title: Novel gallium(III) complexes transported by MDR1 P-glycoprotein: potential PET imaging agents for probing P-glycoprotein-mediated transport activity in vivo.
abstract: BACKGROUND
  Multidrug resistance (MDR) mediated by expression of MDR1 P-glycoprotein (Pgp) represents one of the best characterized barriers to chemotherapy in cancer patients. Positron emission tomography (PET) agents for analysis of Pgp-mediated drug transport activity in vivo would enable noninvasive assessment of chemotherapeutic regimens and MDR gene therapy.
  
  
  RESULTS
  Candidate Schiff-base phenolic gallium(III) complexes were synthesized from their heptadentate precursors and gallium(III)acetylacetonate. Crystal structures demonstrated a hexacoordinated central gallium with overall trans-pseudo-octahedral geometry. Radiolabeled (67)Ga-complexes were obtained in high purity and screened in drug-sensitive (Pgp(-)) and MDR (Pgp(+)) tumor cells. Compared with control, lead compound 6. demonstrated antagonist-reversible 55-fold lower accumulation in Pgp-expressing MDR cells. Futhermore, compared with wild-type control, quantitative pharmacokinetic analysis showed markedly increased penetration and retention of 6. in brain and liver tissues of mdr1a/b((-/-)) gene disrupted mice, correctly mapping Pgp-mediated transport activity at the capillary blood-brain barrier and hepatocellular biliary cannalicular surface in vivo.
  
  
  CONCLUSIONS
  These results indicate that gallium(III) complex 6. is recognized by MDR1 Pgp as an avid transport substrate, thereby providing a useful scaffold to generate (68)Ga radiopharmaceuticals for molecular imaging of Pgp transport activity in tumors and tissues in vivo using PET.
authors.affiliation: Department of Molecular Biology and Pharmacology, Mallinckrodt Institute of Radiology, Washington University Medical School, St. Louis, MO 63110, USA.
authors.forename: V
authors.initials: V
authors.lastname: Sharma
authors.forename: A
authors.initials: A
authors.lastname: Beatty
authors.forename: S P
authors.initials: SP
authors.lastname: Wey
authors.forename: J
authors.initials: J
authors.lastname: Dahlheimer
authors.forename: C M
authors.initials: CM
authors.lastname: Pica
authors.forename: C L
authors.initials: CL
authors.lastname: Crankshaw
authors.forename: L
authors.initials: L
authors.lastname: Bass
authors.forename: M A
authors.initials: MA
authors.lastname: Green
authors.forename: M J
authors.initials: MJ
authors.lastname: Welch
authors.forename: D
authors.initials: D
authors.lastname: Piwnica-Worms
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D005710:Gallium Radioisotopes / Q000493:pharmacokinetics*; D006801:Humans; D007624:KB Cells; D051379:Mice; D018345:Mice, Knockout; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D014055:Tomography, Emission-Computed; D014407:Tumor Cells, Cultured
chemical_list: C409662:(bis(3-ethoxy-2-hydroxybenzylidene)-N,N''-bis(2,2-dimethyl-3-aminopropyl)ethylenediamine)gallium(III) perchlorate; C409664:(bis(5-ethoxy-2-hydroxybenzylidene)-N,N''-bis(2,2-dimethyl-3-aminopropyl)ethylenediamine)gallium(III) iodide; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005710:Gallium Radioisotopes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals