title: Confirmation of fenfluramine effect on 5-HT(1B) receptor binding of [(11)C]AZ10419369 using an equilibrium approach.
abstract: Assessment of serotonin release in the living brain with positron emission tomography (PET) may have been hampered by the lack of suitable radioligands. We previously reported that fenfluramine caused a dose-dependent reduction in specific binding in monkeys using a classical displacement paradigm with bolus administration of [(11)C]AZ10419369. The aim of this study was to confirm our previous findings using an equilibrium approach in monkey. A total of 24 PET measurements were conducted using a bolus infusion protocol of [(11)C]AZ10419369 in three cynomolgus monkeys. Initial PET measurements were performed to assess suitable K(bol) values. The fenfluramine effect on [(11)C]AZ10419369 binding was evaluated in a displacement and pretreatment paradigm. The effect of fenfluramine on [(11)C]AZ10419369 binding potential (BP(ND)) was dose-dependent in the displacement paradigm and confirmed in the pretreatment paradigm. After pretreatment administration of fenfluramine (5.0 mg/kg), the mean BP(ND) of the occipital cortex decreased by 39%, from 1.38±0.04 to 0.84±0.09. This study confirms that the new 5-HT(1B) receptor radioligand [(11)C]AZ10419369 is sensitive to fenfluramine-induced changes in endogenous serotonin levels in vivo. The more advanced methodology is suitable for exploring the sensitivity limit to serotonin release as measured using [(11)C]AZ10419369 and PET.
authors.affiliation: Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. sjoerd.finnema@ki.se
authors.forename: Sjoerd J
authors.initials: SJ
authors.lastname: Finnema
authors.forename: Andrea
authors.initials: A
authors.lastname: Varrone
authors.forename: Tzung-Jeng
authors.initials: TJ
authors.lastname: Hwang
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005277:Fenfluramine / Q000494:pharmacology*; D008252:Macaca fascicularis; D009778:Occipital Lobe / Q000000981:diagnostic imaging / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011859:Radiography; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*
chemical_list: C555067:5'-(2-fluorophenyl)-spiro(1-azabicyclo(2.2.2)octane-3,2'(3'H)-furo(2,3-b)pyridine); D053961:Azabicyclo Compounds; D044302:Receptor, Serotonin, 5-HT1B; D018490:Serotonin Agents; D013141:Spiro Compounds; D005277:Fenfluramine; D012701:Serotonin