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Novel gallium(III) Complexes Transported by MDR1 P-glycoprotein: Potential PET Imaging Agents for Probing P-glycoprotein-mediated Transport Activity in Vivo

Novel gallium(III) Complexes Transported by MDR1 P-glycoprotein: Potential PET Imaging Agents for Probing P-glycoprotein-mediated Transport Activity in Vivo

V Sharma, A Beatty, S P Wey, J Dahlheimer, C M Pica, C L Crankshaw, L Bass, M A Green, M J Welch, D Piwnica-Worms

Chem Biol. 2000 May;7(5):335-43.

PMID: 10801474

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP14405437	Gallium(III) acetylacetonate		14405-43-7	Price

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