title: Evaluation of SCH 39166 as PET ligand for central D1 dopamine receptor binding and occupancy in man.
abstract: SCH 39166 is the first selective D1-dopamine receptor antagonist developed for clinical trials in schizophrenia. SCH 39166 was evaluated as a radioligand for PET, labeled with 11C, and as a D1-dopamine receptor antagonist after single oral doses in healthy men. After intravenous injection of [11C]SCH 39166 distribution of radioactivity in brain grossly reflected D1-dopamine receptor density. The putamen to cerebellum ratio at equilibrium was low (1.54 +/- 0.18 SD), which makes [11C]SCH 39166 less suitable as a radioligand for applied PET studies. Saturability of specific binding was demonstrated after IV injection of [11C]SCH 39166 with low specific radioactivity. Stereospecificity of binding was examined using the stereoisomer [11C]SCH 39165. D1-Receptor occupancy was demonstrated with [11C]SCH 39166 2 h after administration of single oral doses of unlabeled SCH 39166 to each of three healthy subjects (25, 100 and 400 mg). There was a substantial reduction of specific [11C]SCH 39166 uptake in the putamen after all doses. Single oral doses of 100 mg induced approximately 70% D1-dopamine receptor occupancy in the basal ganglia, which should be sufficient to investigate the antipsychotic potential of D1-dopamine receptor antagonism in clinical studies.
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Karlsson
authors.forename: G
authors.initials: G
authors.lastname: Sedvall
authors.forename: C
authors.initials: C
authors.lastname: Halldin
authors.forename: C G
authors.initials: CG
authors.lastname: Swahn
authors.forename: L
authors.initials: L
authors.lastname: Farde
mesh_terms: D000328:Adult; D001552:Benzazepines / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects; D018492:Dopamine Antagonists / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011869:Radioligand Assay; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014055:Tomography, Emission-Computed
chemical_list: D001552:Benzazepines; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; C058081:ecopipam