Multiparametric imaging of tumor perfusion and hypoxia with dynamic ¹⁸F-fluoromisonidazole (¹⁸F-FMISO) PET may allow for an improved response assessment to antiangiogenic therapies. Cediranib (AZD2171) is a potent inhibitor of tyrosine kinase activity associated with vascular endothelial growth factor receptors 1, 2, and 3, currently in phase II/III clinical trials. Serial dynamic ¹⁸F-FMISO PET was performed to investigate changes in tumor biomarkers of perfusion and hypoxia after cediranib treatment. Methods: Twenty-one rats bearing HT29 colorectal xenograft tumors were randomized into a vehicle-treated control group (0.5% methylcellulose daily for 2 d [5 rats] or 7 d [4 rats]) and a cediranib-treated test group (3 mg/kg daily for 2 or 7 d; 6 rats in both groups). All rats were imaged before and after treatment, using a 90-min dynamic PET acquisition after administration of 42.1 ± 3.9 MBq of ¹⁸F-FMISO by tail vein injection. Tumor volumes were delineated manually, and the input function was image-derived (abdominal aorta). Kinetic modeling was performed using an irreversible 1-plasma 2-tissue compartmental model to estimate the kinetic rate constants K₁, K₁/k₂, and k₃—surrogates for perfusion, ¹⁸F-FMISO distribution volume, and hypoxia-mediated entrapment, respectively. Tumor-to-blood ratios (TBRs) were calculated on the last dynamic frame (80–90 min). Tumors were assessed ex vivo by digital autoradiography and immunofluorescence for microscopic visualization of perfusion (pimonidazole) and hypoxia (Hoechst 33342). Results: Cediranib treatment resulted in significant reduction of mean voxelwise ¹⁸F-FMISO TBR, K₁, and K₁/k₂ in both the 2-d and the 7-d groups (P < 0.05). The k₃ parameter was increased in both groups but reached significance only in the 2-d group. In the vehicle-treated groups, no significant change in TBR, K₁, K₁/k₂, or k₃ was observed (P > 0.2). Ex vivo tumor analysis confirmed the presence of hypoxic tumor regions that nevertheless exhibited relatively lower ¹⁸F-FMISO uptake. Conclusion: ¹⁸F-FMISO kinetic modeling reveals a more detailed response to antiangiogenic treatment than a single static image is able to reveal. The reduced mean K₁ reflects a reduction in tumor vascular perfusion, whereas the increased k₃ reflects a rise in hypoxia-mediated entrapment of the radiotracer. However, if only late static images are analyzed, the observed reduction in ¹⁸F-FMISO uptake after treatment with cediranib may be mistakenly interpreted as a global decrease, rather than an increase, in tumor hypoxia. These findings support the use of ¹⁸F-FMISO kinetic modeling to more accurately characterize the response to treatments that have a direct effect on tumor vascularization and perfusion.

动态¹⁸ F-氟代咪唑（¹⁸ F-FMISO）PET对肿瘤灌注和缺氧的多参数成像可改善对抗血管生成疗法的反应评估。Cediranib（AZD2171）是与血管内皮生长因子受体1、2和3相关的酪氨酸激酶活性的有效抑制剂，目前处于II / III期临床试验中。进行了系列动态¹⁸ F-FMISO PET，以研究西地尼布治疗后灌注和缺氧的肿瘤生物标志物的变化。方法：将21只患有HT29大肠异种移植肿瘤的大鼠随机分为媒介物治疗对照组（2天[5只大鼠]或7天[4只大鼠]每天0.5％甲基纤维素）和西地那尼治疗的对照组（3 mg / kg）每天持续2或7天；两组共6只。通过尾静脉注射给予42.1±3.9 MBq的¹⁸ F-FMISO后，使用90分钟动态PET采集对所有大鼠进行治疗前和治疗后的图像。手动描绘肿瘤体积，输入功能源自图像（腹主动脉）。使用不可逆的1-等离子2-组织隔室模型进行动力学建模，以估计动力学速率常数K ₁，K ₁ / k ₂和k ₃-分别代表灌注，¹⁸ F-FMISO分布量和缺氧介导的陷获。在最后一个动态帧（80-90分钟）上计算肿瘤与血液的比率（TBR）。通过数字放射自显影和免疫荧光离体评估肿瘤，以显微镜观察灌注（吡莫尼唑）和缺氧（Hoechst 33342）。结果：西地尼布治疗导致2 d组和7 d组的平均体素¹⁸ F-FMISO TBR，K ₁和K ₁ / k ₂显着降低（P <0.05）。的ķ ₃两组参数均增加，但仅在二维组中达到显着水平。在载体治疗组中，未观察到TBR，K ₁，K ₁ / k ₂或k _3的显着变化（P > 0.2）。离体肿瘤分析证实了低氧肿瘤区域的存在，但是该低氧肿瘤区域表现出相对较低的¹⁸ F-FMISO摄取。结论： ¹⁸ F-FMISO动力学模型显示出比单张静态图像更能显示出对抗血管生成治疗的更详细反应。降低的平均K ₁反映了肿瘤血管灌注的减少，而增加了k ₃反映了低氧介导的放射性示踪剂截留的增加。但是，如果仅分析晚期静态图像，则观察到的西地尼布治疗后¹⁸ F-FMISO摄取的减少可能会错误地解释为肿瘤缺氧的整体减少而不是增加。这些发现支持使用¹⁸ F-FMISO动力学模型来更准确地表征对直接影响肿瘤血管生成和灌注的治疗的反应。