title: In vivo imaging of multidrug resistance using a third generation MDR1 inhibitor.
abstract: Cellular up-regulation of multidrug resistance protein 1 (MDR1) is a common cause for resistance to chemotherapy; development of third generation MDR1 inhibitors-several of which contain a common 6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline substructure-is underway. Efficacy of these agents has been difficult to ascertain, partly due to a lack of pharmacokinetic reporters for quantifying inhibitor localization and transport dynamics. Some of the recent third generation inhibitors have a pendant heterocycle, for example, a chromone moiety, which we hypothesized could be converted to a fluorophore. Following synthesis and teasing of a small set of analogues, we identified one lead compound that can be used as a cellular imaging agent that exhibits structural similarity and behavior akin to the latest generation of MDR1 inhibitors.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital , 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, United States.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Sprachman
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Laughney
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Kohler
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005456:Fluorescent Dyes / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D017239:Paclitaxel / Q000494:pharmacology; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000494:pharmacology*; D062367:ortho-Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D005456:Fluorescent Dyes; D044005:Tetrahydroisoquinolines; D062367:ortho-Aminobenzoates; D017239:Paclitaxel; C000219:anthranilamide