Syntheses and biological activities of novel 2-methoxyestradiol analogs, 2-fluoroethoxyestradiol and 2-fluoropropanoxyestradiol, and a radiosynthesis of 2-[(18)F]fluoroethoxyestradiol for positron emission tomography.
BACKGROUND
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.
Mun
Jiyoung
J
Department of Radiology, Emory University, Atlanta, GA 30322, USA.
Wang
Yuefang
Y
Voll
Ronald J
RJ
Escuin-Borras
Daniel
D
Giannakakou
Paraskevi
P
Goodman
Mark M
MM
D000077584:2-Methoxyestradiol; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D005260:Female; D005462:Fluorine Radioisotopes; D005910:Glioma / Q000532:radiotherapy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007202:Indicators and Reagents; D007553:Isotope Labeling; D009682:Magnetic Resonance Spectroscopy; D008870:Microtubules / Q000000981:diagnostic imaging; D010051:Ovarian Neoplasms / Q000532:radiotherapy; D049268:Positron-Emission Tomography; D011786:Quality Control; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D014018:Tissue Distribution
C531565:2-fluoroethoxyestradiol; C531566:2-fluoropropanoxyestradiol; D005462:Fluorine Radioisotopes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007202:Indicators and Reagents; D019275:Radiopharmaceuticals; D004958:Estradiol; D000077584:2-Methoxyestradiol