Abstract
Analysis of carbon-11 labeled metabolites in plasma was carried out during positron emission tomography (PET) studies with a central benzodiazepine receptor ligand [11C]flumazenil ([11C]FMZ) in 24 human subjects (14–76 y.o.) including five normal volunteers and 19 patients with neurological disorders. Arterial plasma samples were obtained at 3, 5, 10, 15, 20, 30 and 60 min after i.v. injection of the tracer, and were analyzed by high-performance liquid chromatography. The rate of plasma [11C]FMZ degradation was associated with a large individual variation, but no significant difference was found in the degradation of [11C]FMZ either between male and female, young and old, or between normal subjects and patient groups. When the mean fraction of unchanged [11C]FMZ at each time point was used instead of individually measured metabolite data for the arterial input function, as much as a 30% error occurred in the distribution volume of the [11C]FMZ binding in the brain. These results indicate that the mean percentage of unchanged [11C]FMZ fraction in subjects cannot be used as the standardized value, and that the analysis of metabolites in plasma is necessary to determine the exact arterial input function for quantitative PET measurement.
References
Ishiwata K, Hatazawa J, Kubota K, Kameyama M, Itoh M, Matsuzawa T, et al. Metabolic fate of L-[methyl-11C]methionine in human plasma.Eur J Nucl Med 15: 665–669, 1989.
Ishiwata K, Yanai K, Iwata R, Takahashi T, Hatazawa J, Itoh M, et al. Analysis of plasma metabolites during human PET studies with three receptor ligands, [11C]YM-09151-2, [11C]doxepin and [11C]pyrilamine.Tohoku J Exp Med 178: 129–136, 1996.
Pike VW, Halldin C, Crouzel C, Barre L, Nutt DJ, Osman S, et al. Radioligands for PET studies of central benzodiazepine receptors and PK (peripheral benzodiazepine) binding sites—current status.Nucl Med Biol 20: 503–525, 1993.
Malizia AL, Richardson MP. Benzodiazepine receptors and positron emission tomography: ten years of experience. A new beginning?J Psychopharmacol 9: 355–368, 1995.
Swahn C-G, Persson A, Pauli S. Metabolism of the benzodiazepine antagonist11C-Ro 15-1788 after intravenous administration in man.Human Psychopharmacol 4: 297–301, 1989.
Loc’h C, Hantraye Ph, Khalili-Varasteh M, Mazière B, Delforge J, Brouillet E, et al. [11C]-Flumazenil metabolites: measurements of unchanged ligand in plasma using thin layer chromatography and rapid liquid chromatography.J Label Compds Radiopharm 30: 234, 1990.
Frey KA, Holthoff VA, Koeppe RA, Jewett DM, Kilboum MR, Kuhl DE. Parametricin vivo imaging of benzodiazepine receptor distribution in human brain.Ann Neurol 30: 663–672, 1991.
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.Appl Radiat Isot 42: 435–439, 1991.
Debruyne D, Abadie P, Barre L, Albessard F, Moulin M, Zarifian E, et al. Plasma pharmacokinetics and metabolism of the benzodiazepine antagonist [11C]Ro 15-1788 (flumazenil) in baboon and human during positron emission tomography studies.Eur J Drug Metab Pharmacokinet 16: 141–152, 1991.
Pauli S, Liljequist S, Farde L, Swahn C-G, Halldin C, Litton J-E, et al. PET analysis of alcohol interaction with the brain disposition of [11C]flumazenil.Psychopharmacology 107: 180–185, 1992.
Delforge J, Syrota A, Bottlaender M, Varastet M, Loc’h C, Bendriem B, et al. Modeling analysis of [11C]flumazenil kinetics studied by PET: application to a critical study of the equilibrium approaches.J Cereb Blood Flow Metab 13: 454–468, 1993.
Suzuki K, Inoue O, Hashimoto K, Yamasaki T, Kuchiki M, Tamate K. Computer-controlled large scale production of high specific activity [11C]RO 15-1788 for PET studies of benzodiazepine receptors.Appl Radiat Isot 36: 971–976, 1985.
Ishiwata K, Seki H, Ishii K, Ishii S, Nozaki T, Senda M. Synthesis andin vivo evaluation of [11C]semotiadil, a benzothiazine calcium antagonist.Appl Radiat Ihot 45: 439–443, 1994.
Iida H, Miura S, Kanno I, Murakami M, Yamamoto S, Amano M. Design and evaluation of Headtome-IV, a whole-body positron emission tomography.IEEE Trans Nucl Sci NS-37: 1006–1010, 1989.
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 11: 735–744, 1991.
Millet P, Delforge J, Mauguiere F, Pappata S, Cinotti L, Frouin V, et al. Parameter and index images of benzodiazepine receptor concentration in the brain.J Nucl Med 36: 1462–1472, 1995.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ishiwata, K., Itou, T., Ohyama, M. et al. Metabolite analysis of [11C]flumazenil in human plasma: Assessment as the standardized value for quantitative PET studies. Ann Nucl Med 12, 55–59 (1998). https://doi.org/10.1007/BF03165418
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF03165418