In vivo evaluation of limiting brain penetration of probes for α(2C)-adrenoceptor using small-animal positron emission tomography.
To evaluate in vivo brain penetration of α(2C)-adrenoceptor (α(2C)-AR) antagonists as a therapeutic agent, we synthesized two new (11)C-labeled selective α(2C)-AR antagonists 4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methyl-2-aryl-7-methoxybenzofuran ([(11)C]MBF) and acridin-9-yl-[4-(4-methylpiperazin-1-yl)phenyl]amine ([(11)C]JP-1302) as α(2C)-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 [(11)C]MBF initially increased and effluxed immediately from the brain, whereas that with [(11)C]JP-1302 was distributed throughout the brain. However, the regional distribution of radioactivity after injection with [(11)C]JP-1302 in the brain was different from that of α(2C)-ARs. In P-gp/Bcrp knockout mice, uptake of [(11)C]MBF was approximately 3.7-fold higher and that of [(11)C]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.
Department of Molecular Probes Molecular Imaging Center, National Institute of Radiological Sciences,Chiba 263-8555, Japan. kawamur@nirs.go.jp
Kazunori
K
Kawamura
Megumi
M
Akiyama
Joji
J
Yui
Tomoteru
T
Yamasaki
Akiko
A
Hatori
Katsushi
K
Kumata
Hidekatsu
H
Wakizaka
Makoto
M
Takei
Nobuki
N
Nengaki
Kazuhiko
K
Yanamoto
Toshimitsu
T
Fukumura
Ming-Rong
MR
Zhang
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000378:metabolism; D000166:Acridines / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D001692:Biological Transport; D001812:Blood-Brain Barrier; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000032:analysis; D007546:Isoquinolines / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D011807:Quinolizines / Q000493:pharmacokinetics; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
C582725:4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methyl-2-phenyl-7-methoxybenzofuran; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000166:Acridines; D000317:Adrenergic alpha-Antagonists; D001572:Benzofurans; D002250:Carbon Radioisotopes; D007546:Isoquinolines; C518829:JP-1302; D009419:Nerve Tissue Proteins; D010879:Piperazines; D011807:Quinolizines; D018341:Receptors, Adrenergic, alpha-2; C054290:L 657743