11C-Labeled Pictilisib (GDC-0941) as a Molecular Tracer Targeting Phosphatidylinositol 3-Kinase (PI3K) for Breast Cancer Imaging.,Contrast Media & Molecular Imaging

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11C-Labeled Pictilisib (GDC-0941) as a Molecular Tracer Targeting Phosphatidylinositol 3-Kinase (PI3K) for Breast Cancer Imaging.
Contrast Media & Molecular Imaging ( IF 3.009 ) Pub Date : 2019-11-03 , DOI: 10.1155/2019/1760184
Na Han _{1,

2,

3} , Yaqun Jiang _{1,

2} , Yongkang Gai _{1,

2} , Qingyao Liu _{1,

2} , Lujie Yuan _{1,

2} , Yichun Wang _{1,

2} , Mengting Li _{1,

2} , Yongxue Zhang _{1,

2} , Xiaoli Lan _{1,

2}

Affiliation

Pictilisib (GDC-0941) is an inhibitor of phosphatidylinositol 3-kinase (PI3K), part of a signaling cascade involved in breast cancer development. The purpose of this study was to evaluate the pharmacokinetics of pictilisib noninvasively by radiolabeling it with 11C and to assess the usability of the resulting [11C]-pictilisib as a positron-emission tomography (PET) tracer to screen for pictilisib-sensitive tumors. In this study, pictilisib was radiolabeled with [11C]-methyl iodide to obtain 11C-methylated pictilisib ([11C]-pictilisib) using an automated synthesis module with a high radiolabeling yield. Considerably higher uptake ratios were observed in MCF-7 (PIK3CA mutation, pictilisib-sensitive) cells than those in MDA-MB-231 (PIK3CA wild-type, pictilisib-insensitive) cells at all evaluated time points, indicating good in vitro binding of [11C]-pictilisib. Dynamic micro-PET scans in mice and biodistribution results showed that [11C]-pictilisib was mainly excreted via the hepatobiliary tract into the intestines. MCF-7 xenografts could be clearly visualized on the static micro-PET scans, while MDA-MB-231 tumors could not. Biodistribution results of two xenograft models showed significantly higher uptake and tumor-to-muscle ratios in the MCF-7 xenografts than those in MDA-MB-231 xenografts, exhibiting high in vivo targeting specificity. In conclusion, [11C]-pictilisib was first successfully prepared, and it exhibited good potential to identify pictilisib-sensitive tumors noninvasively, which may have a great impact in the treatment of cancers with an overactive PI3K/Akt/mTOR signal pathway. However, the high activity in hepatobiliary system and intestines needs to be addressed.

中文翻译：

11C标签的Pictilisib（GDC-0941）作为靶向磷脂酰肌醇3-激酶（PI3K）的分子示踪剂，用于乳腺癌成像。

Pictilisib（GDC-0941）是磷脂酰肌醇3-激酶（PI3K）的抑制剂，磷脂酰肌醇3-激酶（PI3K）是参与乳腺癌发展的信号级联反应的一部分。这项研究的目的是通过用11C放射标记无创地评估pictilisib的药代动力学，并评估所得的[11C] -pictilisib作为正电子发射断层扫描（PET）示踪剂筛查pictilisib敏感肿瘤的可用性。在这项研究中，使用具有高放射性标记产率的自动化合成模块，用[11C]-甲基碘对Pictilisib进行放射性标记，以获得11C-甲基化的Pictilisib（[11C] -pictilisib）。在所有评估的时间点上，MCF-7（PIK3CA突变，对吡咯西伯不敏感）细胞中的摄取率均比MDA-MB-231（PIK3CA野生型，对不育对Pictilisib不敏感）细胞中的摄取率高得多，表明[11C] -pictilisib的体外结合良好。小鼠动态micro-PET扫描和生物分布结果表明[11C] -pictilisib主要通过肝胆道排入肠道。MCF-7异种移植物可以在静态micro-PET扫描中清晰显示，而MDA-MB-231肿瘤则不能。两种异种移植物模型的生物分布结果表明，MCF-7异种移植物的摄取和肿瘤与肌肉的比例明显高于MDA-MB-231异种移植物，表现出高的体内靶向特异性。总之，首先成功制备了[11C] -pictilisib，它在非侵入性方面鉴定出对pictilisib敏感的肿瘤具有良好的潜力，这可能对PI3K / Akt / mTOR信号通路过度活跃的癌症的治疗产生重大影响。然而，

更新日期：2019-11-01

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