Fluorine-18-labeled estrogens, progestins and corticosteroids for receptor-based imaging of breast tumors and target areas of the brain

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.

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