Figure 2.

(a) Brain penetrance of (S)-MRI-1891 upon a single (acute) dose or 28 days of chronic oral dosing in lean control male C57Bl/6J mice. Drug levels in plasma and buffer-perfused brain were measured by LC/MS/MS 1 h after the last dose (plasma C_max). Free concentration in brain was determined by equilibrium dialysis using crude membranes from the brain of CB₁R-knockout (KO) mice as described and corresponded to 0.3% of total brain levels measured. (b) In vivo binding of (S)-MRI-1891 or rimonabant to mouse brain CB₁R as assessed by displacement of a positron emission tomography (PET) radiotracer administered 1 h after acute dosing or 28 days of chronic oral administration of the CB₁R antagonist, as described in the Supporting Information and in ref (7). Values represent mean ± SEM from 3 to 6 independent experiments. Scans from representative experiments are shown in the bottom. (c) Anxiogenic behavior induced by rimonabant, but not (S)-MRI-1891, as determined by the elevated plus maze test (see the Supporting Information). Columns and vertical bars represent mean ± SEM of 4–6 independent experiments.