Development of 2-(2-(3-(4-([18F]Fluoromethoxy-d2)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione for Positron-Emission-Tomography Imaging of Phosphodiesterase 10A in the Brain
Development of 2-(2-(3-(4-([18F]Fluoromethoxy-d2)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione for Positron-Emission-Tomography Imaging of Phosphodiesterase 10A in the Brain
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DOI：
10.1021/acs.jmedchem.8b01366
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发表时间：
2019-01-24
影响因子：
7.3
通讯作者：
Zhang, Ming-Rong
中科院分区：
文献类型：
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作者：
Mori, Wakana;Yamasaki, Tomoteru;Zhang, Ming-Rong
磷酸二酯酶10A（PDE 10A）是一种新发现的中枢神经系统疾病的治疗靶点。2-（2-（3-（4-（[F-18]氟乙氧基）苯基）-4-氧代-3，4-二氢喹唑啉-2-基）乙基）-4-异丙氧基异吲哚啉-1，3-二酮（[F-18]MNI-659，[F-18]5）是用于人脑中PDE 10A成像的有用的正电子发射断层扫描（PET）配体。然而，[F-18]5的放射性标记代谢物可在脑中蓄积。在这项研究中，使用[F-18]5作为先导化合物，我们设计了四个新的F-18标记的配体（[F-18]6-9），以找到一个比[F-18]5更合适的。其中，2-（2-（3-（4-（[F-18]氟甲氧基-d（2））苯基）-4-氧代-3，4-二氢喹唑啉-2-基）乙基）-4-异丙氧基异吲哚啉-1，3-二酮（[F-18]9）显示出对PDE 10A的高体外结合亲和力（Ki = 2.9 nM）和合适的亲脂性（LogD = 2.2）。在PET研究中，大鼠脑中[F-18]9（5.8）与PDE 10A的结合潜力（BPND）显著高于[F-18]5（4.6）。此外，代谢物分析显示，脑中放射性标记的[18 F]9代谢物的污染水平远低于[F-18]5。总之，[F-18]9是一种有用的PET配体，可用于脑部PDE 10A成像。
Phosphodiesterase 10A (PDE10A) is a newly identified therapeutic target for central nervous system disorders. 2-(2-(3-(4-([F-18]Fluoroethoxy)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([F-18]MNI-659, [F-18]5) is a useful positron emission tomography (PET) ligand for imaging of PDE10A in the human brain. However, the radiolabeled metabolite of [F-18]5 can accumulate in the brain. In this study, using [F-18]5 as a lead compound, we designed four new F-18-labeled ligands ([F-18]6-9) to find one more suitable than [F-18]5. Of these, 2-(2-(3-(4-([F-18]fluoromethoxy-d(2))phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([F-18]9) exhibited high in vitro binding affinity (K-i = 2.9 nM) to PDE10A and suitable lipophilicity (LogD = 2.2). In PET studies, the binding potential (BPND) of [F-18]9 (5.8) to PDE10A in rat brains was significantly higher than that of [F-18]5 (4.6). Furthermore, metabolite analysis showed much lower levels of contamination with radiolabeled metabolites of [18F]9 in the brain than those of [F-18]5. In conclusion, [F-18]9 is a useful PET ligand for PDE10A imaging in brain.