title: [11C]NNC 687 and [11C]NNC 756, dopamine D-1 receptor ligands. Preparation, autoradiography and PET investigation in monkey.
abstract: NNC 687 and NNC 756 [(+)-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl- 8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine and (+)-8-chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine] are two new potent dopamine D-1 receptor antagonists. [11C]NNC 687 and [11C]NNC 756 were both prepared by N-methylation of the corresponding desmethyl compounds with [11C]methyl iodide. The reactions were performed in acetone with subsequent normal-phase semi-preparative HPLC and resulting in 50-60% radiochemical yield (from EOB and decay-corrected) with a total synthesis time of 30-35 min and a radiochemical purity higher than 99%. The specific radioactivity obtained at time of injection was about 1500 Ci/mmol (55 GBq/mumol). Autoradiographic examination of [11C]NNC 687 and [11C]NNC 756 binding in post-mortem human brain sections showed specific binding in the striatum, a region with high density of dopamine D-1 receptors. PET examination of the radioligands in a Cynomolgus monkey demonstrated accumulation of radioactivity predominantly in the striatum. The ratio between radioactivities in the striatum and the cerebellum was about 2 and 8 for [11C]NNC 687 and [11C]NNC 756 after 60 min. [11C]NNC 756 should have potential as PET ligand for examination of central dopamine D-1 receptors in man.
authors.affiliation: Department of Psychiatry and Psychology, Karolinska Hospital, Stockholm, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Halldin
authors.forename: C
authors.initials: C
authors.lastname: Foged
authors.forename: L
authors.initials: L
authors.lastname: Farde
authors.forename: P
authors.initials: P
authors.lastname: Karlsson
authors.forename: K
authors.initials: K
authors.lastname: Hansen
authors.forename: F
authors.initials: F
authors.lastname: Grønvald
authors.forename: C G
authors.initials: CG
authors.lastname: Swahn
authors.forename: H
authors.initials: H
authors.lastname: Hall
authors.forename: G
authors.initials: G
authors.lastname: Sedvall
mesh_terms: D000478:Alkylation; D000818:Animals; D001345:Autoradiography; D001552:Benzazepines / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology*; D001572:Benzofurans / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D016616:Cryoultramicrotomy; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014055:Tomography, Emission-Computed
chemical_list: D001552:Benzazepines; D001572:Benzofurans; D002250:Carbon Radioisotopes; D017447:Receptors, Dopamine D1; C077122:5-(2,3-dihydrobenzofuran-7-yl)-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol; C075357:odapipam