title: Bromine-76 and carbon-11 labelled NNC 13-8199, metabolically stable benzodiazepine receptor agonists as radioligands for positron emission tomography.
abstract: NNC 13-8241 has recently been labelled with iodine-123 and developed as a metabolically stable benzodiazepine receptor ligand for single-photon emission computed tomography (SPECT) in monkeys and man. NNC 13-8199 is a bromo-analogue of NNC 13-8241. This partial agonist binds selectively and with subnanomolar affinity to the benzodiazepine receptors. We prepared 76Br labelled NNC 13-8199 from the trimethyltin precursor by the chloramine-T method. Carbon-11 labelled NNC 13-8199 was synthesised by N-alkylation of the nitrogen of the amide group with [11C]methyl iodide. Positron emission tomography (PET) examination with the two radioligands in monkeys demonstrated a high uptake of radioactivity in the occipital, temporal and frontal cortex. In the study with [76Br]NNC 13-8199, the monkey brain uptake continued to increase until the time of displacement with flumazenil at 215 min after injection. For both radioligands the radioactivity in the cortical brain regions was markedly reduced after displacement with flumazenil. More than 98% of the radioactivity in monkey plasma represented unchanged radioligand 40 min after injection. The low degree of metabolism indicates that NNC 13-8199 is metabolically much more stable than hitherto developed PET radioligands for imaging of benzodiazepine receptors in the primate brain. [76Br]NNC 13-8199 has potential as a radioligand in human PET studies using models where a slow metabolism is an advantage.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, 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: S
authors.initials: S
authors.lastname: Pauli
authors.forename: M
authors.initials: M
authors.lastname: Maziére
authors.forename: H C
authors.initials: HC
authors.lastname: Hansen
authors.forename: T
authors.initials: T
authors.lastname: Suhara
authors.forename: C G
authors.initials: CG
authors.lastname: Swahn
authors.forename: P
authors.initials: P
authors.lastname: Karlsson
authors.forename: L
authors.initials: L
authors.lastname: Farde
mesh_terms: D000818:Animals; D001569:Benzodiazepines; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D001967:Bromine Radioisotopes; D002250:Carbon Radioisotopes; D005442:Flumazenil; D058785:GABA-A Receptor Agonists; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D010069:Oxadiazoles; D010215:Papio; D011963:Receptors, GABA-A / Q000378:metabolism; D014055:Tomography, Emission-Computed
chemical_list: C109607:3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl) 7-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5.alpha)-benzodiazepine; D001967:Bromine Radioisotopes; D002250:Carbon Radioisotopes; D058785:GABA-A Receptor Agonists; D010069:Oxadiazoles; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil