Fluorine-substituted corticosteroids: synthesis and evaluation as potential receptor-based imaging agents for positron emission tomography of the brain.

We have prepared eight fluorine-substituted corticosteroids representing ligands selective for Type I and Type II corticosteroid receptor subtypes as potential imaging agents for corticosteroid receptor-containing regions of the brain. Receptor binding affinity assays show that fluorine substitution for hydroxyl or hydrogen in these steroids generally results in some reduction in affinity, with the result that the absolute affinity of these fluorine-substituted ligands for receptor is less than that typical for steroid hormones that show receptor-based, target selective uptake in vivo. Five of these compounds were prepared in fluorine-18 labeled form by a simple sulfonate ester displacement reaction, and their tissue distribution was studied in the adrenalectomized rat. There is no selective accumulation nor selective retention of the Type I selective corticosteroids (18F-RU 26752, 21-[18F]fluoroprogesterone, 21-[18F]fluoro-11 beta-hydroxyprogesterone) in either the brain, or other target tissues (pituitary, kidney, liver). The Type II selective corticosteroids (18F-RU 28362, 18F-triamcinolone acetonide) show uptake into the hippocampus which can be partially blocked by a competing ligand; in target tissues outside the brain, the blocking is more complete. All of the 18F-labeled compounds show considerable defluorination, evident as high bone activity levels. These results, coupled with earlier findings in the literature, suggest that radiolabeled corticosteroid receptor ligands with both greater metabolic stability and higher receptor binding affinity and selectivity are needed for imaging corticosteroid receptors in the hippocampus.

11 beta-methoxy-, 11 beta-ethyl- and 17 alpha-ethynyl-substituted 16 alpha-fluoroestradiols: receptor-based imaging agents with enhanced uptake efficiency and selectivity.

We have prepared three analogues of 16 alpha-fluoroestradiol (FES) substituted either with an 11 beta-methoxy group (1, 11 beta-MeO-FES), an 11 beta-ethyl group (2, 11 beta-Et-FES), or a 17 alpha-ethynyl group (3, 17 alpha-ethynyl-FES). These substituents all lower the binding of FES to the serum proteins alphafetoprotein and sex steroid binding protein, but their effect on estrogen receptor binding varies: Receptor binding is increased by the 11 beta-ethyl and 17 alpha-ethynyl groups, but decreased by the 11 beta-methoxy group. These substituents also have a parallel effect on the lipophilicity, and hence the nonspecific binding estimated for these compounds. All three compounds were prepared in fluorine-18 labeled form, at effective specific activities of 90-1600 Ci/mmol, by fluoride ion displacement reactions as done previously with FES. Tissue distribution studies in immature rats show high uptake selectivity by target tissue (uterus) and effective competition by an excess of unlabeled estradiol. Percent injected dose per gram values (% ID/g) at 1 h are 6% for 11 beta-MeO-FES and 11-13% for 11 beta-Et-FES and 17 alpha-ethynyl-FES (FES itself has a % ID/g of 9%). Uptake selectivity in terms of uterus to blood or muscle ratios at 1 h is highest for 11 beta-MeO-FES and 17 alpha-ethynyl-FES (43-149). Metabolic consumption studies show that most activity in uterus is unmetabolized and in blood is rapidly and nearly completely metabolized. In muscle, FES and the substituted estrogens show intermediate levels of metabolic consumption; in some cases activity in muscle extracts is nearly unmetabolized. Thus, the substituents on FES cause major alterations in receptor and nonreceptor binding affinity, uptake efficiency and selectivity, and extent of metabolism. It is not readily clear, however, whether the alterations in uptake efficiency and selectivity are the result of differences in receptor or nonreceptor binding or lipophilicity, or altered patterns of metabolism. Nevertheless, these compounds should be useful in providing a spectrum of uptake properties that could be used for imaging different estrogen-receptor-containing structures.