Effective PET Imaging in Liver Cancer

描述（由申请人提供）：肝细胞癌（HCC）在美国的发病率和死亡率都在增加，HCC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。医学影像学提供了一种无创、重复和定量评估HCC进展或状态的方法。然而，目前用于肿瘤成像的主要PET示踪剂[18F]-FDG已被证明对HCC成像无效，因为与周围肝组织相比，许多HCC未显示FDG摄取，这导致假阴性率很高。其他示踪剂，如[11C]-醋酸酯和[11C]-胆碱，在HCC中显示出一定的摄取，尽管这些现有示踪剂的用途尚不清楚。目前迫切需要一种有效的成像示踪剂，用于HCC的早期检测和早期治疗反应的评估。在这项应用中，我们建议研究一种新的放射性标记PET示踪剂L-FMAU在HCC成像中的表现。这种分子最初是作为抗病毒药物开发的。其镜像立体异构体D-FMAU是一种核苷类似物，已被标记为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HCC）的成像有效性尚存疑问。另一方面，L-FMAU是一种非天然核苷类似物，是最近PET成像放射性标记发展的焦点。根据我们的初步结果，L-FMAU确实有潜力成为HCC成像的PET示踪剂。我们将对L-FMAU在肝组织和肝癌中的转运、代谢、降解（或抵抗）机制进行深入研究，并将PET成像数据与癌症特征相关联，以评估L-FMAU在HCC成像中的效用。公共卫生相关性：我们的研究评估了一种新的PET示踪剂对肝细胞癌（HCC）的有效成像。FDG是一种常用的PET示踪剂，通常用于肿瘤学应用，但由于假阴性率高，对HCC成像无效。新型成像示踪剂L- FMAU显示出巨大的前景。我们将探讨其在肝癌成像中的分子机制。具体而言，我们将研究其在HCC早期检测和早期治疗反应评估方面的表现。在成功开发和评估后，这种新型示踪剂的使用将满足对HCC进行有效PET成像的迫切需求，HCC在美国的发病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.