title: Evaluation of EMD 128 130 occupancy of the 5-HT1A and the D2 receptor: a human PET study with [11C]WAY-100635 and [11C]raclopride.
abstract: The use of so-called, atypical antipsychotic medication is becoming more widespread in the treatment of psychotic disorders. EMD 128 130 is a novel compound acting as an agonist at the 5-HT1A receptor, and as an antagonist at the dopamine-2 (D2) receptor. This dual action may confer additional benefits over selective D2 antagonists in the treatment of psychotic disorders. In this study, we investigated the occupancy of EMD 128 130 in vivo at the human D2 and 5-HT1A receptors with positron emission tomography using the radiotracers [11C]raclopride and [11C]WAY-100635. Seven healthy volunteers were examined before and after 5 days of treatment with EMD 128 130, administered in an incremental dose building up to 50 mg, b.d. A significant occupancy was demonstrated at the human D2 receptor (40% following a dose of 50 mg, b.d.) while there was no consistent effect observed at the 5-HT1A receptor, despite a similar affinity of EMD 128 130 for cloned human D2 and 5-HT1A receptors, and the presence of typical, central 5-HT1A agonist side-effects. The differential effects of EMD 128 130 at the D2 and the 5-HT1A receptor (antagonist at D2 receptor, agonist at the 5-HTIA receptor) may explain the differences in occupancy observed.
authors.affiliation: MRC Cyclotron Unit, Hammersmith Hospital, Imperial College School of Medicine, London, UK. eugenii.rabiner@ic.ac.uk
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.forename: Martin R
authors.initials: MR
authors.lastname: Wilkins
authors.forename: Ewen
authors.initials: E
authors.lastname: Sedman
authors.forename: Paul M
authors.initials: PM
authors.lastname: Grasby
mesh_terms: D000328:Adult; D000978:Antiparkinson Agents / Q000493:pharmacokinetics*; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009930:Organic Chemicals; D010879:Piperazines / Q000493:pharmacokinetics; D011725:Pyridines / Q000493:pharmacokinetics; D020891:Raclopride / Q000493:pharmacokinetics; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000493:pharmacokinetics; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics*; D014055:Tomography, Emission-Computed
chemical_list: D000978:Antiparkinson Agents; D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D009930:Organic Chemicals; D010879:Piperazines; D011725:Pyridines; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D020891:Raclopride; C443959:sarizotan; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide