Discovery and Preclinical Validation of [11C]AZ13153556, a Novel Probe for the Histamine Type 3 Receptor
| Autor: | Akihiro Takano, Lars Farde, Peter Johnström, Dean G. Brown, Maria Nilsson, Anders Juréus, Sjoerd J. Finnema, Jonas Malmquist, Nahid Amini, Lenke Tari, Jenny Häggkvist, Steven Wesolowski, Scott Throner, Magnus Schou, Ryuji Nakao, Katarina Varnäs, Charlotte Ahlgren |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Niacinamide Time Factors Physiology Cognitive Neuroscience Guinea Pigs Biology Pharmacology Tritium 01 natural sciences Biochemistry Piperazines Guinea pig Mice chemistry.chemical_compound Histamine Agents Alzheimer Disease In vivo Radioligand medicine Animals Humans Receptors Histamine H3 Tissue Distribution Carbon Radioisotopes Receptor Dose-Response Relationship Drug 010405 organic chemistry Brain Reproducibility of Results Haplorhini Cell Biology General Medicine Human brain Benzazepines Rats 0104 chemical sciences Mice Inbred C57BL 010404 medicinal & biomolecular chemistry medicine.anatomical_structure chemistry Benzamides Autoradiography Female Histamine H3 receptor Histamine Preclinical imaging Protein Binding |
| Zdroj: | ACS Chemical Neuroscience. 7:177-184 |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.5b00268 |
| Popis: | 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 [(3)H]1 and [(3)H]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 [(11)C]1 and [(11)C]5 was examined by PET imaging in mice and nonhuman primates. Bmax values obtained from Scatchard analysis of [(3)H]1 and [(3)H]5 binding were in good agreement. Autoradiography with [(3)H]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 [(3)H]1, and virtually negligible nonspecific binding in tissue. PET measurements in mice and nonhuman primates demonstrated that [(11)C]5 binds specifically and reversibly to H3 receptors in vivo with low nonspecific binding in brain tissue. Whereas [(11)C]1 showed similar binding characteristics in vivo, the binding kinetics appeared faster for [(11)C]5 than for [(11)C]1.[(11)C]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 [(11)C]1. |
| Databáze: | OpenAIRE |
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