Sharma V, Beatty A, Wey S P, Dahlheimer J, Pica C M, Crankshaw C L, Bass L, Green M A, Welch M J, Piwnica-Worms D
Department of Molecular Biology and Pharmacology, Mallinckrodt Institute of Radiology, Washington University Medical School, St. Louis, MO 63110, USA.
Chem Biol. 2000 May;7(5):335-43. doi: 10.1016/s1074-5521(00)00111-3.
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.
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.
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.
由多药耐药蛋白1（MDR1）P-糖蛋白（Pgp）表达介导的多药耐药（MDR）是癌症患者化疗中最具特征的障碍之一。用于分析体内Pgp介导的药物转运活性的正电子发射断层扫描（PET）剂将能够对化疗方案和MDR基因治疗进行无创评估。
候选席夫碱酚镓（III）配合物由其七齿前体和乙酰丙酮镓（III）合成。晶体结构表明中心镓为六配位，具有整体反式假八面体几何构型。以高纯度获得放射性标记的（67）Ga配合物，并在药物敏感（Pgp（-））和MDR（Pgp（+））肿瘤细胞中进行筛选。与对照相比，先导化合物6在表达Pgp的MDR细胞中的积累降低了55倍，具有拮抗剂可逆性。此外，与野生型对照相比，定量药代动力学分析表明，在mdr1a/b（-/-）基因敲除小鼠的脑和肝组织中，6的渗透和滞留显著增加，正确地在体内绘制了Pgp介导的毛细血管血脑屏障和肝细胞胆小管表面的转运活性。
这些结果表明，镓（III）配合物6被MDR1 Pgp识别为一种活跃的转运底物，从而提供了一个有用的支架，用于生成（68）Ga放射性药物，用于使用PET对体内肿瘤和组织中的Pgp转运活性进行分子成像。
