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Title:Fluorine-18-labeled estrogens, progestins and corticosteroids for receptor-based imaging of breast tumors and target areas of the brain
Author(s):Pomper, Martin Gilbert
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Organic Chemistry
Pharmaceutical Chemistry
Health Sciences
Abstract:Estrogens can be labeled with the positron-emitting radionuclide fluorine-18 (t$\sb{1/2}$ = 110 min) by fluoride ion (n-Bu$\sb4$N$\sp{18}$F) displacement of a 16$\beta$-trifluoromethanesulfonate (triflate) derivative of the corresponding estrone 3-triflate, and purification by HPLC. That sequence has been used to synthesize the 11$\beta$-methoxy 1 and 11$\beta$-ethyl 2 analogues of the breast tumor imaging agent, 16$\alpha$-($\sp{18}$F) fluoro-17$\beta$-estradiol (FES). Tissue distribution studies of 1 and 2 in immature female rats show high selectivity for target tissue (T, uterus) vs non-target (NT, muscle and lung), with T/NT ratios being 43 and 17 at one hour after injection for 1 and 2, respectively. The parent estrogen FES has previously been shown to display an intermediate value for tissue selectivity.
The progestin 21-($\sp{18}$F) fluoro-16$\alpha$-ethyl-19-norprogesterone (FENP), synthesized from the 21-triflate precursor, is a high affinity ligand for the progestin receptor, and in vivo, exhibits highly selective uptake by the uterus of estrogen-primed rats. Respective T/NT ratios of 16 and 41 at one and 3 hours after injection have been demonstrated. Two epimeric (at C-21) analogues of the high affinity progestin promegestone (R 5020) were prepared in fluorine-18 labeled form from the corresponding triflate precursors; while 21S-($\sp{18}$F) R 5020 3 showed a T/NT ratio of 4 at 3 hours after injection, 21R-($\sp{18}$F) R 5020 4 showed no selective uptake. Compounds 3 and 4 each suffered extensive in vivo defluorination.
Derivatives of the high affinity Type I and Type II corticosteroid receptor ligands RU 26752 and RU 28362, respectively, were prepared in fluorine-18 labeled form from the corresponding 3$\sp\prime$-methanesulfonates. Neither labeled compound showed selective target tissue (brain) uptake and each underwent substantial in vivo defluorination. 1,2-($\sp3$H$\sb2$) RU 26752 was also synthesized (52 Ci/mmol) as a potential Type I receptor probe.
These fluorine-18 labeled steroids can be prepared within 2 hours of the end of bombardment, and their specific activities range from 500-4000 Ci/mmol. The high target tissue selectivities and uterine uptake values for 1, 2 and FENP suggest that these compounds may be useful for in vivo imaging of estrogen and progestin target tissues and tumors (such as human breast tumors) by positron emission tomography.
Issue Date:1989
Rights Information:Copyright 1989 Pomper, Martin Gilbert
Date Available in IDEALS:2011-05-07
Identifier in Online Catalog:AAI9010990
OCLC Identifier:(UMI)AAI9010990

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