Synthesis and small-animal positron emission tomography evaluation of [11C]-elacridar as a radiotracer to assess the distribution of P-glycoprotein at the blood-brain barrier.
With the aim to develop a positron emission tomography (PET) tracer to assess the distribution of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) in vivo, the potent third-generation P-gp inhibitor elacridar (1) was labeled with (11)C by reaction of O-desmethyl 1 with [(11)C]-methyl triflate. In vitro autoradiography and small-animal PET imaging of [(11)C]-1 was performed in rats (n = 3), before and after administration of unlabeled 1, as well as in wild-type, Mdr1a/b((-/-)) and Bcrp1((-/-)) mice (n = 3). In PET experiments in rats, administration of unlabeled 1 increased brain activity uptake 5.4-fold, whereas blood activity levels remained unchanged. In Mdr1a/b((-/-)) mice, brain activity uptake was 2.5-fold higher compared to wild-type animals, whereas in Bcrp1((-/-)) mice, brain activity uptake was only 1.3-fold higher. In vitro autoradiography showed that 63% of [(11)C]-1 binding was displaceable by an excess of unlabeled 1. As the signal obtained with [(11)C]-1 appeared to be specific for P-gp at the BBB, its utility for the visualization of cerebral P-gp merits further investigation.
Dörner
Bernd
B
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.
Kuntner
Claudia
C
Bankstahl
Jens P
JP
Bankstahl
Marion
M
Stanek
Johann
J
Wanek
Thomas
T
Stundner
Gloria
G
Mairinger
Severin
S
Löscher
Wolfgang
W
Müller
Markus
M
Langer
Oliver
O
Erker
Thomas
T
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis* / Q000037:antagonists & inhibitors; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000166:Acridines; D000818:Animals; D001345:Autoradiography; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging* / Q000378:metabolism; D002250:Carbon Radioisotopes; D051379:Mice; D018345:Mice, Knockout; D049268:Positron-Emission Tomography / Q000379:methods; D051381:Rats; D044005:Tetrahydroisoquinolines; D014018:Tissue Distribution
D018435:ATP Binding Cassette Transporter, Subfamily B; 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; D002250:Carbon Radioisotopes; D044005:Tetrahydroisoquinolines; C095122:multidrug resistance protein 3; C083501:Elacridar