Dose-dependent binding of AZD3783 to brain 5-HT1B receptors in non-human primates and human subjects: a positron emission tomography study with [C-11]AZ10419369

作者：Varnas Katarina^*; Nyberg Svante; Karlsson Per; Pierson M Edward; Kagedal Matts; Cselenyi Zsolt; McCarthy Dennis; Xiao Alan; Zhang Minli; Halldin Christer; Farde Lars

来源：Psychopharmacology, 2011, 213(2-3): 533-545.

DOI：10.1007/s00213-011-2165-z

• Brain imaging
• Serotonin
• Serotonin receptor
• PET

The serotonin 5-HT1B receptor is a potential target for the pharmacologic treatment of depression. Positron emission tomography (PET) determination of 5-HT1B receptor occupancy with drug candidates targeting this receptor in non-human primate and human subjects may facilitate translation of research from animal models and guide dose selection for clinical studies. AZD3783 is a recently developed, orally bioavailable 5-HT1B receptor antagonist with potential antidepressant properties.
To determine the relationship between plasma concentration of AZD3783 and occupancy at primate brain 5-HT1B receptors using PET and the radioligand [C-11]AZ10419369.
PET studies with [C-11]AZ10419369 were performed in three non-human primates at baseline and after intravenous injection of AZD3783. Subsequently, PET measurements were undertaken in six human subjects at baseline and after administration of different single oral doses of AZD3783 (1-40 mg).
After administration in non-human primates and human subjects, AZD3783 reduced regional [C-11]AZ10419369 binding in a dose-dependent and saturable manner. The AZD3783 plasma concentration required for 50% receptor occupancy (K (i,plasma)) for monkeys was 25 and 27 nmol/L in occipital cortex and striatum, respectively. Corresponding estimates for human occipital cortex and ventral striatum were 24 and 18 nmol/L, respectively.
The potential antidepressant AZD3783 binds in a saturable manner to brain 5-HT1B receptors with a similar in vivo affinity for human and monkey receptors. [C-11]AZ10419369 can be successfully used to determine occupancy at brain 5-HT1B receptors in vivo and constitutes a useful tool for dose selection in clinical studies with 5-HT1B receptor compounds.

• 出版日期2011-2