Structure-affinity relationships of estrogen derivatives to ERα as precursors for radiolabeling in endoradiotherapy of breast cancer

Ziel/Aim Estrogens can serve as vehicles for radionuclide transportation into estrogen receptor (ER) positive tumor cells of mammary carcinomas. Key criterion is the affinity of potential estrogen targeting ligands (ETL) to ERa-receptor. Here we demonstrate an affinity study of structurally diverse ETLs that can function as precursors for radiolabeling. Structural moieties which are decisive for binding affinity are identified in this study.

Methodik/Methods Molecular competitor ERα ligand binding assays were carried out in vitro with 22 derivatives of estrogens using a fluorescence polarization method and the Polar Screen^TM ER Alpha Competitor Assay kit, Green from life technologies (Fisher Scientific). The IC₅₀ values were determined by non-linear curve regression of the experimental data and fitting to the Hill equation, when possible, by means of GraphPad Prism^TM 8.02 Software GraphPad Software, Inc.

Ergebnisse/Results The reference mean IC₅₀ = 12.2 nM ± 1.4 nM of estradiol (E1) resulted from 21 independent assay experiments. The IC₅₀ of Diethylstilbestrol (DES) (8.9 nM ± 2.0 nM), 11β-Ethylestradiol (14.1 nM ± 1.3 nM) and 11β-ethyl-17α-vinylestradiol (8.4 nM ± 2.0 nM) showed comparable inhibitory activity in reference to E1. The introduction of an ethyl group at the C11β-position in the E1 framework resulted in a two- to three-fold increase in affinity. The triple bond showed mostly favorable compared to alkane spacing at C17α-position. (PEG)₃-DOTA conjugation resulted in 30-fold decrease in affinity.

Schlussfolgerungen/Conclusions Radioiodination of ETLs is more promising than radiometalation. Small as well as lipophilic molecular substitutions by double or triple bond linkage at C17α-position of the estrogen framework are favorable over large-sized and polar moieties. A C11β-ethyl group should be present.