Molecular imaging and strategies for cancer treatment: A Study to achieve noninvasive in vivo pathological evaluation by molecular imaging

利用正电子发射断层扫描，我们试图开发分子成像策略，使肿瘤的分子机制和/或特征能够在体内成像，从而为癌症患者的个性化治疗做出贡献。1.分子靶向治疗的研究在我们的动物模型中，DNA合成的标志物-F-Flt可以在肿瘤大小发生显著变化之前及早发现吉非替尼分子靶向治疗的抗增殖作用，提示Flt-PET在早期监测肿瘤对分子靶向治疗的反应方面具有潜在的潜力。放射治疗的研究动物模型的结果表明，在发生复杂的变化之前，如放射后的炎症，可以通过18F-FDG的蓄积来预测放射治疗后的反应。针对肿瘤分子机制的分子成像探针的发展。(1)为了开发基于胸苷磷酸化酶(TP)表达的分子成像探针，我们合成了新型的C-11和I-123标记的尿嘧啶衍生物，它们是在一种有效的TP抑制剂的基础上设计的。合成的化合物具有与母体类似的抑制作用。(2)合成了放射性碘标记的塞来昔布衍生物。我们的结果显示，IMTP对COX-2具有很高的抑制效力和选择性，这表明它有可能作为SPECT示踪剂来成像环氧合酶-2的表达。此外，我们还成功地合成了一种非特异性结合减少的放射性碘标记的鲁米拉昔布衍生物。(3)标记的抗MT1-MMP1(膜型1 MMPs)抗体在肿瘤组织中呈时间依赖性地蓄积，提示该标记抗体有可能作为肿瘤肿瘤显像剂。此外，预靶向策略改善了S/N的比率。

Using positron emission tomography, we attempted to developed molecular imaging strategies that enable in vivo imaging of molecular mechanisms and/or characteristics of tumors, in order to contribute to personalized therapy of cancer patients. The results in the present study can be summarized as follows:1. Studies on molecular-targeted therapyIn our animal model, ^<18>F-FLT (a marker of DNA synthesis) can early detect the antiproliferative effects of the molecular-targeting therapy with gefitinib before significant changes in the tumor size, indicating the potential of FLT-PET in early monitoring of tumor response to the molecular-targeting therapy.2. Studies on radiation therapyThe results in an animal model indicated that post-radiation therapy response may be predicted by the accumulation of ^<18>F-FDG before complicated change, such as inflammation following irradiation, occurs.3. Development of molecular imaging probes that target molecular mechanisms of tumors.(1) For developing a thymidine phosphorylase (TP)-expression-based molecular imaging probe, we synthesized novel C-11 and I-123 labeled uracil derivatives, which were designed on the basis of one of the potent TP-inhibitors. The compounds synthesized possessed similar inhibitory potentials to the mother compounds.(2) A radioiodinated celecoxib derivative, ^<125I>-IMTP was synthesized. Our results showed a high inhibitory potency and selectivity of IMTP for COX-2, indicating its potential as a SPECT tracer for imaging cyclooxygenase-2 expression. In addition, we succeed to synthesizing a radioiodinated lumiracoxib derivative with reduced nonspecific bindings.(3) [^<99m>Tc-labeled anti-MT1-MMP (membrane-type-1 MMP) antibody accumulated in the tumor in time-dependent manner, indicating the potential of the labeled antibody for the imaging agent of tumor malignancy. In addition, the pre-targeting strategy improved S/N ratios.