Development of Metabolism Radiotracers to Probe Disease Pathology in Human Subjects with Cancer

我们的团队对探索疾病生物学的新型放射性示踪剂的发现和发展感兴趣。在这五年里，我们提出了一个转化计划，旨在开发下一代成像方法，用于基于代谢的人类疾病生物学研究。使用正电子发射断层扫描（PET）成像仍然是询问包括癌症在内的许多疾病的分子机制的最直接方法之一。PET方法是非破坏性的，允许在感兴趣的物种（人类）中进行组织生物学研究，无侵入性，没有与活检方法相关的采样误差或组织改变。适当的探针的可用性及其在人体中的验证仍然是这一研究领域的主要瓶颈。在过去的五年中，我们以癌症为模型，将新的PET探针推进到人体成像中，以研究相关的分子机制。目前人们感兴趣的是肿瘤如何重新编程它们的新陈代谢，这很难用传统的方法在活体器官和组织中测量。在未来的5年里，我们将引入两种新的人体成像探测器，并完成另一种的工作。这些探针检测组织如何燃烧脂肪酸，以糖原的形式储存能量，以及合成膜的前体。这个程序的连通性-化学设计，自动化，调节，数学建模，并将成像输出与病理学进行比较-将使我们能够提供工具，将我们对重编程肿瘤代谢的后基因组理解转化为对人类原位病变组织的科学研究，同时开发具有管理患者潜力的候选探针。

Our group is interested in discovery and development of novel radiotracers for probing disease biology. In this quinquenium, we propose a translational programme that aims to develop the next generation of imaging approaches for investigation of disease biology in humans based on metabolism. Imaging using positron emission tomography (PET) remains one of the most direct ways of interrogating molecular mechanisms derailed in many diseases including cancer. PET methods are non-destructive and allow tissue biology to be investigated in the species of interest - the human being - non-invasively without associated sampling errors or tissue alterations that occur with biopsy-based approaches. Availability of appropriate probes and their validation in humans remains the major bottleneck in this field of research. Using cancer as the model, we have over the past five years advanced new probes for PET into human imaging to allow associated molecular mechanisms to be investigated. Of current interest is how tumours reprogramme their metabolism, which is difficult to measure by traditional methods in living organs and tissues. In the coming 5 years we will introduce two new imaging probes into humans and complete work on another. These probes detect how tissues burn fatty acids, store energy in the form of glycogen and make synthesise the precursors for membranes. The connectivity of this programme - chemistry design, automation, regulatory, mathematical modelling, and comparing imaging output to pathology - will allow us to provide the tools for translating our post-genome understanding of reprogrammed tumour metabolism into scientific investigation of diseased tissues in situ in humans, while developing candidate probes with potential for managing patients.