SLV 308: plasma levels of effective doses in MPTP‐treated marmosets in comparison with plasma levels and D 2 receptor occupancy (PET) in humans

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 D 2 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 D 2 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 11 C‐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 D 2 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 D 2 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 D 2 receptors in humans. Clinical Pharmacology & Therapeutics (2004) 75 , P70–P70; doi: 10.1016/j.clpt.2003.11.265