goldstein DS, Eisenhofer G, Dunn BB, Armando I, Lenders J, Grossman E, et al. Positron emission tomographic imaging of cardiac sympathetic innervation using 6-[18F]fluorodopamine: initial findings in humans. J Am Coll Cardiol 1993;22:1961–71.

    Article  PubMed  CAS  Google Scholar 

  12. Goldstein DS, Holmes C, Cannon RO, Eisenhofer G, Kopin IJ. Sympathetic cardiomyopathy in dysautonomias. N Engl J Med 1997;336:696–702.

    Article  PubMed  CAS  Google Scholar 

  13. Goldstein DS, Holmes C, Stuhlmuller JE, Lenders JWM, Kopin IJ. 6-[18F]fluorodopamine positron emission tomography scanning in the assessment of cardiac sympathoneural function—studies in normal humans. Clin Auton Res 1997;7:17–29.

    Article  PubMed  CAS  Google Scholar 

  14. Chiueh CC, Zukowska-Grojec Z, Kirk KL, Kopin IJ. 6-Fluorocathecolamines as false adrenergic neurotransmitters. J Pharmacol Exp Ther 1983;225:529–33.

    PubMed  CAS  Google Scholar 

  15. Ding Y-S, Fowler JS, Gatley SJ, Dewey SL, Wolf AP, Schlyer DJ. Synthesis of high specific activity 6-[18F]fluorodopamine for positron emission tomography studies of sympathetic nervous tissue. J Med Chem 1991;34:861–3.

    Article  PubMed  CAS  Google Scholar 

  16. Chirakal R, Coates G, Firnau G, Schrobilgen GJ, Nahmias C. Direct radiofluorination of dopamine: 18F-labeled 6-fluorodopamine for imaging cardiac sympathetic innervation in humans using positron emission tomography. Nucl Med Biol 1996;23:41–5.

    Article  PubMed  CAS  Google Scholar 

  17. Chaly T, Dahl R, Matacchieri R, Bandyopadhyay D, Belakhlef A, Dhawan V, et al. Synthesis of 6-[18F]fluorodopamine with a synthetic unit made up of primarily sterile disposable components and operated by a master slave manipulator. Appl Radiat Isot 1993;44:869–73.

    Article  CAS  Google Scholar 

  18. Namavari M, Satyamurthy N, Barrio JR. Synthesis of 6-[18F]fluorodopamine, 6-[18F]fluoro-m-tyramine and 4-[18F]fluoro-m-tyramine. J Labelled Comp Radiopharm 1995;36:825–33.

    Article  CAS  Google Scholar 

  19. Dunn B, Channing MA, Adams HR, Goldstein DS, Kirk KL, Kiesewetter DO. A single column, rapid quality control procedure for 6-[18F]-fluoro-L-dopa and 6-[18F]fluorodopamine PET imaging agents. Int J Rad Appl Instrum B 1991;18:209–13.

    Article  PubMed  CAS  Google Scholar 

  20. Bergman J, Solin O. Fluorine-18-labeled fluorine gas for synthesis of tracer molecules. Nucl Med Biol 1997;24:677–83.

    Article  PubMed  CAS  Google Scholar 

  21. Lasne M-C, Perrio C, Rouden J, Barré L, Roeda D, Dolle F, et al. Chemistry of β+-emitting compounds based on fluorine-18. Top Curr Chem 2002;222:201–58.

    Article  CAS  Google Scholar 

  22. Goldstein DS, Coronado L, Kopin IJ. 6-[Fluorine-18]fluorodopamine pharmacokinetics and dosimetry in humans. J Nucl Med 1994;35:964–73.

    PubMed  CAS  Google Scholar 

  23. Chang P, Szemeredi K, Grossman E, Kopin I, Goldstein DS. Fate of tritiated 6-fluorodopamine in rats: a false neurotransmitter for positron emission tomographic imaging of sympathetic innervation and function. J Pharmacol Exp Ther 1990;255:809–17.

    PubMed  CAS  Google Scholar 

  24. Pacak K, Eisenhofer G, Goldstein DS. Functional imaging of endocrine tumors: role of positron emission tomography. Endocr Rev 2004;25:568–80.

    Article  PubMed  Google Scholar 

  25. Goldstein DS, Chang PC, Smith CB, Herscovitch P, Austin SM, Eisenhofer G, et al. Dosimetric estimates for clinical positron emission tomographic scanning after injection of [18F]-6-fluorodopamine. J Nucl Med 1991;32:102–10.

    PubMed  CAS  Google Scholar 

  26. Ding Y-S, Fowler JS, Dewey SL, Logan J, Schlyer DJ, Gatley J, et al. Comparison of high specific activity (-) and (+)-6-[18F]fluoronorepinephrine and 6-[18F]fluorodopamine in baboons: heart uptake, metabolism and the effect of desipramine. J Nucl Med 1993;34:619–29.

    PubMed  CAS  Google Scholar 

  27. Brunello N, Mendlewicz J, Kasper S, Leonard B, Montgomery S, Craig Nelson J, et al. The role of noradrenaline and selective noradrenaline reuptake inhibition in depression. Eur Neuropsychopharmacol 2002;12:461–75.

    Article  PubMed  CAS  Google Scholar 

  28. Bellinger DL, Millar BA, Perez S, Carter J, Wood C, ThyagaRajan S, et al. Sympathetic modulation of immunity: relevance to disease. Cell Immunol 2008;252:27–56.

    Article  PubMed  CAS  Google Scholar 

  29. Magee DF. Does the sympathetic nervous system regulate the exocrine pancreas? Int J Pancreatol 1989;5:109–16.

    PubMed  CAS  Google Scholar 

  30. Sundler F, Grunditz T, Håkanson R, Uddman R. Innervation of the thyroid. A study of the rat using retrograde tracing and immunocytochemistry. Acta Histochem Suppl 1989;37:191–8.

    PubMed  CAS  Google Scholar 

  31. Tsunoda M. Recent advances in methods for the analysis of catecholamines and their metabolites. Anal Bioanal Chem 2006;386:506–14.

    Article  PubMed  CAS  Google Scholar 

  32. Goldstein DS, Holmes C. Metabolic fate of the sympathoneural imaging agent 6-[18F]fluorodopamine in humans. Clin Exp Hypertens 1997;19:155–61.

    Article  PubMed  CAS  Google Scholar 

  33. Wang RF, Loc’h C, Mazière B. Determination of unchanged [18F]dopamine in human and non-human primate plasma during positron emission tomography studies: a new solid-phase extraction method comparable to radio-thin-layer chromatography analysis. J Chromatogr B Biomed Sci Appl 1997;693:265–70.

    Article  PubMed  CAS  Google Scholar 

  34. Goldstein DS, Katzper M, Linares O, Kopin IJ. Kinetic model for the fate of 6-[18F]fluorodopamine in the human heart: a novel means to examine cardiac sympathetic neuronal function. Naunyn Schmiedebergs Arch Pharmacol 2002;365:38–49.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Professor Kenneth Kirk for kindly supplying us with 2-fluorodopamine and 6-fluorodopamine free of charge for reference purposes.

Conflicts of interest

None.

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Authors and Affiliations

  1. Turku PET Centre, University of Turku, Radiopharmaceutical Chemistry Laboratory, Kiinamyllynkatu 4-8, 20520, Turku, Finland

    Olli Eskola, Sarita Forsback, Jörgen Bergman & Olof Solin

  2. Turku PET Centre, University of Turku, Medicity/PET Preclinical Imaging, Turku, Finland

    Tove J. Grönroos, Päivi Marjamäki & Merja Haaparanta

  3. Nuclear Medicine/PET Center, Department of Radiology, Haukeland University Hospital, Bergen, Norway

    Alexandru Naum

  4. Turku PET Centre, Accelerator Laboratory, Åbo Akademi University, Turku, Finland

    Jörgen Bergman & Olof Solin

  5. Centre for Prehospital Emergency Care, Kuopio University Hospital, Kuopio, Finland

    Sami Länkimäki

  6. Department of Cardiovascular Surgery, University Medical Center Freiburg, Freiburg, Germany

    Jan Kiss

  7. Department of Surgery, Turku University Hospital, Turku, Finland

    Timo Savunen

  8. Turku PET Centre, University of Turku, Turku, Finland

    Juhani Knuuti

Authors
  1. Olli Eskola
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Correspondence to Olli Eskola.

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Eskola, O., Grönroos, T.J., Naum, A. et al. Novel electrophilic synthesis of 6-[18F]fluorodopamine and comprehensive biological evaluation. Eur J Nucl Med Mol Imaging 39, 800–810 (2012). https://doi.org/10.1007/s00259-011-2032-5

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  • DOI: https://doi.org/10.1007/s00259-011-2032-5

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