HIGH AFFINITY TAMOXIFEN DERIVATIVES AND USES THEREOF

摘要

Applicants describe the synthesis of tamoxifen derivatives, most particularly halo, halo alkyl and hydroxy tamoxifen derivatives, wherein with the native tamoxifen molecule includes a substituted chemical group positioned on the aliphatic chain of the tamoxifen molecule. Particular halogenated tamoxifen derivatives of the invention include chloro, bromo, iodo and fluoro tamoxifen derivatives, and corresponding lower alkyl halogenated forms. The halogenated tamoxifen derivatives possess superior binding affinities for estrogen receptor rich tissues, such as uterine tissue and breast tissue, relative to unsubstituted native tamoxifen. In particular, the fluoro and bromo tamoxifen derivatives have potential use in imaging estrogen receptors by PET whereas the iodinated tamoxifens have potential use in imaging estrogen receptors by SPECT. The bromomethyl tamoxifen derivatives are demonstrated to bind estrogen receptors with the greatest enhancement of binding affinity over native tamoxifen. Rapid and efficient methods of preparing the tamoxifen derivatives having high specific activity (>6 ci/νmol) are also disclosed. Aliphatic chain substituted tamoxifen derivatives are shown to possess greater estrogen receptor binding affinity and more potent tumor cell inhibition than tamoxifen or tamoxifen derivatives substituted at other locations on the molecule (i.e., non-aliphatic chain substituted tamoxifen). The tamoxifen derivatives of the present invention may advantageously be used as anticancer therapeutic agents to halt estrogen-receptor positive tumors, such as those of breast and uterine tissue.