In Vivo Evaluation of Limiting Brain Penetration of Probes for α2C-Adrenoceptor Using Small-Animal Positron Emission Tomography

To evaluate in vivo brain penetration of α2C-adrenoceptor (α2C-AR) antagonists as a therapeutic agent, we synthesized two new 11C-labeled selective α2C-AR antagonists 4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methyl-2-aryl-7-methoxybenzofuran ([11C]MBF) and acridin-9-yl-[4-(4-methylpiperazin-1-yl)phenyl]amine ([11C]JP-1302) as α2C-AR-selective positron emission tomography (PET) probes. The radiochemical yield, specific activity, and radiochemical purity of these probes was appropriate for injection. To evaluate whether the brain penetration of these probes is related to the function of two major drug efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), we performed PET studies using wild-type and P-gp/Bcrp knockout mice. In wild-type mice, the radioactivity level after injection with [11C]MBF initially increased and effluxed immediately from the brain, whereas that with [11C]JP-1302 was distributed throughout the brain. However, the regional distribution of rad...