Research Center, Nihon Medi-Physics Co., Ltd., 299-0266 Sodegaura, Japan.
Graduate School of Medicine, Hokkaido University, 060-8638 Sapporo, Japan.
Nucl Med Biol. 2019 Mar;70:39-45. doi: 10.1016/j.nucmedbio.2019.01.008. Epub 2019 Feb 8.
Hypoxia, a common feature of most solid tumors, is an important predictor of tumor progression and resistance to radiotherapy. We developed a novel hypoxia imaging probe with optimal biological characteristics for use in clinical settings.
We designed and synthesized several new hypoxia probes with additional hydrophilic characteristics compared to [F]fluoromisonidazole ([F]FMISO). These were 1-(2,2-Dihydroxy-methyl-3-[F]-Fluoropropyl) azomycin ([F]DiFA, formerly [F]HIC101) and its analogs ([F]F1 and [F]F2). Biodistribution studies with EMT6 mammary carcinoma cell-bearing mice were performed 1 and 2 h after injection of each probe. Small-animal positron emission tomography (PET) imaging studies were conducted using [F]DiFA and [F]FMISO in the same mice. Tumoral hypoxia was confirmed via pimonidazole staining. Ex vivo digital autoradiographs were obtained for confirming the co-localization of [F]DiFA and pimonidazole in the tumor tissues.
The EMT6 tumors used had pimonidazole-positive regions. In biodistribution studies, the tumor-to-blood ratio and tumor-to-muscle ratio of [F]DiFA was significantly higher than the respective [F]FMISO ratios 1 h after injection. Hence, we selected [F]DiFA as the best hypoxia probe among those tested. Small-animal PET imaging studies showed time-dependent increases in the tumor-to-normal tissue ratio of [F]DiFA uptake. Rapid clearance from the rest of the body was observed primarily via the renal system. Ex vivo autoradiography showed a positive correlation between [F]DiFA uptake and the regions of pimonidazole distribution, indicating that [F]DiFA selectively accumulated in the tumor tissue's hypoxic region.
A better contrast image and a shorter waiting time may be obtained with [F]DiFA than with [F]FMISO.
By optimizing LogP based on the [F]FMISO structure, we demonstrated that [F]DiFA could detect tumor hypoxia regions at an early time point. IMPLICATIONS FOR PATIENT CARE: [F]DiFA imaging facilitates the evaluation of various cancer hypoxic states due to the lower uptake of normal tissues and could contribute to novel treatment development.
缺氧是大多数实体瘤的共同特征，是肿瘤进展和放疗抵抗的重要预测因素。我们开发了一种具有最佳生物学特性的新型缺氧成像探针，可用于临床环境。
我们设计并合成了几种新的缺氧探针，与[F]氟米索硝唑([F]FMISO)相比具有额外的亲水性。这些探针是 1-(2,2-二羟甲基-3-[F]-氟丙基)氮唑([F]DiFA，以前称为[F]HIC101)及其类似物([F]F1 和[F]F2)。用 EMT6 乳腺癌细胞荷瘤小鼠进行 EMT6 乳腺癌细胞荷瘤小鼠的生物分布研究，在注射每种探针后 1 和 2 小时进行。使用[F]DiFA 和[F]FMISO 在相同的小鼠中进行小动物正电子发射断层扫描(PET)成像研究。通过吡咯莫德染色证实肿瘤缺氧。获得用于确认[F]DiFA 与肿瘤组织中吡咯莫德共定位的体外数字放射自显影。
使用的 EMT6 肿瘤有吡咯莫德阳性区域。在生物分布研究中，[F]DiFA 的肿瘤/血液比和肿瘤/肌肉比在注射后 1 小时明显高于相应的[F]FMISO 比值。因此，我们选择[F]DiFA 作为测试中最好的缺氧探针。小动物 PET 成像研究表明，[F]DiFA 摄取的肿瘤/正常组织比值随时间呈依赖性增加。主要通过肾脏系统从体内其他部位快速清除。体外放射自显影显示[F]DiFA 摄取与吡咯莫德分布区域之间存在正相关，表明[F]DiFA 选择性地积聚在肿瘤组织的缺氧区域。
与[F]FMISO 相比，使用[F]DiFA 可能获得更好的对比图像和更短的等待时间。
通过优化基于[F]FMISO 结构的 LogP，我们证明[F]DiFA 可以在早期检测到肿瘤缺氧区域。
[F]DiFA 成像由于正常组织摄取较低，有利于评估各种癌症缺氧状态，并有助于开发新的治疗方法。
