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 [125I]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.

Mechanism Of Leptin On Impaired Ovarian Reserve Function After Cold Exposure In Female Rats

“…GnRH , a decapeptide hormone secreted by nerve cells in the arcate nucleus of the hypothalamus, through the pituitary portal system and the pituitary receptor GnRH-R binding, can promote the gonadal function from upstream of the HPO axis, as we know the so-called reproductive control center commander [12][13][14] . Through GnRH as the point of penetration we try to fig our the mechanism that cold exposure affects reproductive function in female rats.…”