Synthesis and Evaluation of Novel Radioligands for Positron Emission Tomography Imaging of the Orexin-2 Receptor

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• 作者：Norihito Oi ; Michiyuki Suzuki ; Taro Terauchi ; Masaki Tokunaga ; Yosuke Nakatani ; Noboru Yamamoto ; Toshimitsu Fukumura ; Ming-Rong Zhang ; Tetsuya Suhara ; Makoto Higuchi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 22, 2013
• 年：2013
• 卷：56
• 期：16
• 页码：6371-6385
• 全文大小：716K
• 年卷期：v.56,no.16(August 22, 2013)
• ISSN：1520-4804

文摘

Orexin receptors (OXRs) in the brain have been implicated in diverse physiological and neuropsychiatric conditions. Here we describe the design, synthesis, and evaluation of OXR ligands related to (1R,2S)-2-(((2-methyl-4-methoxymethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyridin-2-yl)-2-(3-fluorophenyl)cyclopropanecarboxamide (9a) applicable to positron emission tomography (PET) imaging. Structural features were incorporated to increase binding affinity for OXRs, to enable carbon-11 radiolabeling, and to adjust lipophilicity considered optimal for brain penetration and low nonspecific binding. 9a displayed nanomolar affinity for OXRs, and autoradiography using rat brain sections showed that specific binding of [¹¹C]9a was distributed primarily to neocortical layer VI and hypothalamus, consistent with reported localizations of orexin-2 receptors (OX₂Rs). In vivo PET study of [¹¹C]9a demonstrated moderate uptake of radioactivity into rat and monkey brains under deficiency or blockade of P-glycoprotein, and distribution of PET signals in the brain was in agreement with autoradiographic data. Our approach and findings have provided significant information for development of OX₂R PET tracers.