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)来 加深对癌症治疗反应的理解 利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 以测量感兴趣的新陈代谢途径。11C- 胸腺嘧啶核苷(标记在甲基位置)是一种PET显像剂 它有可能对体内的DNA合成进行量化。 我们正在进行的研究(包括由这笔拨款资助的研究) 证明用~(11)C-胸腺嘧啶核苷(TDR)进行正电子发射计算机断层扫描 可行。我们已经解决了一些问题 与解释11C-TDR的PET图像相关，包括 胞内池对TDR代谢的贡献， 再利用和退化。本提案涉及以下领域 研究需要进一步深入了解生物化学和 TDR代谢动力学研究。需要这些研究来帮助 转换依赖于时间的组织的简单测量 通过层析成像获得的放射性同位素浓度 细胞增殖的定量测量。在我们的努力中 为了检验TDR摄取的测量将 在量化肿瘤生长方面有用，我们将解决 以下问题：1)为了解释PET图像，必须 知道传递给肿瘤的标记前体的量。 因此，我们将开发技术和模型，以 占天然TDR化合物在 发行量。我们还将研究第一次通过提取 TDR及其代谢物的分布。2) 需要改进TDR代谢的动力学模型。 我们使用正电子发射计算机断层扫描积累的数据将使用 分段、图形化和滑动分段建模 接近了。我们将把动力学模型的结果与 直接测量DNA中TdR的掺入 活组织检查。3)对使用PET进行的测量的验证是 必不可少的。这将在患有转移性淋巴瘤的狗身上进行， 在那里活检样本将使用许多 与正电子发射计算机断层扫描相关的细胞和生化技术 测量。我们团队的最终目标是开发一种 ~(11)C-TdR对肿瘤治疗反应的认识 还有PET。为了对细胞进行有意义的测量 使用11C-TDR和PET进行增殖，我们需要生产详细的 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.