Crankshaw C L, Marmion M, Luker G D, Rao V, Dahlheimer J, Burleigh B D, Webb E, Deutsch K F, Piwnica-Worms D
Mallinckrodt Institute of Radiology, and Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, Missouri 63110, USA.
J Nucl Med. 1998 Jan;39(1):77-86.
Overexpression of the multidrug resistance (MDR1) P-glycoprotein (Pgp) correlates with cancer chemotherapeutic failure. Lipophilic cationic radiopharmaceuticals such as 99mTc-sestamibi, 99mTc-tetrofosmin and 99Tc-furifosmin (Tc-Q12) have been validated as transport substrates for the MDR1 Pgp and may enable functional imaging of the MDR phenotype in cancer by observing enhanced washout rates of the tracers in those tumor areas expressing Pgp. To further explore and optimize the Pgp recognition properties of Schiff base phosphine mixed-ligand complexes of the Tc-Q series of nonreducible (Tc(III) cations, a variety of Tc-Q complexes were synthesized and tested in vitro for recognition as transport substrates by the human MDR1 Pgp.
Tracer assays with human drug-sensitive KB-3-1 epidermal carcinoma and MDR KB-8-5 cells expressing nonimmunodetectable and modest levels of MDR1 Pgp, respectively, were used to screen and pharmacologically characterize 37 novel 99mTc-Q analogs.
The ideal agent should have low nonspecific binding, high distinction in net uptake between drug-sensitive cells and MDR tumor cells, and high enhancement of uptake in resistant cells after treatment with an MDR modulator, indicating selective blockade of Pgp-mediated efflux of the radiotracer. Three analogs, trans-[5,5'-(1,2-ethanediyldiimino)bis(2-OEt-2-Me-4-penten-3 -one)]bis[dimethyl(3-OMe-1-propyl)phosphine]99mTc(III) (99mTc-Q63) and two trans-[bis(methyl-bis(3-OMe-1-propyl)phosphine)] analogs (99mTc-Q57 and 99mTc-Q58) displayed transport distinctions between drug-sensitive and MDR cell lines that were equal to or greater than all previously available agents. Cyclosporin A, an MDR modulator, had no significant effect in KB-3-1 cells for these 99mTc-complexes but enhanced tracer accumulations in KB-8-5 cells with IC50 values of approximately 1 microM. In contrast, the non-MDR agents methotrexate and cisplatin had no effect on accumulation of 99mTc-Q complexes and 99mTc-sestamibi in KB-8-5 cells.
Technetium-99m-Q57, 99mTc-Q58 and 99mTc-Q63 are avid transport substrates recognized by the human MDR1 Pgp, and have enhanced in vitro properties that may enable functional imaging of Pgp in vivo with improved signal-to-noise ratios and tissue contrast compared to currently available agents.
多药耐药（MDR1）P-糖蛋白（Pgp）的过表达与癌症化疗失败相关。亲脂性阳离子放射性药物，如99mTc-司他米比、99mTc-替曲膦和99Tc-呋罗膦（Tc-Q12）已被确认为MDR1 Pgp的转运底物，通过观察示踪剂在表达Pgp的肿瘤区域的洗脱率提高，可能实现癌症中MDR表型的功能成像。为了进一步探索和优化Tc-Q系列不可还原的席夫碱膦混合配体配合物（Tc(III)阳离子）的Pgp识别特性，合成了多种Tc-Q配合物，并在体外测试其作为人MDR1 Pgp转运底物的识别情况。
分别用人药物敏感的KB-3-1表皮癌细胞和表达不可检测和适度水平MDR1 Pgp的MDR KB-8-5细胞进行示踪剂分析，以筛选和药理学表征37种新型99mTc-Q类似物。
理想的药物应具有低非特异性结合、药物敏感细胞与MDR肿瘤细胞净摄取的高区分度，以及在用MDR调节剂处理后抗性细胞摄取的高增强，表明Pgp介导的放射性示踪剂外排被选择性阻断。三种类似物，反式-[5,5'-(1,2-乙二胺二亚氨基)双(2-OEt-2-Me-4-戊烯-3-酮)]双[二甲基(3-OMe-1-丙基)膦]99mTc(III)（99mTc-Q63）和两种反式-[双(甲基-双(3-OMe-1-丙基)膦)]类似物（99mTc-Q57和99mTc-Q58）在药物敏感和MDR细胞系之间表现出的转运差异等于或大于所有先前可用的药物。环孢素A，一种MDR调节剂，对这些99mTc配合物在KB-3-1细胞中无显著影响，但在KB-8-5细胞中增强了示踪剂积累，IC50值约为1 microM。相比之下，非MDR药物甲氨蝶呤和顺铂对KB-8-5细胞中99mTc-Q配合物和99mTc-司他米比的积累无影响。
99mTc-Q57、99mTc-Q58和99mTc-Q63是被人MDR1 Pgp识别的 avid 转运底物，并且具有增强的体外特性，与目前可用的药物相比，可能在体内实现Pgp的功能成像，具有改善的信噪比和组织对比度。
