Kinetic Modelling of [11C]flumazenil Using Data-driven Methods

Overview

Journal Eur J Nucl Med Mol Imaging

Specialties Biophysics
Nuclear Medicine
Radiology

Date 2008 Dec 2

PMID 19043703

Citations 10

Authors

Isabelle Miederer

Sibylle I Ziegler

Christoph Liedtke

Mary E Spilker

Matthias Miederer

Till Sprenger

Klaus J Wagner

Alexander Drzezga

Henning Boecker

Affiliations

Soon will be listed here.

Abstract

Purpose: [(11)C]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 [(11)C]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 [(11)C]FMZ using an invasive or noninvasive protocol, and therefore have the potential to reduce the invasiveness of the procedure.

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References

Barre L, Debruyne D, Abadie P, Moulin M, Baron J . 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 Rad Appl Instrum A. 1991; 42(5):435-9. DOI: 10.1016/0883-2889(91)90102-7. View

Ihara M, Tomimoto H, Ishizu K, Mukai T, Yoshida H, Sawamoto N . Decrease in cortical benzodiazepine receptors in symptomatic patients with leukoaraiosis: a positron emission tomography study. Stroke. 2004; 35(4):942-7. DOI: 10.1161/01.STR.0000122624.32167.e0. View

Ichise M, Toyama H, Fornazzari L, Ballinger J, Kirsh J . 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(8):1274-81. View

Logan J, Fowler J, Volkow N, Wang G, Ding Y, Alexoff D . Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab. 1996; 16(5):834-40. DOI: 10.1097/00004647-199609000-00008. View

Lammertsma A, Bench C, Hume S, Osman S, Gunn K, Brooks D . Comparison of methods for analysis of clinical [11C]raclopride studies. J Cereb Blood Flow Metab. 1996; 16(1):42-52. DOI: 10.1097/00004647-199601000-00005. View

Holthoff V, Koeppe R, Frey K, Paradise A, Kuhl D . 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(5):745-52. DOI: 10.1038/jcbfm.1991.131. View

Yaqub M, Boellaard R, Kropholler M, Lammertsma A . Optimization algorithms and weighting factors for analysis of dynamic PET studies. Phys Med Biol. 2006; 51(17):4217-32. DOI: 10.1088/0031-9155/51/17/007. View

Meyer J, Gunn R, Myers R, Grasby P . Assessment of spatial normalization of PET ligand images using ligand-specific templates. Neuroimage. 1999; 9(5):545-53. DOI: 10.1006/nimg.1999.0431. View

Mintun M, Raichle M, Kilbourn M, Wooten G, Welch M . A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol. 1984; 15(3):217-27. DOI: 10.1002/ana.410150302. View

10.

Endres C, Bencherif B, Hilton J, Madar I, Frost J . Quantification of brain mu-opioid receptors with [11C]carfentanil: reference-tissue methods. Nucl Med Biol. 2003; 30(2):177-86. DOI: 10.1016/s0969-8051(02)00411-0. View

11.

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(2):928-42. View

12.

Delforge J, Pappata S, Millet P, Samson Y, Bendriem B, Jobert A . Quantification of benzodiazepine receptors in human brain using PET, [11C]flumazenil, and a single-experiment protocol. J Cereb Blood Flow Metab. 1995; 15(2):284-300. DOI: 10.1038/jcbfm.1995.34. View

13.

Klumpers U, Veltman D, Boellaard R, Comans E, Zuketto C, Yaqub M . Comparison of plasma input and reference tissue models for analysing [(11)C]flumazenil studies. J Cereb Blood Flow Metab. 2007; 28(3):579-87. DOI: 10.1038/sj.jcbfm.9600554. View

14.

Hammers A, Koepp M, Richardson M, Labbe C, Brooks D, Cunningham V . Central benzodiazepine receptors in malformations of cortical development: A quantitative study. Brain. 2001; 124(Pt 8):1555-65. DOI: 10.1093/brain/124.8.1555. View

15.

Cunningham V, Jones T . Spectral analysis of dynamic PET studies. J Cereb Blood Flow Metab. 1993; 13(1):15-23. DOI: 10.1038/jcbfm.1993.5. View

16.

Logan J, Fowler J, Volkow N, Wolf A, Dewey S, Schlyer D . 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(5):740-7. DOI: 10.1038/jcbfm.1990.127. View

17.

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(10):973-6. DOI: 10.1016/0020-708x(84)90215-1. View

18.

Koepp M, Labbe C, Richardson M, Brooks D, Van Paesschen W, Cunningham V . Regional hippocampal [11C]flumazenil PET in temporal lobe epilepsy with unilateral and bilateral hippocampal sclerosis. Brain. 1997; 120 ( Pt 10):1865-76. DOI: 10.1093/brain/120.10.1865. View

19.

Gunn R, Gunn S, Turkheimer F, Aston J, Cunningham V . Positron emission tomography compartmental models: a basis pursuit strategy for kinetic modeling. J Cereb Blood Flow Metab. 2002; 22(12):1425-39. DOI: 10.1097/01.wcb.0000045042.03034.42. View

20.

Lammertsma A, Hume S . Simplified reference tissue model for PET receptor studies. Neuroimage. 1996; 4(3 Pt 1):153-8. DOI: 10.1006/nimg.1996.0066. View