title: Radiosynthesis and in vivo evaluation of 1-[18F]fluoroelacridar as a positron emission tomography tracer for P-glycoprotein and breast cancer resistance protein.
abstract: Aim of this study was to label the potent dual P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) inhibitor elacridar (1) with (18)F to provide a positron emission tomography (PET) radiotracer to visualize Pgp and BCRP. A series of new 1- and 2-halogen- and nitro-substituted derivatives of 1 (4a-e) was synthesized as precursor molecules and reference compounds for radiolabelling and shown to display comparable in vitro potency to 1 in increasing rhodamine 123 accumulation in a cell line overexpressing human Pgp (MDCKII-MDR1). 1-[(18)F]fluoroelacridar ([(18)F]4b) was synthesized in a decay-corrected radiochemical yield of 1.7±0.9% by a 1-step no-carrier added nucleophilic aromatic (18)F-substitution of 1-nitro precursor 4c. Small-animal PET imaging of [(18)F]4b was performed in naïve rats, before and after administration of unlabelled 1 (5 mg/kg, n=3), as well as in wild-type and Mdr1a/b((-/-))Bcrp1((-/-)) mice (n=3). In PET experiments in rats, administration of unlabelled 1 increased brain activity uptake by a factor of 9.5 (p=0.0002, 2-tailed Student's t-test), whereas blood activity levels remained unchanged. In Mdr1a/b((-/-))Bcrp1((-/-)) mice, the mean brain-to-blood ratio of activity at 60 min after tracer injection was 7.6 times higher as compared to wild-type animals (p=0.0002). HPLC analysis of rat brain tissue extracts collected at 40 min after injection of [(18)F]4b revealed that 93±7% of total radioactivity in brain was in the form of unchanged [(18)F]4b. In conclusion, the in vivo behavior of [(18)F]4b was found to be similar to previously described [(11)C]1 suggesting transport of [(18)F]4b by Pgp and/or BCRP at the rodent BBB. However, low radiochemical yields and a significant degree of in vivo defluorination will limit the utility of [(18)F]4b as a PET tracer.
authors.affiliation: Department of Medicinal Chemistry, University of Vienna, Austria.
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörner
authors.forename: Claudia
authors.initials: C
authors.lastname: Kuntner
authors.forename: Jens P
authors.initials: JP
authors.lastname: Bankstahl
authors.forename: Thomas
authors.initials: T
authors.lastname: Wanek
authors.forename: Marion
authors.initials: M
authors.lastname: Bankstahl
authors.forename: Johann
authors.initials: J
authors.lastname: Stanek
authors.forename: Julia
authors.initials: J
authors.lastname: Müllauer
authors.forename: Florian
authors.initials: F
authors.lastname: Bauer
authors.forename: Severin
authors.initials: S
authors.lastname: Mairinger
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Löscher
authors.forename: Donald W
authors.initials: DW
authors.lastname: Miller
authors.forename: Peter
authors.initials: P
authors.lastname: Chiba
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Erker
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000378:metabolism; D000166:Acridines / Q000737:chemistry*; D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism; D001943:Breast Neoplasms / Q000097:blood / Q000000981:diagnostic imaging* / Q000378:metabolism; D018432:Drug Resistance, Multiple; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006801:Humans; D007553:Isotope Labeling; D051379:Mice; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D005462:Fluorine Radioisotopes; D009363:Neoplasm Proteins; D019275:Radiopharmaceuticals; D044005:Tetrahydroisoquinolines; C083501:Elacridar