Large Variation in Brain Exposure of Reference CNS Drugs: a PET Study in Nonhuman Primates

Background: Positron emission tomography microdosing of radiolabeled drugs allows for noninvasive studies of organ exposure in vivo. The aim of the present study was to examine and compare the brain exposure of 12 commercially available CNS drugs and one non-CNS drug. Methods: The drugs were radiolabeled with C-11 (t(1/2) = 20.4 minutes) and examined using a high resolution research tomograph. In cynomolgus monkeys, each drug was examined twice. In rhesus monkeys, a first positron emission tomography microdosing measurement was repeated after preadministration with unlabeled drug to examine potential dose-dependent effects on brain exposure. Partition coefficients between brain and plasma (K-P) were calculated by dividing the AUC(0-90) min for brain with that for plasma or by a compartmental analysis (V-T). Unbound K-P (K-Pu,K-u) was obtained by correction for the free fraction in brain and plasma. Results: After intravenous injection, the maximum radioactivity concentration (C-max,C- (%ID)) in brain ranged from 0.01% to 6.2%. For 10 of the 12 CNS drugs, C-max,C- (%ID) was > 2%, indicating a preferential distribution to brain. A lower C-max,C- %ID was observed for morphine, sulpiride, and verapamil. K-P ranged from 0.002 (sulpiride) to 68 (sertraline) and 7 of 13 drugs had K-Pu,K-u close to unity. For morphine, sulpiride, and verapamil, K-Pu,K-u was < 0.3, indicating impaired diffusion and/or active efflux. Brain exposure at microdosing agreed with pharmacological dosing conditions for the investigated drugs. Conclusions: This study represents the largest positron emission tomography study on brain exposure of commercially available CNS drugs in nonhuman primates and may guide interpretation of positron emission tomography microdosing data for novel drug candidates.