@misc{oai:repo.qst.go.jp:00072367,
 author = {高畑, 圭輔 and 木村, 泰之 and 関, 千江 and 市瀬, 正則 and 河村, 和紀 and 北村, 聡一郎 and 久保田, 学 and 森口, 翔 and 高堂, 裕平 and 張, 明栄 and 須原, 哲也 and 樋口, 真人 and 高畑 圭輔 and 木村 泰之 and 関 千江 and 市瀬 正則 and 河村 和紀 and 北村 聡一郎 and 久保田 学 and 森口 翔 and 高堂 裕平 and 張 明栄 and 須原 哲也 and 樋口 真人},
 month = {Jun},
 note = {Objective: AMPA receptor is a primary mediator of the fast excitatory signaling in the brain. Since its disturbance is linked to a variety of neuropsychiatric diseases such as epilepsy and dementia, AMPA receptor has been a therapeutic target in these diseases. PET imaging using a suitable radioligand for AMPA receptors allows clarification of the neurochemical basis and therapeutic assessments in such diseases. We recently developed a novel PET ligand, 2-(1-(3-([11C]methylamino)phenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitril ([11C]HMS011). This compound is a carbon-11-labelled derivative of perampanel, which is a highly selective noncompetitive antagonist for AMPA receptors. Our previous study demonstrated promising in vivo properties of [11C]HMS011 in rat and monkey brains. In the current study, we performed a human PET study using [11C]HMS011, and evaluated the safety and utility of this radioligand as a PET imaging agent for AMPA receptors.
Methods: Four healthy male subjects were scanned for 120 min with a PET scanner after injection of 344.1 ± 42.5 MBq of [11C]HMS011. Arterial blood sampling and metabolite analysis were performed to obtain parent input functions for 3 subjects using high-performance liquid chromatography. Distribution volumes (VT’s) in several brain regions were calculated by compartment models and Logan’s graphical analysis.
Result: [11C]HMS011 injection did not cause adverse effects in any of the subjects. In the blood, three hydrophilic radiometabolites of [11C]HMS011 were found in all three subjects who underwent a metabolite analysis, and a lipophilic radiometabolite was detected only in one of these tree subjects. A high radioligand uptake in the brain was observed quickly after the injection of [11C]HMS011 with standardized uptake values approximating 2–3, and was followed by a rapid clearance from the brain. The subject with a lipophilic radiometabolite in plasma exhibited relatively slow radioactivity washout from the brain and large variability of regional VT values, while the other three individuals showed almost uniformly low retention of radioactivity across all regions in a late frame. These data indicate the lack of specific radioligand binding in the brain, and a possible entry of a lipophilic radiometabolite into the brain of one subject.
Conclusion: [11C]HMS011 is not suitable for PET imaging of AMPA receptors in the human brain, although the individual diversities of the radioligand metabolism and its possible association with regional radioactivity retention in the brain need to be further investigated. Our result highlights an additional challenge to develop a radioligand with a higher affinity for these receptors., Annual Meeting of Society of Nuclear Medicine and Molecular Imaging},
 title = {A human PET study of [11C]HMS011, a potential radioligand for AMPA receptors},
 year = {2017}
}