Synthesis and Bioevaluation of Novel [F-18]FDG-Conjugated 2-Nitroimidazole Derivatives for Tumor Hypoxia Imaging
Synthesis and Bioevaluation of Novel [F-18]FDG-Conjugated 2-Nitroimidazole Derivatives for Tumor Hypoxia Imaging
复制标题
用于肿瘤缺氧成像的新型 18FDG 缀合 2-硝基咪唑衍生物的合成和生物评价
DOI：
10.1021/acs.molpharmaceut.9b00075
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发表时间：
2019
影响因子：
4.9
通讯作者：
Chu Taiwei
中科院分区：
文献类型：
--
作者：
Yang Xianteng;Wang Fan;Zhu Hua;Yang Zhi;Chu Taiwei
乏氧显像可以指导肿瘤治疗，监测治疗过程中乏氧的变化。但目前尚没有理想的乏氧显像剂可用于临床。本研究合成了两种新型2-硝基咪唑衍生物，并以高放化产率和高放化纯度直接用[18 F]FDG标记。细胞实验，生物分布和正电子发射断层扫描（PET）成像研究也进行了小鼠荷S180或OS 732肿瘤。[18F]FDG-2NNC2ON [（2 R，3S，4 R，E）-2-18F-氟-3，4，5，6-四羟基己醛O-3-（2-（2-硝基-1H-咪唑-1-基）乙氨基）-2-氧代丙基肟]和[18F]FDG-2NNC 5 ON [（2R，3S，4R，E）-2-18F-氟-3，4，5，6-四羟基-3-己醛（5-（2-硝基-1H-咪唑-1-基）戊基氨基）-2-氧代丙基肟]可以从血液中快速清除，并特异性靶向缺氧肿瘤细胞。缺氧细胞对探针的摄取随时间逐渐增加。4 h后，缺氧细胞对[18F]FDG-2NNC 2 ON的摄取值是常氧细胞的3.2倍。相反，缺氧细胞和常氧细胞之间的[18F]FDG摄取没有差异。两种肿瘤模型的生物分布结果表明，肿瘤中两种放射性示踪剂的摄取值在1h时高于2 h和4 h。在1和2 h时，在PET图像上清楚地观察到肿瘤，并且[18 F]FDG-2NNC 5 ON和[18 F]FDG-2NNC 2 ON的成像特征与[18 F]FDG的成像特征不同。与[18 F]FDG-2NNC 5 ON相比，[18 F]FDG-2NNC 2 ON具有更高的肾脏排泄比例，更低的消化道摄取，并且由于其更高的亲水性，成像对比度更好。在2 h时，[18 F]FDG-2NNC 2 ON显示出良好的肿瘤-血液（T/B）比、基于生物分布的肿瘤-肌肉比（Bio-T/M比）和基于PET图像上的感兴趣区域的肿瘤-肌肉比[感兴趣区域（ROI）-T/M比]（在S180肿瘤模型中T/B、Bio-T/M和ROI-T/M比率分别为3.2、2.6和3.9，在OS 732肿瘤模型中分别为3.4、4.2和4.6）。放射自显影显示的影像学特征与免疫荧光显示的HIF 1 α阳性区域基本一致。同时，生物分布研究和PET成像显示，肿瘤中放射性示踪剂的摄取不能被5%葡萄糖竞争，证实[18 F]FDG-2NNC 2 ON靶向肿瘤的缺氧区域，而不是通过葡萄糖代谢途径靶向肿瘤。这些结果表明，新的2-硝基咪唑衍生物共轭与[18 F]FDG，[18 F]FDG-2NNC 2 ON，有潜力作为缺氧显像剂。
Hypoxia imaging can guide tumor treatment and monitor changes in hypoxia during treatment. However, there is still no ideal hypoxia imaging agent for clinical applications. In this study, two novel 2-nitromidazole derivatives were synthesized and directly radiolabeled by [18F]FDG in high radiochemical yield and excellent radiochemical purity. Cell experiments, biodistribution, and positron emission tomography (PET) imaging studies were also conducted in mice-bearing S180 or OS732 tumors. [18F]FDG-2NNC2ON [(2R,3S,4R,E)-2-18F-fluoro-3,4,5,6-tetrahydroxyhexanal O-3-(2-(2-nitro-1H-imidazole-1-yl)ethylamino)-2-oxopropyl oxime] and [18F]FDG-2NNC5ON [(2R,3S,4R,E)-2-18F-fluoro-3,4,5,6-tetrahydroxyhexanal-O-3-(5-(2-nitro-1H-imidazole-1-yl)pentylamino)-2-oxopropyl oxime] can be cleared from the blood quickly and specifically target hypoxic tumor cells. The uptake of the probes by hypoxic cells gradually increases with time. After 4 h, the uptake value of [18F]FDG-2NNC2ON in hypoxic cells is 3.2 times higher than that in normoxia cells. In contrast, there is no difference in the uptake of [18F]FDG between hypoxic cells and normoxia cells. Biodistribution resulting from two tumor models indicate that the uptake values of the two radiotracers in the tumor are higher at 1 h than those at 2 and 4 h. At 1 and 2 h, the tumors are clearly observed on the PET images and the imaging features of [18F]FDG-2NNC5ON and [18F]FDG-2NNC2ON are distinct from those of [18F]FDG. Compared with [18F]FDG-2NNC5ON, [18F]FDG-2NNC2ON has a higher proportion of renal excretion, lower digestive tract uptake, and better imaging contrast because of its higher hydrophilicity. At 2 h, [18F]FDG-2NNC2ON shows a good tumor-to-blood (T/B) ratio, tumor-to-muscle ratio based on biodistribution (Bio-T/M ratio), and tumor-to-muscle ratio based on regions of interest on the PET images [region of interest (ROI)-T/M ratio] in the two tumor models (T/B, Bio-T/M, and ROI-T/M ratios are 3.2, 2.6, and 3.9 in the S180 tumor model and are 3.4, 4.2, and 4.6 in the OS732 tumor model, respectively). The imaging features visualized with autoradiography mostly coincided with the positive areas of HIF1α staining by immunofluorescence. Meanwhile, the biodistribution study and PET imaging revealed that the uptake of the radiotracers in the tumor cannot be competed by 5% glucose, confirming that [18F]FDG-2NNC2ON targets the hypoxic regions of the tumors instead of targeting tumors through the glucose metabolism pathway. These results suggest that the new 2-nitroimidazole derivative conjugated with [18F]FDG, [18F]FDG-2NNC2ON, has potential as an imaging agent for hypoxia.