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

Min Wang, Lu Xu, Mingzhang Gao, Kathy Miller, George W. Sledge, Qi-Huang Zheng

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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 IC 50 value selectively over CAII with 379 nM IC 50 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]CH 3OTf through O-[ 11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) purification in 40-50% radiochemical yields based on [ 11C]CO 2 and decay corrected to end of bombardment (EOB), with 370-740 GBq/μmol specific activity at EOB.

Original languageEnglish
Pages (from-to)864-870
Number of pages7
JournalSteroids
Volume77
Issue number8-9
DOIs
StatePublished - Jul 2012

Fingerprint

Steryl-Sulfatase
Carbonic Anhydrase II
Positron emission tomography
Positron-Emission Tomography
Estradiol
Imaging techniques
Neoplasms
Tumors
Molecular imaging
Methylation
Oncology
Estrone
Carbonic Anhydrase Inhibitors
Carbon Monoxide
Molecular Imaging
Antineoplastic Agents
Solid Phase Extraction
Sulfates
Purification
Zinc

Keywords

  • 2-[ C]Methoxy-3,17β-O,O-bis(sulfamoyl)estradiol
  • Cancer imaging
  • Carbonic anhydrase II (CAII)
  • Positron emission tomography (PET)
  • Radiosynthesis
  • Steroid sulfatase (STS)

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Molecular Biology
  • Organic Chemistry
  • Pharmacology

Cite this

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. / Wang, Min; Xu, Lu; Gao, Mingzhang; Miller, Kathy; Sledge, George W.; Zheng, Qi-Huang.

In: Steroids, Vol. 77, No. 8-9, 07.2012, p. 864-870.

Research output: Contribution to journalArticle

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abstract = "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 IC 50 value selectively over CAII with 379 nM IC 50 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]CH 3OTf through O-[ 11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) purification in 40-50{\%} radiochemical yields based on [ 11C]CO 2 and decay corrected to end of bombardment (EOB), with 370-740 GBq/μmol specific activity at EOB.",
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N2 - 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 IC 50 value selectively over CAII with 379 nM IC 50 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]CH 3OTf through O-[ 11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) purification in 40-50% radiochemical yields based on [ 11C]CO 2 and decay corrected to end of bombardment (EOB), with 370-740 GBq/μmol specific activity at EOB.

AB - 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 IC 50 value selectively over CAII with 379 nM IC 50 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]CH 3OTf through O-[ 11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) purification in 40-50% radiochemical yields based on [ 11C]CO 2 and decay corrected to end of bombardment (EOB), with 370-740 GBq/μmol specific activity at EOB.

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