Synthesis and in vivo evaluation of [11C]tariquidar, a positron emission tomography radiotracer based on a third-generation P-glycoprotein inhibitor

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 15; pp. 5489 - 5497
• Main Authors: Bauer, Florian, Kuntner, Claudia, Bankstahl, Jens P., Wanek, Thomas, Bankstahl, Marion, Stanek, Johann, Mairinger, Severin, Dörner, Bernd, Löscher, Wolfgang, Müller, Markus, Erker, Thomas, Langer, Oliver
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-08-2010; Elsevier
• Subjects: [11C]tariquidar; Animals; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - antagonists & inhibitors; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Autoradiography; Biological and medical sciences; Blood-brain barrier; Blood-Brain Barrier - metabolism; Breast cancer resistance protein; Carbon Radioisotopes - chemistry; Contrast media. Radiopharmaceuticals; Female; Medical sciences; Mice; Mice, Knockout; P-glycoprotein; PET; Pharmacology. Drug treatments; Positron-Emission Tomography; Quinolines - chemistry; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Rats; Rats, Sprague-Dawley; BCRP; BBB; P-gp; SPE; Bcrp1(−/−) mouse; Breast cancer resistance protein; [11C]tariquidar; P-glycoprotein; Mdr1a/b(−/−)Bcrp1(−/−) mouse; Blood-brain barrier; SUV; TAC; Mdr1a/b(−/−) mouse; PET; Antineoplastic agent; Rat; Tariquidar; P Glycoprotein; Central nervous system; Carbon Isotopes; Molecular interaction; Blood brain barrier; Encephalon; Tissue; Scintigraphic agent; Carbon 11; [; Chemical synthesis; Carrier protein; Transmembrane protein; Isoquinoline derivatives; Radiolabelling; Rodentia; In vitro; Autoradiography; In vivo; Vertebrata; Biological fixation; Mammalia; Mouse; Animal; Distribution; Pharmacokinetics; C]tariquidar; Chemosensitizing agent; Positron emission tomography; ABC transporter
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.06.057

The aim of this study was to develop a positron emission tomography (PET) tracer based on the dual P-glycoprotein (P-gp) breast cancer resistance protein (BCRP) inhibitor tariquidar (1) to study the interaction of 1 with P-gp and BCRP in the blood–brain barrier (BBB) in vivo. O-Desmethyl-1 was synthesized and reacted with [11C]methyl triflate to afford [11C]-1. Small-animal PET imaging of [11C]-1 was performed in naïve rats, before and after administration of unlabeled 1 (15mg/kg, n=3) or the dual P-gp/BCRP inhibitor elacridar (5mg/kg, n=2), as well as in wild-type, Mdr1a/b(−/−), Bcrp1(−/−) and Mdr1a/b(−/−)Bcrp1(−/−) mice (n=3). In vitro autoradiography was performed with [11C]-1 using brain sections of all four mouse types, with and without co-incubation with unlabeled 1 or elacridar (1μM). In PET experiments in rats, administration of unlabeled 1 or elacridar increased brain activity uptake by a factor of 3–4, whereas blood activity levels remained unchanged. In Mdr1a/b(−/−), Bcrp1(−/−) and Mdr1a/b(−/−)Bcrp1(−/−) mice, brain-to-blood ratios of activity at 25min after tracer injection were 3.4, 1.8 and 14.5 times higher, respectively, as compared to wild-type animals. Autoradiography showed approximately 50% less [11C]-1 binding in transporter knockout mice compared to wild-type mice and significant displacement by unlabeled elacridar in wild-type and Mdr1a/b(−/−) mouse brains. Our data suggest that [11C]-1 interacts specifically with P-gp and BCRP in the BBB. However, further investigations are needed to assess if [11C]-1 behaves in vivo as a transported or a non-transported inhibitor.