Development of TASP0410457 (TASP457), a novel dihydroquinolinone derivative as a PET radioligand for central histamine H₃ receptors

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 a nonradioactive compound 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.