Synthesis of 2-[¹¹C]methoxy-3,17尾-O,O-bis(sulfamoyl)estradiol as a new potential PET agent for imaging of steroid sulfatase (STS) in cancers

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• 作者：Min Wang^a ; Lu Xu^a ; Mingzhang Gao^a ; Kathy D. Miller^b ; George W. Sledge^b ; Qi-Huang Zheng^a ; ^{qzheng@iupui.edu}
• 关键词：Steroid sulfatase (STS) ; Carbonic anhydrase II (CAII) ; 2-[11C]Methoxy-3 ; 17尾-O ; O-bis(sulfamoyl)estradiol ; Positron emission tomography (PET) ; Radiosynthesis ; Cancer imaging
• 刊名：Steroids
• 出版年：2012
• 期刊代码：142_0039128x
• 类别：bio
• 出版时间：July, 2012
• 卷：77
• 期：8-9
• 页码：864-870
• 文件大小：329 K

摘要

Steroid sulfatase (STS) catalyzes the hydrolysis of steroid sulfates to estrones, the main source of estrogens in tumors. Carbonic anhydrase II (CAII) is highly expressed in red blood cells through a coordination of the monoanionic form of the sulfamate moiety to the zinc atom in the enzyme active site, and CAII is highly expressed in several tumors. 2-Methoxy-3,17尾-O,O-bis(sulfamoyl)estradiol (5) is a dual-function STS-CAII inhibitor inhibited STS with 39 nM IC₅₀ value selectively over CAII with 379 nM IC₅₀ value. This compound exhibited potent antiproferative activity with mean graph midpoint value of 87 nM in the NCI 60-cell-line panel, and antiangiogenic in vitro and in vivo activity in an early-stage Lewis lung model as well. The compound has been recently developed as a multitargeted anticancer agent. Both STS and CAII are over-expressed in cancers and have become attractive targets for cancer treatment and molecular imaging of cancer. Here we report the first design and synthesis of 2-[¹¹C]methoxy-3,17尾-O,O-bis(sulfamoyl)estradiol ([¹¹C]5) as a new potential imaging agent for biomedical imaging technique positron emission tomography (PET) to image STS in cancers. The authentic standard 5 was synthesized from 17尾-estradiol by published procedures in 5 steps with 40%overall chemical yield. The precursor 2-hydroxy-3,17尾-O,O-bis(sulfamoyl)estradiol (14a) for radiolabeling was synthesized from 17尾-estradiol in 10 steps with 5%overall chemical yield. The target tracer [¹¹C]5 was prepared from the precursor 14a with [¹¹C]CH₃OTf through O-[¹¹C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) purification in 40-50%radiochemical yields based on [¹¹C]CO₂ and decay corrected to end of bombardment (EOB), with 370-740 GBq/渭mol specific activity at EOB.