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

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-3,17β-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-3,17β-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 17β-estradiol by published procedures in 5 steps with 40% overall chemical yield. The precursor 2-hydroxy-3,17β-O,O-bis(sulfamoyl)estradiol (14a) for radiolabeling was synthesized from 17β-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/μmol specific activity at EOB.

► New PET tracer 2-[11C]methoxy-3,17β-O,O-bis(sulfamoyl)estradiol was synthesized.
► HPLC combined with solid-phase extraction (SPE) method was used in radiosynthesis.
► New 2-substituted estradiol derivatives were synthesized.