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Discovery of a Lead Brain‐Penetrating Gonadotropin‐Releasing Hormone Receptor Antagonist with Saturable Binding in Brain
Author(s) -
Bekker Roberto B. W.,
Fjellaksel Richard,
Hjornevik Trine,
Nuruddin Syed,
Rafique Waqas,
Hansen Jørn H.,
Sundset Rune,
Haraldsen Ira H.,
Riss Patrick J.
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000256
Subject(s) - antagonist , buserelin , radioligand , radiosynthesis , chemistry , receptor , gonadotropin releasing hormone receptor , radioligand assay , competitive antagonist , gonadotropin releasing hormone , hormone , medicine , pharmacology , endocrinology , positron emission tomography , biochemistry , nuclear medicine , agonist , luteinizing hormone
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 [ 125 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.