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 3,17beta-estradiol in five steps respectively. Drug-induced microtubule depolymerization, antiproliferative activity against human cancer cell lines and HIF-1alpha down-regulation by 2FEE2 and 2FPE2 were investigated to examine whether these molecules possess similar anti-tumor activities as 2-methoxyestradiol. 2-[(18)F]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-1alpha 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-[(18)F]Fluoroethoxyestradiol (2[(18)F]FEE2) was prepared in 8.3% decay-corrected yield in 90 min, based on a production of H[(18)F]F with more than 98% radiochemical purity. CONCLUSIONS: 2FEE2 and 2FPE2 showed similar activity as 2ME2. 2[(18)F]FEE2 was synthesized to be utilized as a PET radiotracer to measure the biological efficacy of 2ME2 and its analogs in vivo.