| Title |
Development of TASP0410457 (TASP457), a novel dihydroquinolinone derivative as a PET radioligand for central histamine H3 receptors
|
|---|---|
| Published in |
EJNMMI Research, February 2016
|
| DOI | 10.1186/s13550-016-0170-2 |
| Pubmed ID | |
| Authors |
Kazumi Koga, Jun Maeda, Masaki Tokunaga, Masayuki Hanyu, Kazunori Kawamura, Mari Ohmichi, Toshio Nakamura, Yuji Nagai, Chie Seki, Yasuyuki Kimura, Takafumi Minamimoto, Ming-Rong Zhang, Toshimitsu Fukumura, Tetsuya Suhara, Makoto Higuchi |
| Abstract |
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. Six compounds were selected from a dihydroquinolinone compound library based on structural capability for (11)C 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 (11)C and evaluated in rats and monkeys using PET. 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 [(11)C]TASP0410457 was superior to [(11)C]TASP0434988 for high-contrast H3R PET imaging. In the monkey brain PET, distribution volume for [(11)C]TASP0410457 could be quantified, and receptor occupancy by a nonradioactive compound was measurable using this radioligand. The specific binding of [(11)C]TASP0410457 to H3Rs was confirmed by autoradiography using rat and monkey brain sections. We developed [(11)C]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. [(11)C]TASP0410457 will help to examine the implication of H3Rs in neuropsychiatric disorders and to characterize emerging therapeutic agents targeting H3Rs. |
Mendeley readers
The data shown below were compiled from readership statistics for 20 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 20 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 7 | 35% |
| Student > Ph. D. Student | 3 | 15% |
| Student > Postgraduate | 2 | 10% |
| Student > Bachelor | 1 | 5% |
| Student > Doctoral Student | 1 | 5% |
| Other | 2 | 10% |
| Unknown | 4 | 20% |
| Readers by discipline | Count | As % |
|---|---|---|
| Neuroscience | 4 | 20% |
| Medicine and Dentistry | 3 | 15% |
| Pharmacology, Toxicology and Pharmaceutical Science | 2 | 10% |
| Computer Science | 2 | 10% |
| Chemistry | 2 | 10% |
| Other | 2 | 10% |
| Unknown | 5 | 25% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 06 January 2017.
All research outputs
#21,376,027
of 23,867,274 outputs
Outputs from EJNMMI Research
#418
of 589 outputs
Outputs of similar age
#346,573
of 406,755 outputs
Outputs of similar age from EJNMMI Research
#10
of 13 outputs
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