The enzyme steroid sulfatase (STS) catalyzes the hydrolysis of steroid sulfates to estrones, the main source of estrogens in tumors. The enzyme 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�-O,O-bis(sulfamoyl)estradiol is a potent irreversible STS inhibitor, and also a highly active reversible CAII inhibitor. 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 by Leese et al. STS and CAII are attractive targets for cancer treatment and molecular imaging of cancer. Here we report the first design and synthesis of 2-[11C]methoxy-3,17�-O,O-bis(sulfamoyl)estradiol as a new potential imaging agent for biomedical imaging technique positron emission tomography (PET) to image STS and CAII in cancers. The authentic standard 2-methoxy-3,17�-O,O-bis(sulfamoyl)estradiol was synthesized from �-estradiol by published procedures in 5 steps with 40% overall chemical yield. The precursor 2-hydroxy-3,17�-O,O-bis(sulfamoyl)estradiol for radiolabeling was synthesized from �-estradiol in 10 steps with 5% overall chemical yield. The target tracer 2-[11C]methoxy-3,17�-O,O-bis(sulfamoyl)estradiol was prepared from the precursor 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/mmol specific activity at EOB.

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

244th National Meeting (2012)

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