Nuclear Medicine and Biology
Volume 35, Issue 5 , Pages 615-622, July 2008

Syntheses and biological activities of novel 2-methoxyestradiol analogs, 2-fluoroethoxyestradiol and 2-fluoropropanoxyestradiol, and a radiosynthesis of 2-[18F]fluoroethoxyestradiol for positron emission tomography

  • Jiyoung Mun

      Affiliations

    • Department of Radiology, Emory University, Atlanta, GA 30322, USA
    • ,
  • Yuefang Wang

      Affiliations

    • Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
    • ,
  • Ronald J. Voll

      Affiliations

    • Department of Radiology, Emory University, Atlanta, GA 30322, USA
    • ,
  • Daniel Escuin-Borras

      Affiliations

    • Department of Hematology/Oncology, Weill Cornell Medical College of Cornell University, New York, NY 10021,USA
    • ,
  • Paraskevi Giannakakou

      Affiliations

    • Department of Hematology/Oncology, Weill Cornell Medical College of Cornell University, New York, NY 10021,USA
    • ,
  • Mark M. Goodman

      Affiliations

    • Department of Radiology, Emory University, Atlanta, GA 30322, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 404 727 9366; fax: +1 404 727 3488.

Received 4 March 2008; received in revised form 31 March 2008; accepted 1 April 2008.

Abstract 

Introduction

2-Methoxyestradiol (2ME2) is an endogenous metabolite of the human hormone, estrogen, which has been shown to possess anti-tumor activity. 2-Fluoroethoxyestradiol (2FEE2) and 2-fluoropropanoxyestradiol (2FPE2), novel analogs of 2-methoxyestradiol, were designed and synthesized to be utilized as F-18 radiotracers for positron emission tomography (PET), with which the bio-distribution and intratumoral accumulations of 2ME2 could be measured in vivo for potential translation to human use.

Methods

2FEE2 and 2FPE2 were synthesized from 3,17β-estradiol in five steps respectively. Drug-induced microtubule depolymerization, antiproliferative activity against human cancer cell lines and HIF-1α down-regulation by 2FEE2 and 2FPE2 were investigated to examine whether these molecules possess similar anti-tumor activities as 2-methoxyestradiol. 2-[18F]Fluoroethoxyestradiol was synthesized for PET.

Results

Novel 2ME2 analogs, 2FEE2 and 2FPE2, were synthesized in 29% and 22% overall yield, respectively. 2FEE2 and 2FPE2 showed microtubule depolymerization and cytotoxicities against the human ovarian carcinoma cell line, 1A9, and the human glioma cell line, LN229. HIF-1α was down-regulated by 2FEE2 and 2FPE2 under hypoxic conditions. 2FEE2 was chosen as an F-18 radiotracer candidate, since it showed stronger antiproliferative activity than 2ME2 and 2FPE2. 2-[18F]Fluoroethoxyestradiol (2[18F]FEE2) was prepared in 8.3% decay-corrected yield in 90 min, based on a production of H[18F]F with more than 98% radiochemical purity.

Conclusions

2FEE2 and 2FPE2 showed similar activity as 2ME2. 2[18F]FEE2 was synthesized to be utilized as a PET radiotracer to measure the biological efficacy of 2ME2 and its analogs in vivo.

Keywords: 2-Fluoroethoxyestradiol, 2-Fluoropropanoxyestradiol, 2-Methoxyestradiol, PET, 2-[18F]Fluoroethoxyestradiol

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PII: S0969-8051(08)00079-6

doi:10.1016/j.nucmedbio.2008.04.003

Nuclear Medicine and Biology
Volume 35, Issue 5 , Pages 615-622, July 2008

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