LABELED THYMIDINE--DEVELOPMENT AS A PET IMAGING AGENT

我们的总体目标是使用正电子发射断层扫描（PET）， 了解癌症对治疗的反应 使用生物化学的非侵入性定量成像。 宠物 必须与适当的正电子标记化合物结合 以测量感兴趣的代谢途径。 11C- 胸苷（标记在甲基位置）是一种PET成像剂 其具有定量体内DNA合成的潜力。 我们正在进行的研究（包括由该补助金资助的研究） 证明使用11 C-胸苷（TdR）的PET成像是 可行 我们已经解决了一些问题 与解释11 C-TdR的PET图像相关，包括 细胞内库对TdR代谢的贡献， 再利用和降解。 该提案涉及以下领域： 研究需要进一步深入了解生物化学， TdR代谢动力学。 这些研究有助于 将时间依赖性组织的简单测量 放射性同位素浓度由断层扫描仪获得， 细胞增殖的定量测量。 在我们努力中 为了检验TdR摄取的测量将 在肿瘤生长的定量中是有用的，我们将讨论 以下问题：1）为了解释PET图像，必须 知道被标记的前体输送到肿瘤的量。 因此，我们将开发技术和模型， 占天然TdR化合物的比例， 流通。 我们还将研究的第一次通过提取 TdR及其代谢产物的分布。 （二） TdR代谢的动力学模型的细化是必要的。 我们用PET积累的数据将使用 分区、图形和滑动段建模 接近。 我们将比较动力学模型的结果， 直接测量掺入DNA的TdR， 活检 3)使用PET进行的测量的验证是 具有本质意义 这将在患有转移性淋巴瘤的狗中进行， 其中活检标本将使用许多 与PET相关的细胞和生物化学技术 测量. 我们小组的最终目标是开发一个 了解癌症对11 C-TdR治疗的反应 PET。 为了进行有意义的细胞测量 使用11 C-TdR和PET进行增殖，我们需要产生详细的 TdR代谢的生化和动力学模型。

Our overall goal is to use Positron emission tomography (PET) to develop an understanding of the response of cancers to therapy using non-invasive quantitative imaging of biochemistry. PET must be combined with the appropriate positron-labeled compound in order to measure the metabolic pathway of interest. 11C- thymidine (labeled in the methyl position) is a PET imaging agent which has the potential for quantitating DNA synthesis in vivo. Our ongoing studies (including those funded by this grant) demonstrate that PET imaging with 11C-thymidine (TdR) is feasible. We have already addressed a number of the problems associated with interpreting the PET images of 11C-TdR including the contributions to TdR metabolism of intracellular pools, reutilization and degradation. This proposal addresses areas of research needed to gain further insight into the biochemistry and kinetics of TdR metabolism. These studies are needed to assist in converting the simple measurement of time-dependent tissue radioisotope concentration obtained by the tomograph into quantitative measurements of cellular proliferation. In our effort to test the hypothesis that the measurement of TdR uptake will be useful in the quantitation of tumor growth, we will address the following problems: 1) In order to interpret PET images one must know the amount of labeled precursor delivered to the tumor. Therefore, we will develop techniques and models which will account for the proportion of native TdR compound remaining in the circulation. We will also study the first pass extraction of TdR and the distribution of the metabolites of TdR. 2) Refinement of the kinetic models of TdR metabolism is needed. The data we are accumulating with PET will be fitted using compartmental, graphical and sliding segment modeling approaches. We will compare the results of the kinetic models to direct measurements of the incorporation of TdR into DNA at biopsy. 3) Validation of the measurements made with PET is essential. This will be done in dogs with metastatic lymphoma, where biopsy specimens will be analyzed using a number of cellular and biochemical techniques for correlation with the PET measurements. The ultimate goal of our group is to develop an understanding of the response of cancer to therapy using 11C-TdR and PET. In order to make meaningful measurements of cellular proliferation using 11C-TdR and PET we need to produce detailed biochemical and kinetic models of TdR metabolism.