11C-通过快速 C-[11C] 甲基化标记无环维甲酸 peretinoin 以揭示隐藏在抗肿瘤剂中的新脑通透性和中枢神经系统活动,Bioorganic & Medicinal Chemistry Letters

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11C-通过快速 C-[11C] 甲基化标记无环维甲酸 peretinoin 以揭示隐藏在抗肿瘤剂中的新脑通透性和中枢神经系统活动
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2023-03-03 , DOI: 10.1016/j.bmcl.2023.129212
Keiichi Suzuki ₁ , Hiroko Koyama ₂ , Narumasa Nakamura ₃ , Yasuyuki Kimura ₄ , Aya Ogata ₅ , Hiroshi Ikenuma ₄ , Hideki Ishii ₆ , Ming-Rong Zhang ₆ , Kazunori Kawamura ₆ , Takafumi Minamimoto ₇ , Yuji Nagai ₇ , Hiroshi Katsuki ₈ , Tetsuya Kimura ₉ , Nobuyuki Kimura ₁₀ , Masanori Ichise ₄ , Takashi Kato ₄ , Kengo Ito ₄ , Masaaki Suzuki ₄

Affiliation

Field of Biological Molecular Sciences, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
Field of Biological Molecular Sciences, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu-shi, Aichi 474-8511, Japan.
Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu-shi, Aichi 474-8511, Japan; Department of Pharmacy, Faculty of Pharmacy, Gifu University of Medical Science, 4-3-3 Nijigaoka, Kani 509-0293, Japan.
Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
Department of Functional Brain Imaging, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Department of Aging Neurobiology, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu-shi, Aichi 474-8511, Japan.
Section of Cell Biology and Pathology, Department of Alzheimer's Disease Research, Center for Development of Advanced Medicine for Dementia, Japan; Laboratory of Experimental Animals, Research and Development Management Center, National Center for Geriatrics and Gerontology, Morioka 7-430, Obu, Aichi 474-8511, Japan; Department of Veterinary Associated Science, Faculty of Veterinary Medicine, Okayama University of Science, 1-3 Ikoinooka, Imabari, Ehime 794-8555, Japan.

最近，从脑疾病诊断和药物开发的角度来看，类维生素A对中枢神经系统（CNS）的作用引起了相当大的关注。首先，我们使用 Pd(0) 介导的相应锡基前体的快速C- [ ^{11 C] 甲基化成功合成了 [}¹¹ C] peretinoin 酯（甲基、乙基和苄基），其中 82%、66% 没有几何异构化，和 57% 的放射化学收率 (RCY)。随后水解¹¹ C 标记的酯，以 13 ± 8% RCY ( n = 3)产生 [ ¹¹ C]peretinoin 。药物配制后，生成的 [ ¹¹ C] 苄酯和 [ ¹¹^{C]peretinoin 具有高放射化学纯度（>99%）和 144 和 118 ± 49 GBq μmol -1}的摩尔活性，总合成时间分别为 31 分钟和 40 ± 3 分钟。^{[ 11} C] 酯的大鼠大脑 PET 成像揭示了独特的时间-放射性曲线，表明酸 [ ¹¹ C] peretinoin 参与了大脑通透性。^{然而，[ 11} C]peretinoin的曲线在较短的时间滞后后稳步上升，在 60 分钟时达到 1.4 标准化摄取值 (SUV)。酯和酸之间的这些不同现象在猴脑中变得更加明显（90 分钟时 SUV > 3.0）。有机会识别高大脑吸收 [ ¹¹C]peretinoin，我们发现了一种名为 peretinoin 的候选药物的 CNS 活性，例如诱导干细胞向神经元细胞分化和抑制神经元损伤。

"点击查看英文标题和摘要"

11C-Labeling of acyclic retinoid peretinoin by rapid C-[11C]methylation to disclose novel brain permeability and central nervous system activities hidden in antitumor agent

Recently, retinoid actions on the central nervous system (CNS) have attracted considerable attention from the perspectives of brain disease diagnosis and drug development. Firstly, we successfully synthesized [¹¹C]peretinoin esters (methyl, ethyl, and benzyl) using a Pd(0)-mediated rapid C-[¹¹C]methylation of the corresponding stannyl precursors without geometrical isomerization in 82%, 66%, and 57% radiochemical yields (RCYs). Subsequent hydrolysis of the ¹¹C-labeled ester produced [¹¹C]peretinoin in 13 ± 8% RCY (n = 3). After pharmaceutical formulation, the resulting [¹¹C]benzyl ester and [¹¹C]peretinoin had high radiochemical purity (>99% each) and molar activities of 144 and 118 ± 49 GBq μmol⁻¹ at total synthesis times of 31 min and 40 ± 3 min, respectively. Rat brain PET imaging for the [¹¹C]ester revealed a unique time-radioactivity curve, suggesting the participation of the acid [¹¹C]peretinoin for the brain permeability. However, the curve of the [¹¹C]peretinoin rose steadily after a shorter time lag to reach 1.4 standardized uptake value (SUV) at 60 min. These various phenomena between the ester and acid became more pronounced in the monkey brain (SUV of > 3.0 at 90 min). With the opportunity to identify high brain uptake of [¹¹C]peretinoin, we discovered CNS activities of a drug candidate called peretinoin, such as the induction of a stem-cell to neuronal cell differentiation and the suppression of neuronal damages.

更新日期：2023-03-03

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