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

• Published in: Journal of medicinal chemistry Vol. 52; no. 19; pp. 6073 - 6082
• Main Authors: Dörner, Bernd, Kuntner, Claudia, Bankstahl, Jens P, Bankstahl, Marion, Stanek, Johann, Wanek, Thomas, Stundner, Gloria, Mairinger, Severin, Löscher, Wolfgang, Müller, Markus, Langer, Oliver, Erker, Thomas
• Format: Journal Article
• Language: English
• Published: Columbus, OH American Chemical Society 08-10-2009
• Subjects: Acridines; Animals; ATP Binding Cassette Transporter, Sub-Family B - genetics; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - analysis; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; Autoradiography; Biological and medical sciences; Blood-Brain Barrier - diagnostic imaging; Blood-Brain Barrier - metabolism; Carbon Radioisotopes; Contrast media. Radiopharmaceuticals; Medical sciences; Mice; Mice, Knockout; Pharmacology. Drug treatments; Positron-Emission Tomography - methods; Rats; Tetrahydroisoquinolines; Tissue Distribution; Transmembrane protein; Elacridar; Rat; Rodentia; P Glycoprotein; Central nervous system; Carbon Isotopes; Blood brain barrier; In vitro; Autoradiography; In vivo; Vertebrata; Metabolic stability; Mammalia; Mouse; Scintigraphic agent; Animal; Distribution; Carbon 11; Radioisotopic product; Chemical synthesis; Positron emission tomography; ABC transporter; Carrier protein
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900940f

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 11C by reaction of O-desmethyl 1 with [11C]-methyl triflate. In vitro autoradiography and small-animal PET imaging of [11C]-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 [11C]-1 binding was displaceable by an excess of unlabeled 1. As the signal obtained with [11C]-1 appeared to be specific for P-gp at the BBB, its utility for the visualization of cerebral P-gp merits further investigation.