Effective PET Imaging in Liver Cancer

描述(申请人提供)：在美国，肝细胞癌的发病率和死亡率正在增加，而肝癌发病率的快速增加与肝炎病毒感染的增加有关。早期诊断和准确评估治疗反应需要可靠的、局部的、可重复的和定量的测量。医学成像为无创、重复和定量评估肝细胞癌的进展或状态提供了这样一种手段。然而，目前用于肿瘤成像的主要PET示踪剂[18F]-FDG已被证明对肝癌成像无效，因为许多肝癌与周围肝组织相比没有显示FDG摄取，这导致了很高的假阴性率。其他示踪剂如[11C]-醋酸盐和[11C]-胆碱在肝细胞癌中已显示出一定的摄取，尽管这些现有示踪剂的用途仍不清楚。迫切需要一种有效的成像示踪剂，用于肝细胞癌的早期检测和早期治疗反应的评估。在这一应用中，我们建议研究一种新型的放射性标记PET示踪剂L-FMAU，以研究其在肝癌成像中的性能。这种分子最初是作为一种抗病毒药物而开发的。它的镜像立体异构体D-FMAU是一种核苷类似物，已被标记用于PET成像，尽管由于其在肝脏中的高背景摄取，其对原发性肝癌(如肝癌)的成像有效性受到质疑。另一方面，L-FMAU是一种非天然的核苷类似物，一直是近年来正电子发射计算机断层成像放射性标记技术发展的焦点。基于我们的初步结果，L荧光微球有可能成为一种用于肝癌成像的正电子发射计算机断层扫描示踪剂。我们将对L-FMAU在肝组织中的转运、代谢、降解(或抵抗)和肝癌的机制进行深入的研究，并将PET成像数据与肿瘤的特征相关联，以评价L-FMAU在肝癌成像中的作用。公共卫生相关性：我们的研究评估了一种新的PET示踪剂，用于有效地对肝细胞癌(HCC)进行成像。FDG是一种常用的肿瘤用PET示踪剂，但由于假阴性率高，对肝细胞癌成像无效。新的成像示踪剂L-FMAU显示出了巨大的前景。我们将研究其在肝癌成像中的分子机制。具体地说，我们将检查其在早期发现和评估对肝癌治疗的早期反应方面的表现。在成功开发和评估后，这种新的示踪剂的使用将满足对有效的肝细胞癌PET成像的迫切需求，在美国，肝细胞癌的发生率和死亡率正在迅速增加。

DESCRIPTION (provided by applicant): Hepatocellular Carcinoma (HCC) is increasing in frequency and mortality in United States, and the rapid increase of HCC incidence correlates with increase in hepatitis viral infection. Early diagnosis and accurate assessment of treatment response require a reliable, localized, repeatable, and quantitative measure. Medical imaging offers such a means for non-invasive, repeated, and quantitative evaluation of the progression or status of HCC. However, the main PET tracer currently used for oncology imaging, [18F]-FDG, has been shown to be ineffective for imaging HCC since many HCCs do not show FDG uptake in contrast to the surrounding hepatic tissues, which has led to a high false negative rate. Other tracers such as [11C]- Acetate and [11C]-Choline have shown some uptake in HCC although the utilities of these existing tracers are still unclear. There is an urgent need for an effective imaging tracer that can be used in HCC for early detection and assessment of early response to treatment. In this application, we propose to study a new radiolabeled PET tracer L-FMAU for its performance in HCC imaging. The molecule was developed initially as an anti-viral agent. Its mirrored stereoisomer, D-FMAU, a nucleoside analog, has been labeled for PET imaging although its usefulness for imaging primary liver cancer such as HCC is in doubt due to the high background uptake in the liver. L-FMAU, on the other hand, is a non-natural nucleoside analog and has been the focal interest of recent radiolabeling development for PET imaging. There is a real potential for L-FMAU to be a PET tracer for imaging HCC based on our preliminary results. We will conduct thorough investigations for the mechanisms responsible for L-FMAU's transport, metabolism, degradation (or resistance to it) in the liver tissue and liver cancer, and will correlate PET imaging data with characteristics of the cancer to evaluate L-FMAU's utility i imaging HCC. PUBLIC HEALTH RELEVANCE: Our study evaluates a new PET tracer for effective imaging of hepatocellular carcinoma (HCC). FDG, the available PET tracer commonly used for oncological applications, is ineffective for HCC imaging due to a high false negative rate. The new imaging tracer, L- FMAU has shown great promise. We will investigate the molecular mechanisms for its use in liver cancer imaging. Specifically, we will examine its performance for early detection and assessment of early response to the treatment of HCC. Upon successful development and evaluation as proposed, the use of this new tracer will meet the urgent need for effective PET imaging for HCC, which is increasing rapidly in frequency and mortality in United States.