Discovery of a Tritiated Radioligand with High Affinity and Selectivity for the Histamine H₃ Receptor

Radioligands used previously for histamine H₃ receptor (H₃R) are accompanied by a number of disadvantages. In this study, we report the synthesis of the new H₃R radioligand [³H]UR-MN259 ([³H]11) with high (radio)chemical purity and stability. The radioligand exhibits sub-nanomolar affinity for the target receptor (pK_i (H₃R) = 9.56) and displays an outstanding selectivity profile within the histamine receptor family (>100,000-fold selective). [³H]UR-MN259 is ideally suitable for the characterization of H₃R ligands in competition binding and shows one-site binding to the H₃R in saturation binding experiments. The radiotracer shows fast association to the receptor (τ_assoc = 6.11 min), as well as full dissociation from the receptor (τ_dissoc = 14.48 min) in kinetic binding studies. The distinguished profile of [³H]UR-MN259 makes it a highly promising pharmacological tool to further investigate the role of the H₃R in the CNS.