Discovery of a lead brain-penetrating gonadotropin-releasing hormone receptor antagonist with saturable binding in brain

Abstract

We report the synthesis, radiosynthesis and biological characterisation of two gonadotropin‐releasing hormone receptor (GnRH−R) antagonists with nanomolar binding affinity. A small library of GnRH−R antagonists was synthesised in 20–67 % overall yield with the aim of identifying a high‐affinity antagonist capable of crossing the blood–brain barrier. Binding affinity to rat GnRH−R was determined by autoradiography in competitive‐binding studies against [¹²⁵l]buserelin, and inhibition constants were calculated by using the Cheng–Prusoff equation. The radioligands were obtained in 46–79 % radiochemical yield and >95 % purity and with a molar activity of 19–38 MBq/nmol by direct nucleophilic radiofluorination. Positron emission tomography imaging in rat under baseline conditions in comparison to pretreatment with a receptor‐saturating dose of GnRH antagonist revealed saturable uptake (0.1 %ID/mL) into the brain.