Novel gallium(III) complexes transported by MDR1 P-glycoprotein: potentialPET imaging agents for probing P-glycoprotein-mediated transport activity in vivo

Background: Multidrug resistance (MDR) mediated by expression of MDR1 P-gly coprotein (Pgp) represents one of the best characterized barriers to chemot herapy in cancer patients. Positron emission tomography (PET) agents for an alysis of Pgp-mediated drug transport activity in vivo would enable noninva sive assessment of chemotherapeutic regimens and MDR gene therapy. Results: Candidate Schiff-base phenolic gallium(III) complexes were synthes ized from their heptadentate precursors and gallium(III)acetylacetonate. Cr ystal structures demonstrated a hexacoordinated central gallium with overal l trans-pseudo-octahedral geometry. Radiolabeled Ga-67-complexes were obtai ned in high purity and screened in drug-sensitive (Pgp(-)) and MDR (Pgp(+)) tumor cells. Compared with control, lead compound 6 demonstrated antagonis t-reversible 55-fold lower accumulation in Pgp-expressing MDR cells. Furthe rmore, compared with wild-type control, quantitative pharmacokinetic analys is showed markedly increased penetration and retention of 6 in brain and li ver tissues of mdr1a/b((-/-)) gene disrupted mice, correctly mapping Pgp-me diated transport activity at the capillary blood-brain barrier and hepatoce llular biliary cannalicular surface in vivo. Conclusions: These results indicate that gallium(III) complex 6 is recogniz ed by MDR1 Pgp as an avid transport substrate, thereby providing a useful s caffold to generate Ga-68 radiopharmaceuticals for molecular imaging of Pgp transport activity in tumors and tissues in vivo using PET.