Discovery of a Lead Brain-Penetrating Gonadotropin-Releasing Hormone Receptor Antagonist with Saturable Binding in Brain.

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 [ I]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.