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

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journal contribution
posted on 21.07.2010, 00:00 by Kazunori Kawamura, Megumi Akiyama, Joji Yui, Tomoteru Yamasaki, Akiko Hatori, Katsushi Kumata, Hidekatsu Wakizaka, Makoto Takei, Nobuki Nengaki, Kazuhiko Yanamoto, Toshimitsu Fukumura, Ming-Rong Zhang
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 radioactivity after injection with [11C]JP-1302 in the brain was different from that of α2C-ARs. In P-gp/Bcrp knockout mice, uptake of [11C]MBF was approximately 3.7-fold higher and that of [11C]JP-1302 was approximately 1.6-fold higher than those in wild-type mice. These results indicate that brain penetration of the two PET probes was affected by modulation of P-gp and Bcrp functions.