title: Assessment of the in vitro and in vivo properties of a (99m)Tc-labeled inhibitor of the multidrug resistant gene product P-glycoprotein.
abstract: Overexpression of P-glycoprotein (Pgp), which is present in the plasma membrane of various tumor cells and in several normal cell types, contributes to the multidrug resistance (MDR) phenotype of many human cancers. As a prerequisite for therapy, the expression of Pgp must be studied. The available clinical radiopharmaceuticals for studying the expression of Pgp include the lipophilic (99m)Tc cations (sestamibi, tetrofosmin) as well as [(99m)Tc]Q57, [(99m)Tc]Q58, and [(99m)Tc]Q63. Here we describe the in vitro and in vivo properties of the structurally different complex (3-thiapentane-1, 5-dithiolato)[[N-(3-phenylpropyl)-N-2(3-quinazoline-2, 4-dionyl)-ethyl]amino-ethylthiolato¿ oxotechnetium(V) ((99/99m)Tc1) as a potential inhibitor of Pgp. (99)Tc1 enhances the net cell accumulation of Pgp substrates [(3)H]vinblastine, [(3)H]vincristine, [(3)H]colchicine, [(99m)Tc]sestamibi, and [(99m)Tc]tetrofosmin in rat brain endothelial cells (RBE4), an immortalized endothelial cell line that expresses Pgp. In addition, the cell accumulation of (99m)Tc1 could be increased by verapamil and reserpine, which are known Pgp inhibitors. A multitracer approach was used to study the side effects of (99)Tc1 on cell metabolism. The cells were simultaneously incubated with [(99m)Tc]sestamibi, 2-[(18)F]fluoro-2-deoxyglucose ([(18)F]FDG), and various (3)H-labeled tracers. Two-dimensional scatter plots of [(99m)Tc]sestamibi uptake/[(18)F]FDG uptake show typical changes of known Pgp inhibitors including (99)Tc1. The effects of (99)Tc1 on the in vivo distribution of [(99m)Tc]sestamibi and [(18)F]FDG in rats also are comparable with the effects of verapamil, an established Pgp inhibitor and calcium channel blocker. We conclude that (99/99m)Tc1 is a transport substrate and a potential inhibitor of Pgp. Our approach may be useful in the design of further radiotracers with specificity to Pgp.
authors.affiliation: Forschungszentrum Rossendorf, Institut Fü;-1qr Bioanorganische und Radiopharmazeutische Chemie, Dresden, Germany. R.Bergmann@fzrossendorf.de
authors.forename: R
authors.initials: R
authors.lastname: Bergmann
authors.forename: P
authors.initials: P
authors.lastname: Brust
authors.forename: M
authors.initials: M
authors.lastname: Scheunemann
authors.forename: H J
authors.initials: HJ
authors.lastname: Pietzsch
authors.forename: S
authors.initials: S
authors.lastname: Seifert
authors.forename: F
authors.initials: F
authors.lastname: Roux
authors.forename: B
authors.initials: B
authors.lastname: Johannsen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D019788:Fluorodeoxyglucose F18; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D009943:Organophosphorus Compounds; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019275:Radiopharmaceuticals; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017256:Technetium Tc 99m Sestamibi; D014407:Tumor Cells, Cultured
chemical_list: C411185:3-thiapentane-1,5-dithiolato)((N-(3-phenylpropyl)-N-2(3-quinazoline-2, 4-dionyl)ethylaminoethylthiolato)oxotechnetium(V); D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; D015609:Organotechnetium Compounds; D012333:RNA, Messenger; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C078700:technetium tc-99m tetrofosmin; D017256:Technetium Tc 99m Sestamibi