High occupancy of sigma-1 receptors in the human brain after single oral administration of fluvoxamine:: A positron emission tomography study using [11C]SA4503

Background: Sigma-1 receptors might be implicated in the pathophysiology of psychiatric diseases, as well as in the mechanisms of action of some selective serotonin reuptake inhibitors (SSRIs). Among the several SSRIs, fluvoxamine has the highest affinity for sigma-1 receptors (Ki = 36 nM), whereas paroxetine shows low affinity (Ki = 1893 nM). The present study was undertaken to examine whether fluvoxamine binds to sigma-1 receptors in living human brain. Methods: A dynamic positron emission tomography (PET) data acquisition using the selective sigma-1 receptor ligand [C-11]SA4503 was performed with arterial blood sampling to evaluate quantitatively the binding of [C-11]SA4503 to sigma-1 receptors in 15 healthy male volunteers. Each subject had two PET scans before and after randomly receiving a single dose of either fluvoxa mine (50,100,150, or 200 mg) or paroxetine (20 mg). The binding potential of [C-11]SA4503 in 9 regions of the brain was calculated by a 2-tissue 3-compartment model. In addition, we examined the effects of functional polymorphisms of the sigma-1 receptor (SIGMARI) gene on the binding potential of [C-11]SA4503. Results: Fluvoxamine bound to sigma-1 receptors in all brain regions in a dose-dependent manner, whereas paroxetine did not bind to sigma-1 receptors. However, there was no association between the SIGMAR1 gene polymorphism GC-241-240TT and binding potential. Conclusions: The study demonstrated that fluvoxamine bound to sigma-1 receptors in living human brain at therapeutic doses. These findings suggest that sigma-1 receptors may play an important role in the mechanism of action of fluvoxamine.