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Discovery of a Lead Brain-Penetrating Gonadotropin-Releasing Hormone Receptor Antagonist with Saturable Binding in Brain |
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| Authors: | Roberto B. W. Bekker Dr. Richard Fjellaksel Dr. Trine Hjornevik Dr. Syed Nuruddin Dr. Waqas Rafique Prof. Jørn H. Hansen Prof. Rune Sundset Dr. Ira H. Haraldsen Prof. Patrick J. Riss |
| Affiliation: | 1. Department of Chemistry, University of Oslo, Sem Sælands vei, 26, 0371 Oslo, Norway;2. Department of Clinical Medicine, UiT The Arctic University of Norway, Hansine Hansens veg 18, 9019 Tromsø, Norway PET Imaging Center, University Hospital of North Norway, Sykehusvegen 38, 9019 Tromsø, Norway Department of Chemistry, UiT – The Arctic University of Norway, Hansine Hansens veg 18, 9019 Tromsø, Norway;3. Department of Diagnostic Physics, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway;4. Norwegian Medical Cyclotron AS, Rikshospitalet, Sognsvannsveien 20, Oslo, Norway;5. Department of Chemistry, UiT – The Arctic University of Norway, Hansine Hansens veg 18, 9019 Tromsø, Norway;6. Department of Clinical Medicine, UiT The Arctic University of Norway, Hansine Hansens veg 18, 9019 Tromsø, Norway PET Imaging Center, University Hospital of North Norway, Sykehusvegen 38, 9019 Tromsø, Norway;7. Clinical Neurosciences, Oslo University Hospital-Ulleval, Kirkeveien 166, post code?, Oslo, Norway |
| 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. |
| Keywords: | elagolix fluorine-18 GnRH−R GnRH PET |