Discovery of a Tritiated Radioligand with High Affinity and Selectivity for the Histamine H 3 Receptor.

Radioligands used previously for histamine H 3 receptor (H 3 R) are accompanied by a number of disadvantages. In this study, we report the synthesis of the new H 3 R radioligand [ 3 H]UR-MN259 ([ 3 H] 11 ) with high (radio)chemical purity and stability. The radioligand exhibits sub-nanomolar affinity for the target receptor (p K i (H 3 R) = 9.56) and displays an outstanding selectivity profile within the histamine receptor family (>100,000-fold selective). [ 3 H]UR-MN259 is ideally suitable for the characterization of H 3 R ligands in competition binding and shows one-site binding to the H 3 R 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 [ 3 H]UR-MN259 makes it a highly promising pharmacological tool to further investigate the role of the H 3 R in the CNS.