WEKO3
アイテム
Nitroxyl radicals as low toxic spin-labels for non-invasive magnetic resonance imaging of blood-brain barrier permeability for conventional therapeutics
https://repo.qst.go.jp/records/45690
https://repo.qst.go.jp/records/45690947e3420-34ee-49bb-9cdd-379798313ff2
| Item type | 学術雑誌論文 / Journal Article(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2009-12-22 | |||||
| タイトル | ||||||
| タイトル | Nitroxyl radicals as low toxic spin-labels for non-invasive magnetic resonance imaging of blood-brain barrier permeability for conventional therapeutics | |||||
| 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_6501 | |||||
| 資源タイプ | journal article | |||||
| 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 |
Zhelev, Zhivko
× Zhelev, Zhivko× Bakalova-Zheleva, Rumiana× Aoki, Ichio× Matsumoto, Kenichiro× Veselina, Gadjeva× Anzai, Kazunori× Kanno, Iwao× Ｚｈｅｌｅｖ Ｚｈｉｖｋｏ× バカロバ ルミアナ× 青木 伊知男× 松本 謙一郎× 安西 和紀× 菅野 巖 |
|||||
| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | The non-invasive real-time imaging of blood-brain barrier (BBB) permeability for drugs is an indispensible step in the preclinical and clinical testing of new pharmaceuticals for brain diseases. The precise mapping of a drug in the brain has a significant impact on its dosing and prognostication of its target-specific effect. \nThe conventional methods for investigation of BBB permeability are usually invasive, time- and cost-consuming, often suffer from artefacts, and require a large number of experimental animals.1–6 In vitro models of BBB (e.g., cell and tissue cultures, immobilized artificial membranes, etc.) often serve as a major approach for indirect evaluation of drug permeability for brain tissue. The development of new methodologies for in vivo imaging of BBB permeability which are non-invasive, environmentally friendly, with minimal animal loss and minimal risk for volunteers, is a major goal of the modern pharmaceutical industry. \nCurrently, radiopharmaceuticals combined with autoradiography or positron-emission tomography (PET) are the only option for non-invasive real-time imaging of BBB permeability.7-9 Despite this approach being highly sensitive and valuable, it suffers from several restrictions which prevent it from being widely applicable in preclinical and clinical trials of new pharmaceuticals. Radio-labelling carries a risk for human safety and requires special experimental equipment and facilities, which increases markedly the cost of this analysis. Radiotracers are usually used for labelling of diagnostic markers, but not for labelling of therapeutics and real-time imaging of their BBB permeability and distribution in the organism. \nIn the present study, we would like to introduce a novel non-radioactive and environmentally friendly alternative for non-invasive real-time imaging of BBB permeability for conventional drugs, using stable nitroxyl radicals as spin-labels and magnetic resonance imaging (MRI). \nNitroxyl radicals are well known from electron paramagnetic resonance (EPR) studies.10-13 In 1984, it was reported that they have T1 contrast properties and could be applied in MRI.14 The nitroxyls are small molecules, sensitive to the redox status of biological samples and their use in life science research is limited predominantly to tissue oxygen and redox mapping in vitro and in vivo. 10-13,15-17 The paramagnetic nitroxyl radical could be reduced to diamagnetic hydroxylamine with the loss of the EPR signal or 1H-MRI relaxation time and thus could serve as a reduction sensor. However, the diamagnetic hydroxylamine could be re-converted via oxygenation to paramagnetic nitroxyl radical with the appearance of the EPR or MRI signal and thus could serve as an oxidation sensor. The rate constants of both processes could be used for evaluation of reduction/oxidation balance in cells and tissues. \nNitroxyl radicals are characterized by comparatively high T1 contrast properties, lower toxicity in comparison with the conventional MRI contrast agents (e.g., gadolinium derivatives), and some of them possess an excellent cell permeability. All these characteristics make them attractive for MRI diagnostics and their application in life science research could be extended beyond the limits mentioned above. In this context, we supposed that nitroxyl radicals could be appropriate spin-labels for non-invasive real-time MRI of BBB permeability for conventional therapeutics, which is an important step in their preclinical testing. Below, we would like to give a proof of the reality of this concept. In addition, MRI is characterized by much higher spatial resolution than EPR imaging (and even PET) and gives an excellent anatomical reference, which facilitates the exact localization of a nitroxyl probe in the organism. \nWe synthesized a TEMPO-labelled analogue (SLENU) of the conventional anticancer drug Lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, CCNU] (Fig. 1). Lomustine significantly improves the health-related quality of life of patients treated for brain and other tumours.18 Both TEMPO radical and Lomustine are permeable for BBB and cell membranes.15,19 |
|||||
| 書誌情報 |
Chemical Communications 巻 2009, 号 1, p. 53-55, 発行日 2008-11 |
|||||
| ISSN | ||||||
| 収録物識別子タイプ | ISSN | |||||
| 収録物識別子 | 1359-7345 | |||||
| DOI | ||||||
| 識別子タイプ | DOI | |||||
| 関連識別子 | 10.1039/b816878d | |||||
