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

Na Han,Lujie Yuan,Mengting Li,Qingyao Liu,Yongkang Gai,Xiaoli Lan,Yichun Wang,Yaqun Jiang,Yongxue Zhang

doi:10.1155/2019/1760184

Abstract

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.

Highlights

Of breast cancers have abnormal activation of phosphatidylinositol 3-kinase (PI3K)/Akt [6]. e mutation in the PIK3CA gene, which encodes the p110α catalytic subunit of PI3K, and loss of expression of tensin homology deleted on chromosome ten (PTEN), plays an important role in breast cancer [7, 8]
Two compounds were obtained after pictilisib methylation using methyl iodide. ey were isomers and were named as GDCI (4-(2-methyl-1H-indazol-4-yl)6-((4-(methylsulfonyl) piperazin-1-yl)thieno [3,2-d]pyrimidin-4-yl)morpholine) and GDCM (4-(2-methyl-2Hindazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)thieno [3,2-d]pyrimidin-4-yl)morpholine) (Figure 2(a)). e characteristics of the reference standards were identified by 1H-NMR and 13C-NMR (Figure S1). e results of NMR spectroscopy were listed in the supplement data
Pictilisib, a PI3K inhibitor, is a small molecule which is under clinical trial

Summary

Introduction

Of breast cancers have abnormal activation of PI3K/Akt [6]. e mutation in the PIK3CA gene, which encodes the p110α catalytic subunit of PI3K, and loss of expression of tensin homology deleted on chromosome ten (PTEN), plays an important role in breast cancer [7, 8]. Drug resistance and poor prognosis were associated with abnormal activation of the PI3K pathway among patients with breast cancer treated with trastuzumab [12]. For this reason, the pathway has been an attractive target for cancer therapeutics in recent years, and multiple pharmaceutical companies and academic laboratories are actively developing PI3K inhibitors. Researchers reported that adding pictilisib to anastrozole significantly increased suppression of tumor cell proliferation in luminal B primary breast cancer [18]. It is essential to develop a PI3K/Akt-targeting tracer with better in vivo performance for the investigation of this signaling pathway and identification of candidates for pictilisib treatment

Methods

Results

Conclusion