Estrogen receptor based imaging agents. 2. Synthesis and receptor binding affinity of side-chain halogenated hexestrol derivatives

Abstract

We have synthesized as potential imaging agents for human breast tumors a series of hexestrol analogues bearing the halogens fluorine, chlorine, bromine, and iodine at the terminus of the hexane chain. The binding affinity of these compounds for the estrogen receptor from uterine tissues forms a monotonically decreasing series, starting at 129% of that of estradiol for the fluoro analogue and decreasing to 60% for the iodo analogue. Such a modest decrease in binding affinity is thought to reflect the preference of the receptor for lipophilic groups and for substituents of moderate steric size at this site, parameters which change in opposite directions in the halogen sequence going from fluorine to iodine. Three estrogenic bis(trifluoromethyl)diphenylethylenes, prepared by DuPont, also showed substantial binding affinities for the estrogen receptor. In terms of ease of radiolabeling and high receptor binding selectivity, the compound that appears to be the most promising candidate for a breast tumor imaging agent in these series is the chain terminal fluorohexestrol.

Labelling, purification, and receptor affinity of radioactive iododiethylstilbestrol (*I‐DES) with high specific activity and first structure analysis with natI‐DES

“…After separation by RP-HPLC all products were characterized by NMR-techniques ( 1 H-, 13 C-NMR, H,H-COSY, and HMBC) for the very first time and the main product 3 0 -Iodo-DES % 2 as well as some by-products like the p-toluol-sulfonic acid amide % 3, % 1, and 1-chloro-1-(4 0 -hydroxy-phenyl)-propene-1 % 4 could be identified. 5 hexestrol, 6 4-iodotamoxifen, 7 and E/Z-11b-methoxy-17a-iodovinyl-estradiol, 8 but they never were commonly accepted for clinical routine.…”

“…Afterwards 1 H-NMR, 13 C-NMR, H,H-COSY (two-dimensional H,H-Correlation Spectroscopy), and HMBC (Heteronuclear Multiple Bond Correlation) were carried out.…”

Localization of Abscess with an Iodinated Synthetic Chemotactic Peptide

“…The potential importance of this class of radiopharmaceuticals is obvious. It may be used to provide diagnostic information about human breast tumors that have significant levels of estrogen receptors (5), to map the distribution of neuroreceptors in health and disease (6) or as potential myocardial imaging agents (4).…”

Reaction of 4′‐Benzyloxy‐2‐(4‐pyridinyl)acetophenone with Ethylmagnesium Chloride: Unusual C‐Benzylation and in situ Reduction by β‐Hydrogen Transfer

“…Analytical and spectral data of the major diastereomer which was obtained as a colorless oil (more mobile product of the first crop) and identified as (d,aromatic: 6 = 7.18 (d,J = 8.6 Hz,2H,7.10 (m,5H,phenyl),6.86 (d,J = 8.6 Hz,2H,5.01 (s,2H,CH20),4H,1.26 (ddq,J = 12.8,7.1 and 7.2 Hz,IH,),1.18 (ddq,J = 12.8,7.1 and 7.2 Hz,l H , The hydroxyphenyl products 2b and 3b were prepared in 95 and 97% yield, respectively, by catalytic hydrogenolysis [ 1 bar pressure, 5 h, with PdlC catalyst in methanollacetic acid (1 : l)] of their corresponding benzylated diastereoisomers 2a and 3a.…”