LABELED THYMIDINE--DEVELOPMENT AS A PET IMAGING AGENT

我们研究的最终目标是发展对 通过测量癌症和病毒感染对治疗的反应 细胞DNA合成和正电子发射断层扫描(PET)成像。 为了对细胞增殖进行有意义的测量，使用 我们正在开发合适的标记核苷并生产 他们代谢的详细生化和动力学模型。我们正在进行的 研究已经开发出获得PET图像所需的技术 [C-11]胸腺嘧啶核苷(TDR)，它结合在DNA中，可用于 监测细胞增殖情况。我们已经解决了一些问题 与解释[C-11]TDR PET图像有关的问题 包括细胞内池对TDR新陈代谢的贡献， 再利用。和退化。要进一步验证映像，请使用 我们正在继续研究胸腺嘧啶核苷的生物化学和动力学。 新陈代谢。特别是，这项提案将研究 胸苷的主要代谢物，标记为CO2，及其组织固定。 这些信息正在被合并到动力学模型中。我们对此更加愤怒 开发此类模型以简化我们的数据分析方案，并 制作DNA合成的图像。而胸腺嘧啶核苷在临床上被证明 有用的是，我们已经开始寻找核苷类似物 细胞增殖，并具有改进的成像特性。我们计划 测试两种胸腺嘧啶核苷二氟类似物的假设， 富达(5-fluoro-l-(2‘-fluoro-2’deoxy-beta-D-ribofuranosyl)uracil)和 5-fluoro-l-(2‘-fluoro-2’-deoxy-beta-Darabinosyl)uracil(法拉乌)，Will 提供更高的肿瘤与血液比率，并经历很少的降解 活着。当用F-18标记这种示踪剂时，可以极大地简化成像 通过消除分析代谢物的需要，实现了对细胞生长的控制。作为一种 额外的好处是，这些化合物也被吸收并保留在细胞中 被病毒感染。我们计划测试这些假设 核苷类似物，以及[F-18]标记的腺苷类似物 (+/-)9-[(1beta，2alpha，3beta)-2，3-bis(hydroxymethyl)-l-cyclobutyl]adenine (F-环-A)，可用于检测和跟踪对 病毒感染。作为一个模型，我们选择研究巨细胞病毒 小鼠的巨细胞病毒(CMV)感染，因为巨细胞病毒是患者的一个主要问题 艾滋病和那些正在接受器官移植的人。

The ultimate goal of our research is to develop an understanding of the response of cancer and viral infections to therapy using measurements of cellular DNA synthesis and positron emission tomography (PET) imaging. In order to make meaningful measurements of cellular proliferation using PET we are developing appropriate labeled nucleosides and producing detailed biochemical and kinetic models of their metabolism. Our ongoing studies have developed the techniques needed to obtain PET images with [C- 11] thymidine (TdR), which is incorporated in DNA and can be used to monitor cellular proliferation. We have already addressed a number of the problems associated with interpreting the PET images of [C- 11]TdR including the contributions to TdR metabolism of intracellular pools, reutilization., and degradation. To further validate imaging with thymidine we are continuing to study the biochemistry and kinetics of TdR metabolism. In particular this proposal will study the distribution of the major metabolite of thymidine, labeled CO2, and its tissue fixation. This information is being combined into kinetic models. We ire further developing such models to simplify our data analysis scheme and to produce images of DNA synthesis. While thymidine is proving clinically useful, we have begun to search for nucleoside analogs which will monitor cell proliferation and have improved imaging characteristics. We plan to test the hypothesis that two diflourinated analogs of thymidine, 5-fluoro-l-(2'-fluoro-2'deoxy-beta-D-ribofuranosyl)uracil (FFUdR) and 5-fluoro-l-(2'-fluoro-2'-deoxy-beta-Darabinosyl)uracil (FFaraU), will provide increased tumor to blood ratios and undergo little degradation in vivo. Such tracers when labeled with F-18 could greatly simplify imaging of cell growth, by eliminating the need for analyzing metabolites. As an added benefit, these compounds are also taken up and retained in cells infected by viruses. We plan to test the hypotheses that these nucleoside analogs, as well as the [F- 18] -labeled adenosine analog (+/-)9-[(1beta,2alpha,3beta)-2,3-bis(hydroxymethyl)-l-cyclobutyl]adenine (F-cyclobut-A), may be useful in detecting and following the response to viral infections. As a model we have chosen to study cytomegalovirus (CMV) infection in mice, since CMV is a major problem in patients with AIDS and those undergoing organ transplants.