@article{oai:repo.qst.go.jp:00047652,
 author = {Koga, Kazumi and Maeda, Jun and Tokunaga, Masaki and Hanyu, Masayuki and Kawamura, Kazunori and Ohmichi, Mari and Nakamura, Toshio and Nagai, Yuji and Seki, Chie and Kimura, Yasuyuki and Minamimoto, Takafumi and Zhang, Ming-Rong and Fukumura, Toshimitsu and Suhara, Tetsuya and Higuchi, Makoto and 古閑 一実 and 前田 純 and 徳永 正希 and 破入 正行 and 河村 和紀 and 永井 裕司 and 関 千江 and 木村 泰之 and 南本 敬史 and 張 明栄 and 福村 利光 and 須原 哲也 and 樋口 真人},
 issue = {1},
 journal = {EJNMMI Research},
 month = {Feb},
 note = {Background: Histamine H3 receptor (H3R) is a potential therapeutic target of sleep- and cognition-related disorders. The purpose of the present study is to develop a novel positron emission tomography (PET) ligand for H3Rs from dihydroquinolinone derivatives, which we previously found to have high affinity with these receptors.
Methods: Six compounds were selected from a dihydroquinolinone compound library based on structural capability for 11C labeling and binding affinity for H3Rs. Their in-vivo kinetics in the rat brain were examined in a comparative manner by liquid chromatography and tandem mass spectrometry (LC-MS/MS). Chemicals with appropriate kinetic properties were then labeled with 11C and evaluated in rats and monkeys using PET. 
Results: Of the six compounds, TASP0410457 (also diminutively called TASP457) and TASP0434988 exhibited fast kinetics and relatively high brain uptakes in ex vivo LC-MS/MS, and were selected as candidate PET imaging agents. PET data in rat brains were mostly consistent with LC-MS/MS findings, and rat and monkey PET scans demonstrated that [11C]TASP0410457 was superior to [11C]TASP0434988 for high-contrast H3R PET imaging. In the monkey brain PET, distribution volume for [11C]TASP0410457 could be quantified, and receptor occupancy by nonradioactive compounds was measurable using this radioligand. The specific binding of [11C]TASP0410457 to H3Rs was confirmed by autoradiography using rat and monkey brain sections.
Conclusions: We developed [11C]TASP0410457 as a radioligand enabling a robust quantification of H3Rs in all brain regions, and demonstrated the utility of ex vivo LC-MS/MS and in vivo PET assays for selecting appropriate imaging tracers. [11C]TASP0410457 will help to examine the implication of H3Rs in neuropsychiatric disorders and to characterize emerging therapeutic agents targeting H3Rs.},
 title = {Development of TASP0410457 (TASP457), a novel dihydroquinolinone derivative as a PET radioligand for central histamine H3 receptors},
 volume = {6},
 year = {2016}
}