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

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• 作者：Magnus Schou ; Katarina Varnäs ; Anders Jureus ; Charlotte Ahlgren ; Jonas Malmquist ; Jenny Häggkvist ; Lenke Tari ; Steven S. Wesolowski ; Scott R. Throner ; Dean G. Brown ; Maria Nilsson ; Peter Johnström ; Sjoerd J. Finnema ; Ryuji Nakao ; Nahid Amini ; Akihiro Takano ; Lars Farde
• 刊名：ACS Chemical Neuroscience
• 出版年：2016
• 出版时间：February 17, 2016
• 年：2016
• 卷：7
• 期：2
• 页码：177-184
• 全文大小：496K
• ISSN：1948-7193

文摘

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. B_max 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 slices showed specific binding in regions known to be enhanced in H₃ receptors, a high degree of colocalization with [³H]1, and virtually negligible nonspecific binding in tissue. PET measurements in mice and nonhuman primates demonstrated that [¹¹C]5 binds specifically and reversibly to H₃ receptors in vivo with low nonspecific binding in brain tissue. Whereas [¹¹C]1 showed similar binding characteristics in vivo, the binding kinetics appeared faster for [¹¹C]5 than for [¹¹C]1. Conclusions: [¹¹C]5 has suitable properties for quantification of H₃ receptors in nonhuman primate brain and has the potential to offer improved binding kinetics in man compared to [¹¹C]1.