Abstract
MDL 100,907 is a potent and selective antagonist of 5-HT2A serotonin receptors. Animal studies suggest that MDL 100,907 may behave as an atypical antipsychotic drug. Positron emission tomograph (PET) using [11C]NMSP as the radiotracer was used to define the time course of 5-HT2 receptor occupancy in the human frontal cerebral cortex after a single oral dose of MDL 100,907 (10 or 20 mg) in nine healthy subjects. After the baseline scan each subject was studied three times post dosing at various time points. 5-HT2 occupancies were in the range of 70 and 90% after each dose. While the occupancy remains in this range over 24 hours after 20 mg MDL 100,907, it decreases by about 20% at 24 hours compared to the timepoint at 8 hours, when only 10 mg are administered (p < 0.05). Our results should allow determination of the appropriate dosing regimen for future trials in schizophrenic patients.
Similar content being viewed by others
Article PDF
References
Blin J, Pappata S, Kiyosawa M, Crouzel C, Baron JC (1988): [18F]setoperone: a new high-affinity ligand for postron emission tomography study of the serotonin–2 receptors in baboon brain in vivo. Eur J Pharmacol 147:73–82
Camps M, Cortes R, Gueye B, Probst A, Palacios JM (1989): Dopamine receptors in human brain: autoradiographic distribution of D2 sites. Neuroscience 28:275–290
Canton H, Verriele L, Millan MJ (1994): competitive antagonism of serotonin (5-HT)2C and 5-HT2A receptor-mediated phosphoinositide (PI) turnover by clozapine in the rat: a comparison to other antipsychotics. Neurosci Lett 181:65–68
Carlsson A (1988): The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1:179
Dannals RF, Ravert HT, Wilson AA, Wagner HN Jr (1986): An improved synthesis of (3–N– [11C]methyl)spiperone. Int J Rad Appl Instrum [A] 37:433–434
Evans AC, Marret S, Torrescorzo J, Ku S, Collins L (1991): MRI–PET correlative analysis using a volume of interest (VOI) atlas. J Cereb Blood Flow Metab 11:A69–A78
Farde L, Wiesel F-A, Halldin C, Sedvall G (1988): Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45:71–76
Farde L, Nordstöm A-L, Wiesel F-A, Pauli S, Halldin C, Sedvall G (1992): Positron emission tomographic analysis of central D1- and D2-dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine—relation to extrapyramidal side effects. Arch Gen Psychiatry 49:538–544
Frost JJ, Smith AC, Kuhar MJ, Dannals RF, Wagner HN Jr (1987): In vivo binding of [3H]–N–methylspiperone to dopamine and serotonin receptors. Life Sciences 40:987–995
Kim SE, Wong DF, Conley RC, Yokoi F, Marenco S, Chan B, Tamminga CA (1994): Assessment of receptor occupancy using positron emission tomography: comparison of ratio/slope analysis and kinetic modeling. J Nucl Med 35:197P
Lemaire C, Cantineau R, Guillaume M, Plenevaux A, Christiaens L (1991): Fluorine-18-altanserin: a radioligand for the study of serotonin receptors with PET: radiolabeling and in vivo biologic behavior in rats. J Nucl Med 32:2266–2272
Lidow MS, Goldman-Rakic PS, Rakic P, Innis RB (1989): Dopamine D2 receptors in the cerebral cortex: Distribution and pharmacological characterization with [3H]raclopride. Proc Natl Acad Sci USA 86:6412–6416
Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, MacGregor RR, Hitzemann R, Bendriem B, Gatley SJ, et al. (1990): 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 10:740–747
Lyon RA, Titeler M, Frost JJ, Whitehouse PJ, Wong DF, Wagner HN Jr, Dannals RF, Links JM, Kuhar MJ (1986): 3H–3–N–methylspiperone labels D2 dopamine receptors in basal ganglia and S2 serotonin receptors in cerebral cortex. J Neurosci 6:2941–2949
McElvain J, Perkins P, Vandiver V, Eichmeier L (1997): Validation of a LC/MS method for quantifying MDL 100,907 and its metabolite, MDL 105,725, in plasma. American Society of Mass Spectrometry Abstracts (in press)
Meltzer HY, Matsubara S, Lee J-C (1989): The ratios of serotonin2 and dopamine2 affinities differentiate atypical and typical antipsychotic drugs. Psychopharmacol Bull 25:390–392
Murrin LC, Gibbens DL, Ferrer JL (1985): Ontogeny of dopamine, serotonin and spirodecanone receptors in rat forebrain - an autoradiographic study. Brain Res 355:91–109
Nordström A-L, Farde L, Halldin C (1993): High 5-HT2 receptor occupancy in clozapine treated patients demonstrated by PET. Psychopharmacology 110:365–367
Offord SJ, Mochoviak S, Mitziti J (1993): Imaging dopamine D2 receptors as a tool for selecting dose regimen of a new antipsychotic agent. Pharm Res 10:S358
Palfreyman MG, Schmidt CJ, Sorensen SM, Dudley MW, Kehne JH, Moser P, Gittos MW, Carr AA (1993): Electrophysiological, biochemical and behavioral evidence for 5-HT2 and 5-HT3 mediated control of dopaminergic function. Psychopharmacology 112:S60–S67
Pazos A, Probst A, Palacios JM (1987): Serotonin receptors in the human brain. IV: Autoradiographic mapping of serotonin-2 receptors. Neuroscience 21:123–139
Schmidt CJ, Fadayel GM (1995): The selective 5-HT2 receptor antagonist, MDL 100,907, increases dopamine efflux in the prefrontal cortex of the rat. Eur J Pharamacol 273:273–279
Schmidt CJ, Fadayel GM, Sullivan CK, Taylor VL (1992): 5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4–methylenedioxymethamphetamine. Eur J Pharmacol 223:65–74
Schotte A, Maloteaux JM, Laduron PM (1983): Characterization and regional distribution of serotonin S2-receptors in human brain. Brain Res 276:231–235
Seibyl JP, Zea-Ponce Y, Brenner L, Baldwin RM, Krystal JH, Offord SJ, Mochoviak S, Charney DS, Hoffer PB, Innis RB (1996): Continuous intravenous infusion of iodine-123-IBZM for SPECT determination of human brain dopamine receptor occupancy by antipsychotic agent RWJ-37796. J Nucl Med 37:11–15
Wong DF, Wagner HN Jr, Dannals RF, Links JM, Frost JJ, Ravert HT, Wilson AA, Rosenbaum AE, Gjedde A, Douglass KH, Petronis JD, Folstein MF, Toung JKT, Burns HD, Kuhar MJ (1984): Effects of age on dopamine and serotonin receptors measured by positron emission tomography in the living human brain. Science 226:1393–1396
Wong DF, Gjedde A, Wagner HN Jr (1986): Quantification of neuroreceptors in the living human brain. I. Irreversible binding of ligands. J Cereb Blood Flow Metab 6:137–146
Wong DF, Lever JR, Hartig PR, Dannals RF, Villemagne V, Hoffman BJ, Wilson AA, Ravert HT, Links JM, Scheffel U, Wagner HN Jr (1987): Localization of serotonin 5-HT2 receptors in living human brain by positron emission tomography using N1-([11C]-methyl)–2Br–LSD. Synapse 1:393–398
Wong DF, Gjedde A, Young D (1989): Reply to Swart and Korf. J Cereb Blood Flow Metab 9:908–910
Wong DF, Yung BCK, Giorgianni JA, Chen C, Chan B, Gisclon L, Dannals RF, Ravert HT, Shaya E, Curtin CR, Offord SJ (1993): D2 dopamine receptor occupancy as a function of intravenous rising dose of RWJ-37796 in normal living human brain. J Nucl Med 34:109P
Wong DF, GrĂ¼nder G, Yokoi F, Szymanski S, Ravert HT, Mathews WB, Musachio JL, Scheffel U, Dannals RF (1996): Imaging human cerebral serotonin 5-HT2A receptors with C–11 MDL 100,907. J Nucl Med 37:112P
Acknowledgements
We gratefully appreciate the help of Boon Chan, Anquing Chen, Andrew H. Crabb, Abdul Kalaff, David N. Krasenbaum, and Igor Simakhodskiy. The study was supported in part by Hoechst-Marion-Roussel, Cincinnati, Ohio. G.G. was supported by the Deutsche Forschungsgemeinschaft (Gr 1399/1–1).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
GrĂ¼nder, G., Yokoi, F., Offord, S. et al. Time Course of 5-HT2A Receptor Occupancy in the Human Brain after a Single Oral Dose of the Putative Antipsychotic Drug MDL 100,907 Measured by Positron Emission Tomography. Neuropsychopharmacol 17, 175–185 (1997). https://doi.org/10.1016/S0893-133X(97)00044-4
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1016/S0893-133X(97)00044-4
Keywords
This article is cited by
-
Characterization of the serotonin 2A receptor selective PET tracer (R)-[18F]MH.MZ in the human brain
European Journal of Nuclear Medicine and Molecular Imaging (2020)
-
Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels
Neuropsychopharmacology (2019)
-
Imaging Agonist-Induced D2/D3 Receptor Desensitization and Internalization In Vivo with PET/fMRI
Neuropsychopharmacology (2016)
-
Applications of Imaging Biomarkers in the Early Clinical Development of Central Nervous System Therapeutic Agents
Clinical Pharmacology & Therapeutics (2012)
-
The Role of Imaging in Proof of Concept for CNS Drug Discovery and Development
Neuropsychopharmacology (2009)