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Development of a PET tracer for imaging of redox status in the brain
https://repo.qst.go.jp/records/71874
https://repo.qst.go.jp/records/71874ad69f002-1864-4f98-98a1-7f2fee175fe2
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2015-11-25 | |||||
| タイトル | ||||||
| タイトル | Development of a PET tracer for imaging of redox status in the brain | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_c94f | |||||
| 資源タイプ | conference object | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Okamura, Toshimitsu
× Okamura, Toshimitsu× Okada, Maki× Kikuchi, Tatsuya× Wakizaka, Hidekatsu× Zhang, Ming-Rong× 岡村 敏充× 岡田 真希× 菊池 達矢× 脇坂 秀克× 張 明栄 |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Objectives Reactive oxygen species (ROS) function as important signaling molecules at moderate concentrations, whereas high concentrations of ROS cause the disruption of redox homeostasis. This has been implicated in the pathogenesis of several brain diseases. In vivo imaging of brain redox status would therefore be useful for elucidating pathologic conditions and aiding in diagnoses of brain diseases. However, little has been reported on PET tracers for imaging of brain redox status. Here, we report the development of a PET tracer for redox status.1 Figure 1 shows our approach for imaging of brain redox status. A lipophilic tracer (reduced form) enters the brain across the blood–brain barrier (BBB) after intravenous injection. A portion of the tracer is oxidized to a hydrophilic metabolite (oxidized form) depending on brain redox status, while the rest diffuses back into the blood. The metabolite is trapped or eliminated slowly because of its hydrophilicity. Hence, the brain radioactivity increases when oxidative stress occurs. By contrast, enhancement of antioxidant defense systems or inhibition of oxidases involved in oxidative stress results in the decrease in brain radioactivity. In this study, we designed a 11C-labeled dihydroquinoline derivative ([11C]Qred) and evaluated as a PET tracer for imaging of redox status in the brain. Results and Discussion The stability of [11C]Qred was examined in phosphate-buffered saline and mouse brain homogenate. The PET tracer [11C]Qred was stable in phosphate buffered saline; however, it was rapidly converted to its oxidized form ([11C]Qoxi) in the mouse brain homogenate. To confirm whether [11C]Qred can respond to the alteration of redox status, we employed diphenyleneiodonium and apocynin to modulate redox status and examined their effect on the oxidation of [11C]Qred. Diphenyleneiodonium and apocynin significantly decreased the initial velocity of [11C]Qred oxidation. Moreover, apocynin (0.01 to 10 mmol/L) caused the reduction of the initial velocity in a concentration dependent fashion. Thus, [11C]Qred was found to respond to the changes of redox status in mouse brain homogenate. For imaging of brain redox status by the metabolic trapping, the reduced form [11C]Qred in blood must enter the brain across the BBB, whereas the oxidized form [11C]Qoxi in blood should not. The BBB permeability of [11C]Qred and [11C]Qoxi was examined by PET. The PET tracer [11C]Qred exhibited high uptake in the brain 1 min after administration, whereas the brain radioactivity of hydrophilic [11C]Qoxi was much lower than that of [11C]Qred for 60 minutes. The result indicates that [11C]Qred can readily diffuse into the brain but [11C]Qoxi formed in peripheral tissues cannot enter the brain from blood. We investigated whether [11C]Qred can respond to the brain redox status altered by apocynin in vivo. Radioactivity in the brain of control mice reached a maximum level after injection of [11C]Qred and then slowly decreased, whereas the apocynin treatment caused a rapid decrease in brain radioactivity compared with control mice. We also analyzed the chemical form of radioactive compounds in the brain after intravenous administration of [11C]Qred. The reduced form [11C]Qred disappeared from the brain tissue of control mice, and the main radioactive compound in the brain was the oxidized form [11C]Qoxi. By contrast, [11C]Qred remained largely intact in the brain of the apocynin-treated mice. The rapid clearance of radioactivity for the apocynin group would therefore be due to the inhibition of the oxidation of [11C]Qred to hydrophilic [11C]Qoxi in the brain followed by the rapid diffusion of lipophilic [11C]Qred out of the brain. Thus, the difference in the [11C]Qred kinetics reflects the change in redox status caused by apocynin. \nConclusion This study shows that [11C]Qred is a potential PET tracer for imaging of redox status in the living brain, and this tracer might be useful for studying the relationship between the development or pathogenesis of brain diseases and redox status. |
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| 会議概要（会議名, 開催地, 会期, 主催者等） | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | Ninth Japan-China Joint Seminar on Radiopharmaceutical Chemistry | |||||
| 発表年月日 | ||||||
| 日付 | 2015-11-09 | |||||
| 日付タイプ | Issued | |||||
