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In-vivo imaging characteristics of two fluorinated flumazenil radiotracers in the rat

European Journal of Nuclear Medicine and Molecular Imaging volume 36, pages 958–965 (2009)Cite this article

Abstract

Purpose

[11C]Flumazenil shows promise as a clinical and research PET radiotracer to image changes in GABAA central benzodiazepine receptor (cBZR), but its widespread use has been limited by practical limitations of [11C]. This study evaluated the imaging characteristics of two fluorinated PET radiotracers in rats in vivo: [18F]fluoroflumazenil ([18F]FFMZ) and [18F]flumazenil ([18F]FMZ).

Methods

PET acquisitions were performed on a small-animal scanner following injection of [18F]FFMZ in nine rats and [18F]FMZ in eight rats. The following treatments were investigated: (1) injection of the tracer dose, (2) presaturation then injection of the tracer dose, and (3) injection of the tracer dose followed by a displacement injection. Unchanged tracer was measured in plasma and brain structures in four animals 10 and 30 min after injection, and ex-vivo autoradiography was also performed.

Results

For both [18F]FFMZ and [18F]FMZ maximal brain activity peaked rapidly, and was highest in the hippocampus (1.12±0.06 SUV, 1.24±0.10 SUV, respectively), and lowest in the pons (1.00±0.07 SUV, 1.03±0.09 SUV, respectively). By 50 min after injection, maximal uptake for [18F]FFMZ and [18F]FMZ had decreased in the hippocampus to 18±3% and 80±1% (p<0.01), respectively. The presaturation and displacement studies showed a higher nonspecific component for [18F]FFMZ than for [18F]FMZ. Metabolite studies showed that at 30 min only 10% of the signal was from [18F]FFMZ in the brain. This nonspecific binding was apparent on autoradiography. In contrast, [18F]FMZ accounted for >70% of the signal in the brain, which resulted in well-defined regional binding on autoradiography.

Conclusion

These results demonstrate that [18F]FMZ is a superior radiotracer to [18F]FFMZ for in-vivo PET imaging of the GABAA/cBZR, having slower metabolism and leading to lower concentrations of metabolites in the brain that results in a substantially better signal-to-noise ratio.

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References

  1. Haefely W. Antagonists of benzodiazepines: functional aspects. Adv Biochem Psychopharmacol 1983;38:73–93.

    PubMed  CAS  Google Scholar 

  2. Leveque P, Labar D, Gallez B. Biodistribution, binding specificity and metabolism of [18F]fluoroethylflumazenil in rodents. Nucl Med Biol 2001;28(7):809–14.

    Article  PubMed  CAS  Google Scholar 

  3. Grunder G, Siessmeier T, Lange-Asschenfeldt C, Vernaleken I, Buchholz HG, Stoeter P, et al. [18F]Fluoroethylflumazenil: a novel tracer for PET imaging of human benzodiazepine receptors. Eur J Nucl Med 2001;28(10):1463–70.

    Article  PubMed  CAS  Google Scholar 

  4. Mitterhauser M, Wadsak W, Wabnegger L, Mien L-K, Togel S, Langer O, et al. Biological evaluation of 2′-[18F]fluoroflumazenil ([18F]FFMZ), a potential GABA receptor ligand for PET. Nucl Med Biol 2004;31(2):291–5.

    Article  PubMed  CAS  Google Scholar 

  5. Chang YS, Jeong JM, Yoon YH, Kang WJ, Lee SJ, Lee DS, et al. Biological properties of 2′-[18F]fluoroflumazenil for central benzodiazepine receptor imaging. Nucl Med Biol 2005;32(3):263–8.

    Article  PubMed  CAS  Google Scholar 

  6. Ryzhikov NN, Seneca N, Krasikova RN, Gomzina NA, Shchukin E, Fedorova OS, et al. Preparation of highly specific radioactivity [18F]flumazenil and its evaluation in cynomolgus monkey by positron emission tomography. Nucl Med Biol 2005;32(2):109–16.

    Article  PubMed  CAS  Google Scholar 

  7. Yoon YH, Jeong JM, Kim HW, Hong SH, Lee YS, Kil HS, et al. Novel one-pot one-step synthesis of 2′-[(18)F]fluoroflumazenil (FFMZ) for benzodiazepine receptor imaging. Nucl Med Biol 2003;30(5):521–7.

    Article  PubMed  CAS  Google Scholar 

  8. Huisman MC, Reder S, Weber AW, Ziegler SI, Schwaiger M. Performance evaluation of the Philips MOSAIC small animal PET scanner. Eur J Nucl Med Mol Imaging 2007;34(4):532–40.

    Article  PubMed  Google Scholar 

  9. Mandema JW, Gubbens-Stibbe JM, Danhof M. Stability and pharmacokinetics of flumazenil in the rat. Psychopharmacology (Berl) 1991;103(3):384–7.

    Article  CAS  Google Scholar 

  10. Hilton J, Yokoi F, Dannals RF, Ravert HT, Szabo Z, Wong DF. Column-switching HPLC for the analysis of plasma in PET imaging studies. Nucl Med Biol 2000;27(6):627–30.

    Article  PubMed  CAS  Google Scholar 

  11. Halldin C, Stone-Elander S, Thorell J-O, Persson A, Sedvall G. 11C-Labelling of Ro 15-1788 in two different positions, and also 11C-labelling of its main metabolite Ro 15-3890, for PET studies of benzodiazepine receptors. Appl Radiat Isot 1988;39(9):993–7.

    Article  CAS  Google Scholar 

  12. Zoghbi SS, Shetty HU, Ichise M, Fujita M, Imaizumi M, Liow JS, et al. PET imaging of the dopamine transporter with 18F-FECNT: a polar radiometabolite confounds brain radioligand measurements. J Nucl Med 2006;47(3):520–7.

    PubMed  CAS  Google Scholar 

  13. Tewson TJ, Welch MJ. Preparation and preliminary biodistribution of “no carrier added” fluorine-18 fluoroethanol. J Nucl Med 1980;21(6):559–64.

    PubMed  CAS  Google Scholar 

  14. Kleingeist B, Bocker R, Geisslinger G, Brugger R. Isolation and pharmacological characterization of microsomal human liver flumazenil carboxylesterase. J Pharm Pharm Sci 1998;1(1):38–46.

    PubMed  CAS  Google Scholar 

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Acknowledgments

We want to thank Filomena Mattner, Thomas Bourdier, Tim Jackson, Paula Berghofer, Paul Callaghan, Patrice Ballantyne, Gita Rahardjo and Paul Pellegrini for their assistance during the metabolite study and QC analysis. This work was supported by the CRC for Biomedical Imaging Development, which is supported by a grant from the Australian Government.

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Authors and Affiliations

  1. Department of Medicine (RMH), University of Melbourne, Royal Parade, Parkville, 3050, VIC, Australia

    Stefanie Dedeurwaerdere, Lucy Vivash, Terence J. O’Brien & Damian E. Myers

  2. Radiopharmaceuticals Research Institute, ANSTO, Sydney, Australia

    Stefanie Dedeurwaerdere, Marie-Claude Gregoire, Christopher Fookes, Ivan Greguric, Tien Pham, Christian Loc’h & Andrew Katsifis

  3. Centre for Molecular Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia

    Peter Roselt, David Binns & Rodney J. Hicks

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  1. Stefanie Dedeurwaerdere
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  2. Marie-Claude Gregoire
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  3. Lucy Vivash
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  4. Peter Roselt
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  7. Ivan Greguric
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  8. Tien Pham
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  9. Christian Loc’h
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  12. Terence J. O’Brien
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  13. Damian E. Myers
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Correspondence to Terence J. O’Brien.

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Dedeurwaerdere, S., Gregoire, MC., Vivash, L. et al. In-vivo imaging characteristics of two fluorinated flumazenil radiotracers in the rat. Eur J Nucl Med Mol Imaging 36, 958–965 (2009). https://doi.org/10.1007/s00259-009-1066-4

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  • DOI: https://doi.org/10.1007/s00259-009-1066-4

Keywords

  • Radioligand
  • Flumazenil
  • PET
  • Rat
  • GABAA/cBZ receptor