¹Solvay Pharmaceuticals BV, Weesp, Netherlands

Abstract

Purpose: to compare plasma levels of effective doses of SLV 308 in 1-methylphenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets with levels giving at least 60% occupancy at the striatal dopamine D₂ receptors in humans.

Methods: Six MPTP-treated marmosets received SLV 308 (0.087, 0.26 and 0.87 mg/kg, po). Locomotor activity and disability counts were investigated in comparison with L-dopa (12.5mg/kg po plus carbidopa 12.5mg/kg po). Plasma samples were taken at 1.5, 4 and 7 hours post-administration of SLV308 (0.087 and 0.26 mg/kg). Striatal D₂ receptor occupancy was investigated in 5 volunteers receiving SLV 308 in escalating doses from 0.1 to 5 mg tid over 10-11 days. PET scans with ¹¹C-raclopride were made at 1, 8, 12 and 24 hours after different doses of SLV 308 (0.5, 1 and 5 mg). Plasma levels of SLV 308 were determined and the relation with D₂ receptor occupancy was investigated.

Results: In MPTP-treated marmosets, SLV 308 (0.087 and 0.26 and 0.87 mg/kg) resulted in an increase in locomotor activity and a decrease in disability counts over the 7 hours tested, although the highest dose resulted in sedation and ataxia in the initial 4 hours. Mean plasma levels were between 3 and 38 ng/ml. In humans a D₂ receptor occupancy of at least 60% corresponded with plasma levels of SLV 308 exceeding 3 ng/ml.

Conclusion: Effective plasma levels of SLV 308 in MPTP-treated marmosets are comparable to those giving at least 60% occupancy at the striatal D₂ receptors in humans.