PET imaging of P-glycoprotein at the blood-brain barrier with new 18F-tracers

Brain is protected from the molecules circulating in the bloodstream by the blood-brain barrier (BBB). Transporter proteins at the BBB, especially P-glycoprotein (P-gp), have been found to be important in regulating brain entry of several compounds by removing them out of the brain. Decreased or increased P-gp function is linked to several neurological diseases, such as epilepsy and Alzheimer’s disease. We developed novel radiotracers for measuring P-gp function by imaging using positron emission tomography (PET). PET scanner locates and measures radioactive tracers that have been injected into the body. We used fluorine-18 to label our P-gp imaging tracers. Fluorine-18 has a half-life of 110 min, optimal radionuclide properties for imaging, and permits transport to other imaging centers. These new radiotracers were evaluated in cells assays and in several animal models. A compound called [18F]MC225 was identified as a weak P-gp substrate. In the normal situation, it has a low uptake in the brain since it is transported out by P-gp but when P-gp function is inhibited, the brain uptake increases. In addition, [18F]MC225 had good selectivity to P-gp and moderate metabolic stability. Therefore, [18F]MC225 is a suitable tracer for measuring P-gp function with PET.