Importance of the field: The incorporation of brain tissue binding routinely in CNS drug discovery screening strategies has markedly changed the way CNS drug discovery is performed and is proving to be a valuable tool in identifying new therapies for CNS diseases. For many years emphasis has been placed on the magnitude of the brain to blood ratio, the bigger the better, even though, in many cases, brain total concentration (C(brain)) has no or, at best, poor correlation with receptor occupancy/pharmacodynamic readout. Today, C(brain) values measured during in vivo experiments are corrected for the fraction unbound measured through in vitro experiments using brain tissue homogenate or brain tissue slice to obtain an estimate of the brain unbound concentration (C(u,brain)), and this has been demonstrated across a range of CNS targets to give a much better correlation with receptor occupancy/pharmacodynamic readout. This apparently simple change in CNS lead optimisation strategy has de facto revolutionised the vision of the brain penetration concepts.
Areas covered in this review: This review will provide an overview of the use and applications of assessing brain free fraction to determine C(u,brain).
Take home message: Assessing brain free fraction to determine C(u,brain) in CNS lead optimisation strategies is the surrogate of choice for rapidly assessing biophase concentration for the majority of CNS targets.