Rationale

The serotonin 5-HT(1B) receptor is a potential target for the pharmacologic treatment of depression. Positron emission tomography (PET) determination of 5-HT(1B) 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-HT(1B) receptor antagonist with potential antidepressant properties.

Objectives

To determine the relationship between plasma concentration of AZD3783 and occupancy at primate brain 5-HT(1B) receptors using PET and the radioligand [(11)C]AZ10419369.

Methods

PET studies with [(11)C]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).

Results

After administration in non-human primates and human subjects, AZD3783 reduced regional [(11)C]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.

Conclusions

The potential antidepressant AZD3783 binds in a saturable manner to brain 5-HT(1B) receptors with a similar in vivo affinity for human and monkey receptors. [(11)C]AZ10419369 can be successfully used to determine occupancy at brain 5-HT(1B) receptors in vivo and constitutes a useful tool for dose selection in clinical studies with 5-HT(1B) receptor compounds.