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，使分子机制和/或肿瘤特征的体内成像，以促进癌症患者的个性化治疗。本文的研究结果可以总结如下：1.研究结果表明：分子靶向治疗的研究在我们的动物模型中，^<18 b>的F-FLT （DNA合成标志物）可以在肿瘤大小发生显著变化之前早期检测到吉非替尼分子靶向治疗的抗增殖作用，这表明FLT-PET在早期监测肿瘤对分子靶向治疗的反应方面具有潜力。放射治疗的研究动物模型的结果表明，放射治疗后的反应可以通过^<18 b> F-FDG的积累来预测，然后再发生复杂的变化，如放射后的炎症。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，我们合成了新的C-11和I-123标记的尿嘧啶衍生物，这些衍生物是在一种有效的TP抑制剂的基础上设计的。合成的化合物具有与母化合物相似的抑制电位。(2)合成了放射性碘化塞来昔布衍生物^<125I>-IMTP。我们的研究结果显示，IMTP对COX-2具有很高的抑制效能和选择性，这表明它有可能成为环氧化酶-2表达成像的SPECT示踪剂。此外，我们成功地合成了一种非特异性结合减少的放射性碘化lumiracoxib衍生物。(3) [^<99m>] tc标记的抗mt1 -MMP（膜型-1 MMP）抗体在肿瘤中呈时间依赖性积累，表明该标记抗体具有作为肿瘤恶性显像剂的潜力。此外，预定位策略提高了信噪比。

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.