title: 11C- and 76Br-labelled NNC 22-0010, selective dopamine D1 receptor radioligands for PET.
abstract: NNC 22-0010 is a new dopamine antagonist with a high affinity and selectivity for D1 receptors in vitro. NNC 22-0010 has both an N-methyl group and a bromine, which allows radiolabelling with either 11C or 76Br. We labelled [11C]NNC 22-0010 by N-methylation of the free base of the secondary amine with [11C]methyl iodide in a total radiochemical yield of 40%. The total synthesis time was 30 min. The specific radioactivity at time of injection of the radioligand was 48 to 55 GBq/mumol. The [76Br]NNC 22-0010 was synthesized from the iodine precursor by an exchange reaction with 76Br using a Cu(+)-assisted nucleophilic substitution reaction. The radiochemical yield was 60% after purification. Specific radioactivity at time of injection of the radioligand was 6 to 20 GBq/mumol. In PET experiments with [11C]NNC 22-0010 and [76Br]NNC 22-0010 there was a rapid uptake of radioactivity in the monkey brain. The striatum-to-cerebellum ratio was 2-2.5 after 1 h. Binding in the striatum was displaced by SCH 23390, whereas binding in the cerebellum was not reduced. Metabolite studies showed that 1 h after injection about 20% of the radioactivity in plasma represented unchanged radioligand. This value was on the same level for at least 6 h. The results indicate that radiolabelled NNC 22-0010 has potential for imaging dopamine D1 receptors selectively in the human brain.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Karolinska Hospital, Stockholm, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Foged
authors.forename: C
authors.initials: C
authors.lastname: Halldin
authors.forename: C
authors.initials: C
authors.lastname: Loc'h
authors.forename: B
authors.initials: B
authors.lastname: Mazière
authors.forename: P
authors.initials: P
authors.lastname: Karlsson
authors.forename: M
authors.initials: M
authors.lastname: Mazière
authors.forename: C G
authors.initials: CG
authors.lastname: Swahn
authors.forename: L
authors.initials: L
authors.lastname: Farde
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001572:Benzofurans / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging / Q000648:ultrastructure; D001967:Bromine Radioisotopes; D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D007553:Isotope Labeling; D008252:Macaca fascicularis; D008297:Male; D010215:Papio; D011869:Radioligand Assay; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013379:Substrate Specificity; D014055:Tomography, Emission-Computed
chemical_list: D001552:Benzazepines; D001572:Benzofurans; D001967:Bromine Radioisotopes; D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; C096844:berupipam