Russian Chemical Bulletin

, Volume 65, Issue 3, pp 794–800 | Cite as

A novel approach to the synthesis of [18F]flumazenil, a radioligand for PET imaging of central benzodiazepine receptors

  • M. Nasirzadeh
  • D. D. Vaulina
  • O. F. Kuznetsova
  • N. A. Gomzina
Full Articles


An express method of solid-phase extraction was proposed for the first time for isolation and purification of [18F]flumazenil, a radioligand used to quantify the density of central benzodiazepine receptors by positron emission tomography (PET). This novel approach afforded the radioligand with >97% radiochemical purity and a high chemical purity (nitromazenil content <1 μg mL–1) and considerably reduced the time of the synthesis (from 90 to 50 min). The nonoptimized decay-corrected radiochemical yield was 8%, and the specific radioactivity was >37 GBq μmol–1. The novel synthetic procedure easily can be integrated into automatic modules for the synthesis of clinically used PET radiopharmaceuticals.

Key words

central benzodiazepine receptors positron emission tomography fluorine-18 radioligand [18F]flumazenil solid-phase extraction 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    W. D. Heiss, K. Herholz, J. Nucl. Med., 2006, 47, 302.Google Scholar
  2. 2.
    S. M. Ametamey, P. A. Schubiger, Nucl. Sci. Tech., 2006, 17, 143.CrossRefGoogle Scholar
  3. 3.
    J. D. Andersson, C. Halldin, J. Labelled Compd. Radiopharm., 2013, 56, 196.CrossRefGoogle Scholar
  4. 4.
    P. H. Elsinga, Nucl. Med. Rev., 2012, 15 (Suppl. C), 13.Google Scholar
  5. 5.
    J. Y. Njiwa, K. R. Gray, N. Costes, F. Mauguiere, P. Ryvlin, A. Hammers, NeuroImage: Clin., 2015, 7, 122.CrossRefGoogle Scholar
  6. 6.
    T. Geeraerts, J. P. Coles, F. I. Aigbirhio, J. D. Pickard, D. K. Menon, T. D. Fryer, Y. T. Hong, Ann. Nucl. Med., 2011, 25, 396.CrossRefGoogle Scholar
  7. 7.
    S. M. Moerlein, J. S. Perlmutter, Eur. J. Pharmacol., 1992, 218, 109.CrossRefGoogle Scholar
  8. 8.
    P. Leveque, S. Sanabria-Bohorquez, A. Bol, A. De Volder, D. Labar, K. Van Rijckevorse, B. Gallez, Eur. J. Nucl. Med. Mol. Imaging, 2003, 30, 1630.CrossRefGoogle Scholar
  9. 9.
    Y. H. Yoon, J. M. Jeong, W. H. Kim, S. H. Hong, Y. Lee, H. S. Kil, M. C. Lee, Nucl. Med. Biol., 2003, 30, 521.CrossRefGoogle Scholar
  10. 10.
    M. Mitterhauser, W. Wadsak, L. Wabnegger, L. K. Mien, S. Tögel, O. Langer, W. Sieghart, H. Viernstein, K. Kletter, R. Dudczak, Nucl. Med. Biol., 2004, 31, 291.CrossRefGoogle Scholar
  11. 11.
    Y. S. Chang, J. M. Jeong, Y. H. Yoon, W. J. Kang, S. J. Lee, D. S. Lee, J.-K. Chung, M. C. Lee, Nucl. Med. Biol., 2005, 32, 263.CrossRefGoogle Scholar
  12. 12.
    H.-J. Park, C. H. Kim, E. S. Park, B. Park, S. R. Oh, M.-K. Oh, Ch. Park, J. D. Lee, J. Nucl. Med., 2013, 54, 1263.CrossRefGoogle Scholar
  13. 13.
    N. N. Ryzhikov, N. A. Gomzina, O. S. Fedorova, D. A. Vasilév, A. P. Kostikov, R. N. Krasikova, Radiochemistry, 2004, 46, 290.CrossRefGoogle Scholar
  14. 14.
    J. Delforge, L. Spelle, B. Bendriem, Y. Samson, M. Bottlaender, S. Papageorgiou, A. Syrota, J. Nucl. Med., 1996, 37, 5.Google Scholar
  15. 15.
    N. N. Ryzhikov, N. Seneca, R. N. Krasikova, N. A. Gomzina, E. Shchukin, O. S. Fedorova, D. A. Vassiliev, B. Gulyás, H. Hall, I. Savic, C. Halldin, Nucl. Med. Biol., 2005, 32, 109.CrossRefGoogle Scholar
  16. 16.
    G. Massaweh, E. Schirrmacher, C. La Fougere, M. Kovacevic, C. Wängler, D. Jolly, P. Gravel, A. J. Reader, A. Thiel, R. Schirrmacher, Nucl. Med. Biol., 2009, 36, 721.CrossRefGoogle Scholar
  17. 17.
    B. S. Moon, H. S. Kil, J. H. Park, J. S. Kim, J. Park, D. Y. Chi, B. C. Lee, S. E. Kim, Org. Biomol. Chem., 2011, 9, 8346.CrossRefGoogle Scholar
  18. 18.
    R. Wong, R. Iwata, H. Saiki, S. Furumoto, Y. Ishikawa, E. Ozeki, Appl. Radiat. Isot., 2012, 70, 193.CrossRefGoogle Scholar
  19. 19.
    K. S. Mandap, T. Ido, Y. Kiyono, M. Kobayashi, T. G. Lohith, T. Mori, S. Kasamatsu, T. Kudo, H. Okazawa, Y. Fujibayashi, Nucl. Med. Biol., 2009, 36, 403.CrossRefGoogle Scholar
  20. 20.
    I. Odano, C. Halldin, P. Karlsson, A. Varrone, A. J. Airaksinen, R. N. Krasikova, L. Farde, Neuroimage, 2009, 45, 891.CrossRefGoogle Scholar
  21. 21.
    S. Dedeurwaerdere, M.-K. Gregoire, L. Vivash, P. Roselt, D. Binns, C. Fookes, I. Greguric, T. Pham, C. Loc´h, A. Katsifis, R. J. Hicks, T. J. O´Brien, D. E. Myers, Eur. J. Nucl. Med. Mol. Imaging, 2009, 36, 958.CrossRefGoogle Scholar
  22. 22.
    L. Vivash, M.-K. Gregoire, V. Bouilleret, A. Berard, C. Wimberley, D. Binns, P. Roselt, A. Katsifis, D. E. Myers, R. J. Hicks, T. J. O´Brien, S. Dedeurwaerdere, PLoS One, 2014, 9, 86722.CrossRefGoogle Scholar
  23. 23.
    R. Schirrmacher, A. Kostikov, H. Massaweh, M. Kovacevic, K. Wangler, A. Thiel, in Radiopharmaceuticals for Positron Emission Tomography, Eds P. J. H. Scott, B. G. Hockley, John Wiley and Sons, New York, 2012, p. 111.Google Scholar
  24. 24.
    B. S. Moon, J. H. Park, H. J. Lee, B. C. Lee, S. E. Kim, Mol. Imaging Biol., 2014, 16, 619.CrossRefGoogle Scholar
  25. 25.
    A. Jackson, M. R. Battle, D. M. O´Shea, W.-F. Chau, A. Gaeta, S. L. Brown, A. L. Ewan, C. L. Jones, P. A. Jones, J. L. Woodcraft, D. R. Bouvet, B. B. Guilbert, W. Trigg, Nucl. Med. Biol., 2014, 41, 196.CrossRefGoogle Scholar
  26. 26.
    D. Ory, J. Van den Brane, T. de Groot, K. Serdons, M. Bex, L. Declercq, F. Cleeren, M. Ooms, K. Van Laere, A. Verbruggen, G. Bormans, J. Pharm. Biomed. Anal., 2015, 111, 209.CrossRefGoogle Scholar
  27. 27. (a)
    Gosudarstvennaya farmakopeya RF [State Pharmacopoeia of the Russian Federation], XII ed., Scientific Center for Drug Appraisal, Moscow, 2008, 704 pp. (in Russian)Google Scholar
  28. (b).
    European Pharmacopoeia 8.0, Strasbourg, France, 2008, p. 1054.Google Scholar
  29. 28.
    S. K. Chitneni, K. Serdons, N. Evens, H. Fonge, S. Celen, Ch. M. Deroose, Z. Debyser, L. Mortelmans, A. M. Verbruggen, G. M. Bormans, J. Chromatogr. A, 2008, 1189, 323.CrossRefGoogle Scholar
  30. 29.
    C. R. Mallet, J. R. Mazzeo, U. Neue, Rapid Commun. Mass Spectrom., 2001, 15, 1075.CrossRefGoogle Scholar
  31. 30.
    S. J. Lee, J. S. Hyun, S. J. Oh, K. H. Yu, J. S. Ryu, J. Labelled Compd. Radiopharm., 2013, 56, 731.CrossRefGoogle Scholar
  32. 31.
    L. Xiong, R. Wang, C. Liang, X. Teng, F. Jiang, L. Zeng, H. Ye, C. Ni, X. Yuan, Y. Rao, Y. Zhang, J. Chromatogr. A, 2015, 1395, 99.CrossRefGoogle Scholar
  33. 32.
    B. H. Mock, W. Winkle, M. T. Vawrek, Nucl. Med. Biol., 1997, 24, 193.CrossRefGoogle Scholar
  34. 33.
    Guidance for Industry Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches, U.S. Department of Health and Human Services FDA for CDER, 2008, 16 pp.Google Scholar
  35. 34.
    H. Sun, S. G. Di Magno, J. Fluorine Chem., 2007, 128, 806.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • M. Nasirzadeh
    • 1
  • D. D. Vaulina
    • 2
  • O. F. Kuznetsova
    • 2
  • N. A. Gomzina
    • 2
  1. 1.Institute of ChemistrySt. Petersburg State UniversitySt. PetersburgRussian Federation
  2. 2.N. P. Bechtereva Institute of Human BrainRussian Academy of SciencesSt. PetersburgRussian Federation

Personalised recommendations