Abstract
Ro 15-4513, a partial inverse agonist at the benzodiazepine (BZ) receptor site was labelled with11C and used for in vitro autoradiography on human post mortem brain sections and for positron emission tomography (PET) on Cynomolgus monkeys. The total radiochemical yield of [11C]Ro 15-4513 was 30–40% with an overall synthesis time of 40 min. The specific radioactivity was about 1000 Ci/mmol at end of synthesis. In vitro autoradiography showed that [11C]Ro 15-4513 bound specifically predominately in the neocortex of the human brain. Specific binding was also demonstrated in the basal ganglia and the cerebellar cortex. Flumazenil (Ro 15-1788) and clonazepam inhibited the binding in cerebral regions, but a significant proportion in the cerebellum was not inhibited by these agents. This proportion may represent α6-containing BZ receptors. PET examination of [11C]Ro 15-4513 binding in Cynomolgus monkeys demonstrated high uptake of radioactivity in neocortex. The uptake of radioactivity was markedly displaced by high doses of Ro 15-4513 or clonazepam. [11C]Ro 15-4513 should be a useful ligand to examine BZ receptor characteristics in the living human brain by PET.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bonetti EP, Polc P, Pieri L (1984) An azido analogue of the benzodiazepine antagonist Ro 15-1788 (Ro 15-4513) behaves as a partial inverse benzodiazepine agonist. Neurosci Lett 18 (suppl):30
Bonetti EP, Burkard WP, Gabl M, Möhler H (1985) The partial inverse benzodiazepine agonist Ro 15-4513 antagonizes acute ethanol effects in mice and rats. Br J Pharmacol 86:463
Bonetti EP, Burkard WP, Gabl M, Hunkeler W, Lorez H-P, Martin JR, Moehler H, Osterrieder W, Pieri L, Polc P, Richards JG, Schaffner R, Scherschlicht R, Schoch P, Haefely WE (1989) Ro 15-4513: partial inverse antagonism at BZR and interaction with etanol. Pharmacol Biochem Behav 31:733–749
Ehrin E, Johnström P, Stone-Elander S, Nilsson JLG, Persson A, Farde L, Sedvall G, Litton J-E, Eriksson L, Widen L, Greitz T (1984) Preparation and preliminary positron emission tomography studies of11C-Ro 15-1788, a selective benzodiazepine receptor antagonist. Acta Pharm Suec 21:183–188
Eriksson L, Holte S, Bohm C, Kesselberg M, Hovander B (1988) Automated blood sampling systems for positron emission tomography. IEEE Trans Nucl Sci 35:703–707
Fadda F, Mosca E, Colombo G, Gessa GL (1987) Protection against ethanol mortality in rats by the imidazobenzodiazepine Ro 15-4513. Eur J Pharmacol 136:265–266
Frost JJ, Wagner HN, Dannals RF, Ravert HT, Wilson AA, Links JM, Rosenbaum AE, Trifiletti RR, Snyder SH (1986) Imaging benzodiazepine receptors in man with [11C]suriclone by positron emission tomography. Eur J Pharmacol 122:381–383
Haefely WE (1990) The GABAA-Benzodiazepine receptor: biology and pharmacology. In: Burrows GD, Roth M, Noyes R Jr (eds) Neurobiology of anxiety. Elsevier, Handbook of Anxiety 3:165–188
Hall H, Farde L, Sedvall G (1988) Human dopamine receptor subtypes — in vitro binding analysis using3H-SCH 23390 and3H-raclopride. J Neural Transm 73:7–21
Hall H, Halldin C, Sedvall G (1992) Binding of the partial inverse benzodiazepine agonist [3H]Ro 15-4513 to human post mortem brain tissue (manuscript in preparation)
Halldin C, Stone-Elander S, Thorell J-O, Persson A, Sedvall G (1988)11C-Labelling of Ro 15-1788 in two different positions and also11C-labelling of its main metabolite Ro 15-3890, for PET studies of benzodiazepine receptors. Appl Radiat Isot 39:993–997
Halldin C, Farde L, Högberg T, Hall H, Sedvall G (1990)11C-Labelling of eticlopride in two different positions — a selective high-affinity ligand for the study of dopamine D-2 receptors using PET. Appl Radiat Isot 41:669–674
Hantraye P, Kaijima M, Prenant C, Giubert B, Sastre J, Crouzel M, Naquet R, Comar D, Mazière D (1984) Central type benzodiazepine binding sites: a positron emission tomography study in the baboons brain. Neurosci Lett 48:115–120
Hoffman PL, Tabakoff B, Szabo G, Suzdak PD, Paul SM (1987) Effect of an imidazobenzodiazepine, Ro 15-4513, on the incoordination and hypothermia produced by ethanol and pentobarbital. Life Sci 41:611–619
Litton J-E, Baker JR, Huesman RH, Mathis CA, Budinger TF (1987) Evaluation and application of an on-line blood sampling system for positron emission tomography. Lawrence Berkeley Lab report, LBL 23298
Litton J-E, Holte S, Eriksson L (1990) Evaluation of the Karolinska new positron camera system; the Scanditronix PC2048-15B. IEEE Trans Nucl Sci 37:743–748
Litton J-E, Farde L, Neiman J, Halldin C, Sedvall G (1991) Positron emission tomography of benzodiazepine receptors binding in alcoholics — equilibrium quantification. J Cereb Blood Flow Metab 11 (suppl):617
Lüddens H, Wisden W (1991) Function and pharmacology of multiple GABAA receptor subunits. TIPS 12:49–51
Mazière M, Hantraye P, Prenant C, Sastre J, Comar D (1984) 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 35:973–976
Möhler H, Okada T (1977) Benzodiazepine receptors: demonstration in the central nervous system. Science 198:849–851
Olsen RW, Venter CJ (1986) Benzodiazepine/GABA receptors and chloride channels: structural and functional properties. Liss, New York
Persson A, Ehrin E, Eriksson L, Farde L, Hedström CG, Litton J-E, Mindus P, Sedvall G (1985) Imaging of11C-labelled Ro 15-1788 binding to benzodiazepine receptors in the human brain by positron emission tomography. J Psychiatr Res 19:609–622
Persson A, Pauli S, Halldin C, Stone-Elander S, Farde L, Sjögren I, Sedvall G (1989) Saturation analysis of specific11C-Ro 15-1788 binding to the human neocortex using positron emission tomography. Human Psychopharmacology 4:21–31
Persson A, d'Argy R, Gillberg P-G, Halldin C, Litton J-E, Swahn C-G, Sedvall G (1991) Autoradiography with saturation experiments of11C-Ro 15-1788 binding to human brain sections. J Neurosci Methods 36:53–61
Polc P, Bonetti EP, Schaffner R, Haefely W (1982) A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonists Ro 15-1788, benzodiazepine tranquilizres, β-carbolines, and phenobarbitone. Naunyn-Schmiedeberg's Arch Pharmacol 321:260–264
Sadzot B, Frost JJ and Wagner HN (1989) In vivo labeling of central benzodiazepine receptors with the partial inverse agonist [3H]Ro 15-4513. Brain Res 491:128–135
Samson Y, Hantraye P, Baron J-C, Soussaline F, Comar D, Mazière M (1985) Kinetics and displacement of [11C]Ro 15-1788, a benzidiazepine antagonist, studied in human brain in vivo by positron emission tomography. Eur J Pharmacol 110:247–251
Savic I, Roland P, Sedvall G, Persson A, Pauli S, Widen L (1988) In vivo demonstration of reduced benzodiazepine receptor binding in human epileptic foci. Lancet 16:863–866
Sedvall G, Farde L, Persson A, Wiesel F-A (1986) Imaging of neurotransmitter receptors in the living human brain. Arch Gen Psychiatry 43:995–1005
Seeburg PH (1990) Elucidating GABAA receptor heterogeneity — an integrated molecular approach. GABA and Benzodiazepine Receptor Subtypes 46:15–21
Shinotoh H, Yamasaki T, Inoue O, Itoh T, Suzuki K, Hashimoto K, Tateno Y, Ikehira H (1986) Visualization of specific binding sites of benzodiazepine in human brain. J Nucl Med 27:1593–1599
Suzuki K, Inoue O, Hashimoto K, Yamasaki T, Kuchiki M, Tamate K (1985) Computer-controlled large scale production of high specific activity [11C]Ro 15-1788 for PET studies of benzodiazepine receptors. Int J Appl Radiat Isot 36:971–976
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Halldin, C., Farde, L., Litton, JE. et al. [11C]Ro 15-4513, a ligand for visualization of benzodiazepine receptor binding. Psychopharmacology 108, 16–22 (1992). https://doi.org/10.1007/BF02245279
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02245279