Skip to main content
Top
Published in: European Journal of Nuclear Medicine and Molecular Imaging 4/2009

01-04-2009 | Original Article

Kinetic modelling of [11C]flumazenil using data-driven methods

Authors: Isabelle Miederer, Sibylle I. Ziegler, Christoph Liedtke, Mary E. Spilker, Matthias Miederer, Till Sprenger, Klaus J. Wagner, Alexander Drzezga, Henning Boecker

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 4/2009

Login to get access

Abstract

Purpose

[11C]Flumazenil (FMZ) is a benzodiazepine receptor antagonist that binds reversibly to central-type gamma-aminobutyric acid (GABA-A) sites. A validated approach for analysis of [11C]FMZ is the invasive one-tissue (1T) compartmental model. However, it would be advantageous to analyse FMZ binding with whole-brain pixel-based methods that do not require a-priori hypotheses regarding preselected regions. Therefore, in this study we compared invasive and noninvasive data-driven methods (Logan graphical analysis, LGA; multilinear reference tissue model, MRTM2; spectral analysis, SA; basis pursuit denoising, BPD) with the 1T model.

Methods

We focused on two aspects: (1) replacing the arterial input function analyses with a reference tissue method using the pons as the reference tissue, and (2) shortening the scan protocol from 90 min to 60 min. Dynamic PET scans were conducted in seven healthy volunteers with arterial blood sampling. Distribution volume ratios (DVRs) were selected as the common outcome measure.

Results

The SA, LGA with and without arterial input, and MRTM2 agreed best with the 1T model DVR values. The invasive and noninvasive BPD were slightly less well correlated. The full protocol of a 90-min emission data performed better than the 60-min protocol, but the 60-min protocol still delivered useful data, as assessed by the coefficient of variation, and the correlation and bias analyses.

Conclusion

This study showed that the SA, LGA and MRTM2 are valid methods for the quantification of benzodiazepine receptor binding with [11C]FMZ using an invasive or noninvasive protocol, and therefore have the potential to reduce the invasiveness of the procedure.
Literature
1.
go back to reference Koeppe RA, Holthoff VA, Frey KA, Kilbourn MR, Kuhl DE. Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography. J Cereb Blood Flow Metab 1991;11:735–44.PubMed Koeppe RA, Holthoff VA, Frey KA, Kilbourn MR, Kuhl DE. Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography. J Cereb Blood Flow Metab 1991;11:735–44.PubMed
2.
go back to reference Holthoff VA, Koeppe RA, Frey KA, Paradise AH, Kuhl DE. Differentiation of radioligand delivery and binding in the brain: validation of a two-compartment model for [11C]flumazenil. J Cereb Blood Flow Metab 1991;11:745–52.PubMed Holthoff VA, Koeppe RA, Frey KA, Paradise AH, Kuhl DE. Differentiation of radioligand delivery and binding in the brain: validation of a two-compartment model for [11C]flumazenil. J Cereb Blood Flow Metab 1991;11:745–52.PubMed
3.
go back to reference Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, et al. Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 1990;10:740–7.PubMed Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, et al. Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 1990;10:740–7.PubMed
4.
go back to reference Cunningham VJ, Jones T. Spectral analysis of dynamic PET studies. J Cereb Blood Flow Metab 1993;13:15–23.PubMed Cunningham VJ, Jones T. Spectral analysis of dynamic PET studies. J Cereb Blood Flow Metab 1993;13:15–23.PubMed
5.
go back to reference Ihara M, Tomimoto H, Ishizu K, Mukai T, Yoshida H, Sawamoto N, et al. Decrease in cortical benzodiazepine receptors in symptomatic patients with leukoaraiosis: a positron emission tomography study. Stroke 2004;35:942–7.PubMedCrossRef Ihara M, Tomimoto H, Ishizu K, Mukai T, Yoshida H, Sawamoto N, et al. Decrease in cortical benzodiazepine receptors in symptomatic patients with leukoaraiosis: a positron emission tomography study. Stroke 2004;35:942–7.PubMedCrossRef
6.
go back to reference Koepp MJ, Labbe C, Richardson MP, Brooks DJ, Van Paesschen W, Cunningham VJ, et al. Regional hippocampal [11C]flumazenil PET in temporal lobe epilepsy with unilateral and bilateral hippocampal sclerosis. Brain 1997;120(Pt 10):1865–76.PubMedCrossRef Koepp MJ, Labbe C, Richardson MP, Brooks DJ, Van Paesschen W, Cunningham VJ, et al. Regional hippocampal [11C]flumazenil PET in temporal lobe epilepsy with unilateral and bilateral hippocampal sclerosis. Brain 1997;120(Pt 10):1865–76.PubMedCrossRef
7.
go back to reference Hammers A, Koepp MJ, Richardson MP, Labbé C, Brooks DJ, Cunningham VJ, et al. Central benzodiazepine receptors in malformations of cortical development: a quantitative study. Brain 2001;124:1555–65.PubMedCrossRef Hammers A, Koepp MJ, Richardson MP, Labbé C, Brooks DJ, Cunningham VJ, et al. Central benzodiazepine receptors in malformations of cortical development: a quantitative study. Brain 2001;124:1555–65.PubMedCrossRef
8.
go back to reference Lammertsma AA, Bench CJ, Hume SP, Osman S, Gunn K, Brooks DJ, et al. Comparison of methods for analysis of clinical [11C]raclopride studies. J Cereb Blood Flow Metab 1996;16:42–52.PubMedCrossRef Lammertsma AA, Bench CJ, Hume SP, Osman S, Gunn K, Brooks DJ, et al. Comparison of methods for analysis of clinical [11C]raclopride studies. J Cereb Blood Flow Metab 1996;16:42–52.PubMedCrossRef
9.
go back to reference Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage 1996;4:153–8.PubMedCrossRef Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage 1996;4:153–8.PubMedCrossRef
10.
go back to reference Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 1996;16:834–40.PubMedCrossRef Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 1996;16:834–40.PubMedCrossRef
11.
go back to reference Gunn RN, Gunn SR, Turkheimer FE, Aston JA, Cunningham VJ. Positron emission tomography compartmental models: a basis pursuit strategy for kinetic modeling. J Cereb Blood Flow Metab 2002;22:1425–39.PubMedCrossRef Gunn RN, Gunn SR, Turkheimer FE, Aston JA, Cunningham VJ. Positron emission tomography compartmental models: a basis pursuit strategy for kinetic modeling. J Cereb Blood Flow Metab 2002;22:1425–39.PubMedCrossRef
12.
go back to reference Klumpers UM, Veltman DJ, Boellaard R, Comans EF, Zuketto C, Yaqub M, et al. Comparison of plasma input and reference tissue models for analysing [(11)C]flumazenil studies. J Cereb Blood Flow Metab 2008;28:579–87.PubMedCrossRef Klumpers UM, Veltman DJ, Boellaard R, Comans EF, Zuketto C, Yaqub M, et al. Comparison of plasma input and reference tissue models for analysing [(11)C]flumazenil studies. J Cereb Blood Flow Metab 2008;28:579–87.PubMedCrossRef
13.
go back to reference Millet P, Graf C, Buck A, Walder B, Ibanez V. Evaluation of the reference tissue models for PET and SPECT benzodiazepine binding parameters. Neuroimage 2002;17:928–42.PubMedCrossRef Millet P, Graf C, Buck A, Walder B, Ibanez V. Evaluation of the reference tissue models for PET and SPECT benzodiazepine binding parameters. Neuroimage 2002;17:928–42.PubMedCrossRef
14.
go back to reference Delforge J, Pappata S, Millet P, Samson Y, Bendriem B, Jobert A, et al. Quantification of benzodiazepine receptors in human brain using PET, [11C]flumazenil, and a single-experiment protocol. J Cereb Blood Flow Metab 1995;15:284–300.PubMed Delforge J, Pappata S, Millet P, Samson Y, Bendriem B, Jobert A, et al. Quantification of benzodiazepine receptors in human brain using PET, [11C]flumazenil, and a single-experiment protocol. J Cereb Blood Flow Metab 1995;15:284–300.PubMed
15.
go back to reference Ichise M, Toyama H, Fornazzari L, Ballinger JR, Kirsh JC. Iodine-123-IBZM dopamine D2 receptor and technetium-99m-HMPAO brain perfusion SPECT in the evaluation of patients with and subjects at risk for Huntington’s disease. J Nucl Med 1993;34:1274–81.PubMed Ichise M, Toyama H, Fornazzari L, Ballinger JR, Kirsh JC. Iodine-123-IBZM dopamine D2 receptor and technetium-99m-HMPAO brain perfusion SPECT in the evaluation of patients with and subjects at risk for Huntington’s disease. J Nucl Med 1993;34:1274–81.PubMed
16.
go back to reference Maziere M, Hantraye P, Prenant C, Sastre J, Comar D. Synthesis of ethyl 8-fluoro-5,6-dihydro-5-[11C]methyl-6-oxo-4H-imidazo [1,5-a] [1,4]benzodiazepine-3-carboxylate (RO 15.1788-11C): a specific radioligand for the in vivo study of central benzodiazepine receptors by positron emission tomography. Int J Appl Radiat Isot 1984;35:973–6.PubMedCrossRef Maziere M, Hantraye P, Prenant C, Sastre J, Comar D. Synthesis of ethyl 8-fluoro-5,6-dihydro-5-[11C]methyl-6-oxo-4H-imidazo [1,5-a] [1,4]benzodiazepine-3-carboxylate (RO 15.1788-11C): a specific radioligand for the in vivo study of central benzodiazepine receptors by positron emission tomography. Int J Appl Radiat Isot 1984;35:973–6.PubMedCrossRef
17.
go back to reference Barre L, Debruyne D, Abadie P, Moulin M, Baron JC. A comparison of methods for the separation of [11C]Ro 15-1788 (flumazenil) from its metabolites in the blood of rabbits, baboons and humans. Int J Radiat Appl Instrum 1991;42:435–9.CrossRef Barre L, Debruyne D, Abadie P, Moulin M, Baron JC. A comparison of methods for the separation of [11C]Ro 15-1788 (flumazenil) from its metabolites in the blood of rabbits, baboons and humans. Int J Radiat Appl Instrum 1991;42:435–9.CrossRef
18.
go back to reference Meyer JH, Gunn RN, Myers R, Grasby PM. Assessment of spatial normalization of PET ligand images using ligand-specific templates. Neuroimage 1999;9:545–53.PubMedCrossRef Meyer JH, Gunn RN, Myers R, Grasby PM. Assessment of spatial normalization of PET ligand images using ligand-specific templates. Neuroimage 1999;9:545–53.PubMedCrossRef
19.
go back to reference Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ. A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol 1984;15:217–27.PubMedCrossRef Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ. A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol 1984;15:217–27.PubMedCrossRef
20.
go back to reference Yaqub M, Boellaard R, Kropholler MA, Lammertsma AA. Optimization algorithms and weighting factors for analysis of dynamic PET studies. Phys Med Biol 2006;51:4217–32.PubMedCrossRef Yaqub M, Boellaard R, Kropholler MA, Lammertsma AA. Optimization algorithms and weighting factors for analysis of dynamic PET studies. Phys Med Biol 2006;51:4217–32.PubMedCrossRef
21.
go back to reference Millet P, Graf C, Buck A, Walder B, Westera G, Broggini C, et al. Similarity and robustness of PET and SPECT binding parameters for benzodiazepine receptors. J Cereb Blood Flow Metab 2000;20:1587–603.PubMedCrossRef Millet P, Graf C, Buck A, Walder B, Westera G, Broggini C, et al. Similarity and robustness of PET and SPECT binding parameters for benzodiazepine receptors. J Cereb Blood Flow Metab 2000;20:1587–603.PubMedCrossRef
22.
go back to reference Endres CJ, Bencherif B, Hilton J, Madar I, Frost JJ. Quantification of brain mu-opioid receptors with [11C]carfentanil: reference-tissue methods. Nucl Med Biol 2003;30:177–86.PubMedCrossRef Endres CJ, Bencherif B, Hilton J, Madar I, Frost JJ. Quantification of brain mu-opioid receptors with [11C]carfentanil: reference-tissue methods. Nucl Med Biol 2003;30:177–86.PubMedCrossRef
23.
go back to reference Abadie P, Baron JC, Bisserbe JC, Boulenger JP, Rioux P, Travère JM, et al. Central benzodiazepine receptors in human brain: estimation of regional Bmax and KD values with positron emission tomography. Eur J Pharmacol 1992;213:107–15.PubMedCrossRef Abadie P, Baron JC, Bisserbe JC, Boulenger JP, Rioux P, Travère JM, et al. Central benzodiazepine receptors in human brain: estimation of regional Bmax and KD values with positron emission tomography. Eur J Pharmacol 1992;213:107–15.PubMedCrossRef
Metadata
Title
Kinetic modelling of [11C]flumazenil using data-driven methods
Authors
Isabelle Miederer
Sibylle I. Ziegler
Christoph Liedtke
Mary E. Spilker
Matthias Miederer
Till Sprenger
Klaus J. Wagner
Alexander Drzezga
Henning Boecker
Publication date
01-04-2009
Publisher
Springer-Verlag
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 4/2009
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-008-0990-z

Other articles of this Issue 4/2009

European Journal of Nuclear Medicine and Molecular Imaging 4/2009 Go to the issue