Health & Environment Department, Biomedical Systems, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
Nucl Med Biol. 2012 Nov;39(8):1219-25. doi: 10.1016/j.nucmedbio.2012.08.005. Epub 2012 Sep 13.
With the aim to develop a PET tracer to visualize P-glycoprotein (Pgp) expression levels in different organs, the Pgp inhibitor MC113 was labeled with (11)C and evaluated using small-animal PET.
[(11)C]MC113 was synthesized by reaction of O-desmethyl MC113 with [(11)C]methyl triflate. Small-animal PET was performed with [(11)C]MC113 in FVB wild-type and Mdr1a/b((-/-)) mice (n=3 per group) and in a mouse model of high (EMT6Ar1.0) and low (EMT6) Pgp expressing tumor grafts (n=5). In the tumor model, PET scans were performed before and after administration of the reference Pgp inhibitor tariquidar (15mg/kg).
Brain uptake of [(11)C]MC113, expressed as area under the time-activity curve from time 0 to 60min (AUC(0-60)), was moderately but not significantly increased in Mdr1a/b((-/-)) compared with wild-type mice (mean±SD AUC(0-60), Mdr1a/b((-/-)): 88±7min, wild-type: 62±6min, P=0.100, Mann Whitney test). In the tumor model, AUC(0-60) values were not significantly different between EMT6Ar1.0 and EMT6 tumors. Neither in brain nor in tumors was activity concentration significantly changed in response to tariquidar administration. Half-maximum effect concentrations (IC(50)) for inhibition of Pgp-mediated rhodamine 123 efflux from CCRFvcr1000 cells were 375±60nM for MC113 versus 8.5±2.5nM for tariquidar.
[(11)C]MC113 showed higher brain uptake in mice than previously described Pgp PET tracers, suggesting that [(11)C]MC113 was only to a low extent effluxed by Pgp. However, [(11)C]MC113 was found unsuitable to visualize Pgp expression levels presumably due to insufficiently high Pgp binding affinity of MC113 in relation to Pgp densities in brain and tumors.
为了开发一种用于可视化不同器官中 P-糖蛋白（Pgp）表达水平的 PET 示踪剂，我们将 Pgp 抑制剂 MC113 标记上 (11)C，并使用小动物 PET 进行评估。
用 [(11)C]甲基三氟甲磺酸对 O-去甲 MC113 进行反应，合成 [(11)C]MC113。用 [(11)C]MC113 在 FVB 野生型和 Mdr1a/b((-/-)) 小鼠（每组 3 只）以及高（EMT6Ar1.0）和低（EMT6）Pgp 表达肿瘤移植物的小鼠模型中进行小动物 PET（n=5）。在肿瘤模型中，在给予参考 Pgp 抑制剂 tariquidar（15mg/kg）前后进行 PET 扫描。
脑内 [(11)C]MC113 的摄取，以 0 至 60 分钟的时间-活性曲线下面积（AUC(0-60)）表示，在 Mdr1a/b((-/-)) 与野生型小鼠之间中度增加，但无统计学意义（Mdr1a/b((-/-))：88±7min，野生型：62±6min，P=0.100，Mann Whitney 检验）。在肿瘤模型中，EMT6Ar1.0 和 EMT6 肿瘤之间的 AUC(0-60) 值没有显著差异。在脑内和肿瘤内，tariquidar 给药后活性浓度均无明显变化。MC113 对 CCRFvcr1000 细胞中 rhodamine 123 外排的 Pgp 介导的半最大效应浓度（IC(50)）为 375±60nM，而 tariquidar 为 8.5±2.5nM。
与之前描述的 Pgp PET 示踪剂相比，[(11)C]MC113 在小鼠中显示出更高的脑摄取，这表明 [(11)C]MC113 仅被 Pgp 低度外排。然而，[(11)C]MC113 被发现不适合可视化 Pgp 表达水平，可能是由于 MC113 与脑和肿瘤中的 Pgp 密度相比，其与 Pgp 的结合亲和力不够高。
