[Imaging blood-brain barrier function by using positron emission tomography to evaluate drug penetration into the...

In drug development, the extent to which a target drug penetrates the blood-brain barrier (BBB) is important. Positron emission tomography (PET) has enabled imaging of BBB functions in vivo, directly or indirectly, based on the characteristics of PET probes. Recent studies have demonstrated that drug penetration into the brain is limited by drug efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein , which are expressed at the BBB. [11C]verapamil is the first probe used to evaluate P-gp function at the BBB because verapamil is a substrate of P-gp and is usually extruded from the brain via active transport by P-gp. However, many studies have shown that [11C]verapamil uptake is altered on administration of P-gp inhibitors and in neuropsychiatric diseases. Further, various PET probes evaluating these efflux transporters are currently under development. We used [11C]FLB 457 to evaluate dopamine D2 receptor occupancy by several antipsychotic drugs in the pituitary gland located outside the BBB and the temporal cortex located in the brain. We compared the receptor occupancy in both regions and found that high occupancy in the pituitary gland meant low penetration of the drug into the brain, as in the case of sulpiride, whereas low occupancy in the pituitary gland meant high penetration, as in the case of olanzapine. This indicated that sulpiride penetrated less into the brain and caused hyperprolactinemia due to the high pituitary occupancy. Furthermore, we developed a tracer, [11C]sulpiride, to directly demonstrate the low penetration of sulpiride into the brain.