title: Synthesis and in vivo evaluation of ¹⁸F-fluoroethyl GF120918 and XR9576 as positron emission tomography probes for assessing the function of drug efflux transporters.
abstract: The purpose of this study was to synthesize two new positron emission tomography (PET) probes, N-(4-(2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl)phenyl)-9,10-dihydro-5-[¹⁸F]fluoroethoxy-9-oxo-4-acridine carboxamide ([¹⁸F]3) and quinoline-3-carboxylic acid [2-(4-{2-[7-(2-[¹⁸F]fluoroethoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]ethyl}phenylcarbamoyl)-4,5-dimethoxyphenyl]amide ([¹⁸F]4), and to evaluate the potential of these PET probes for assessing the function of two major drug efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). [¹⁸F]3 and [¹⁸F]4 were synthesized by ¹⁸F-alkylation of each O-desmethyl precursor with [¹⁸F]2-fluoroethyl bromide for injection as PET probes. In vitro accumulation assay showed that treatment with P-gp/BCRP inhibitors (1 and 2) enhanced the intracellular accumulation capacity of P-gp- and BCRP-overexpressing MES-SA/Dx5 cells. In PET studies, the uptake (AUC(brain[0-)₆₀ (min])) of [¹⁸F]3 and [¹⁸F]4 in wild-type mice co-injected with 1 were approximately sevenfold higher than that in wild-type mice, and the uptake of [¹⁸F]3 and [¹⁸F]4 in P-gp/Bcrp knockout mice were eight- to ninefold higher than that in wild-type mice. The increased uptake of [¹⁸F]3 and [¹⁸F]4 was similar to that of parent compounds ([¹¹C]1 and [¹¹C]2) previously described, indicating that radioactivity levels in the brain after injection of [¹⁸F]3 and [¹⁸F]4 are related to the function of drug efflux transporters. Also, these results suggest that the structural difference between parent compounds ([¹¹C]1 and [¹¹C]2) and fluoroethyl analogs ([¹⁸F]3 and [¹⁸F]4) do not obviously affect the potency against drug efflux transporters. In metabolite analysis of mice, the unchanged form in the brain and plasma at 60 min after co-injection of [¹⁸F]4 plus 1 were higher (95% for brain; 81% for plasma) than that after co-injection of [¹⁸F]3 plus 1. [¹⁸F]4 is a promising PET probe to assess the function of drug efflux transporters.
authors.affiliation: Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba, Japan. kawamur@nirs.go.jp
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Fujiko
authors.initials: F
authors.lastname: Konno
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yanamoto
authors.forename: Hidekatsu
authors.initials: H
authors.lastname: Wakizaka
authors.forename: Masanao
authors.initials: M
authors.lastname: Ogawa
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nengaki
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Fukumura
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D005462:Fluorine Radioisotopes / Q000737:chemistry; D006801:Humans; D051379:Mice; D015335:Molecular Probes / Q000138:chemical synthesis* / Q000737:chemistry; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D005462:Fluorine Radioisotopes; D015335:Molecular Probes; D011804:Quinolines; D019275:Radiopharmaceuticals; D044005:Tetrahydroisoquinolines; C402343:tariquidar; C083501:Elacridar