Synthesis and Evaluation of Novel 18F Labeled 2-Pyridinylbenzoxazole and 2-Pyridinylbenzothiazole Derivatives as Ligands for Positron Emission Tomography (PET) Imaging of β-Amyloid Plaques
Synthesis and Evaluation of Novel 18F Labeled 2-Pyridinylbenzoxazole and 2-Pyridinylbenzothiazole Derivatives as Ligands for Positron Emission Tomography (PET) Imaging of β-Amyloid Plaques
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DOI：
10.1021/jm300973k
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发表时间：
2012-11-08
影响因子：
7.3
通讯作者：
Liu, Boli
中科院分区：
文献类型：
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作者：
Cui, Mengchao;Wang, Xuedan;Liu, Boli
合成了一系列氟聚乙二醇化（FPEG）2-吡啶基苯并恶唑和2-吡啶基苯并噻唑衍生物，并评价了它们作为新型β-淀粉样蛋白（A β）PET成像探针的性能。它们显示出对A β（1-42）聚集体的结合亲和力，范围为2.7至101.6 nM。选择7个具有高亲和力的配体用于F-18标记。体外放射自显影结果证实了这些放射性示踪剂的高亲和力。在正常小鼠体内的生物分布实验表明，具有短FPEG链的放射性示踪剂（n = 1）表现出高的初始摄取和快速从脑中洗脱。2-吡啶基苯并恶唑衍生物之一，[F-18]-5-（5-（2-氟乙氧基）苯并[d]恶唑-2-基）-N-甲基吡啶-2-胺（[F-18]32）（Ki = 8.0 +/-3.2 nM）显示出4.66的脑（2 min）/脑（60 min）比率，这对于A β成像剂是高度期望的。通过转基因模型小鼠的离体放射自显影实验验证了[F-18]32与A β斑块的靶特异性结合。总的来说，[F-18]32是一种有前途的PET A β显像剂，值得在人类受试者中进一步评价。
A series of fluoro-pegylated (FPEG) 2-pyridinylbenzoxazole and 2-pyridinylbenzothiazole derivatives were synthesized and evaluated as novel beta-amyloid (A beta) imaging probes for PET. They displayed binding affinities for A beta(1-42) aggregates that varied from 2.7 to 101.6 nM. Seven ligands with high affinity were selected for F-18 labeling. In vitro autoradiography results confirmed the high affinity of these radiotracers. In vivo biodistribution experiments in normal mice indicated that the radiotracers with a short FPEG chain (n = 1, displayed high initial uptake into and rapid washout from the brain. One of the 2-pyridinylbenzoxazole derivatives, [F-18]-5-(5-(2-fluoroethoxy)benzo[d]oxazol-2-yl)-N-methylpyridin-2-amine ([F-18]32) (K-i = 8.0 +/- 3.2 nM) displayed a brain(2min)/brain(60min) ratio of 4.66, which is highly desirable for A beta imaging agents. Target specific binding of [F-18]32 to A beta plaques was validated by ex vivo autoradiographic experiment with transgenic model mouse. Overall, [F-18]32 is a promising A beta imaging agent for PET and merits further evaluation in human subjects.