Discovery and Preclinical Validation of [11C]AZ13153556, a Novel Probe for the Histamine Type 3 Receptor

The histamine type 3 receptor (H3) is a G protein-coupled receptor implicated in several disorders of the central nervous system. Herein, we describe the radiolabeling and preclinical evaluation of a candidate radioligand for the H3 receptor, 4-(1S,2S)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl]-N-methyl-benzamide (5), and its comparison with one of the frontrunner radioligands for H3 imaging, namely, GSK189254 (1). Compounds 1 and 5 were radiolabeled with tritium and carbon-11 for in vitro and in vivo imaging experiments. The in vitro binding of [3H]1 and [3H]5 was examined by (i) saturation binding to rat and nonhuman primate brain tissue homogenate and (ii) in vitro autoradiography on tissue sections from rat, guinea pig, and human brain. The in vivo binding of [11C]1 and [11C]5 was examined by PET imaging in mice and nonhuman primates. Bmax values obtained from Scatchard analysis of [3H]1 and [3H]5 binding were in good agreement. Autoradiography with [3H]5 on rat, guinea pig, and human brain sli...