LABELED THYMIDINE--DEVELOPMENT AS A PET IMAGING AGENT

我们研究的最终目标是了解 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， PET我们正在开发适当的标记核苷和生产 详细的生化和动力学模型，他们的新陈代谢。 我们正在进行的 研究已经开发了获得PET图像所需的技术， [C-11]胸苷（TdR），其掺入DNA中并可用于 监测细胞增殖。 我们已经处理了一些 解释[C- 11]TdR PET图像的相关问题 包括细胞内库对TdR代谢的贡献， 再利用。和退化。 为了进一步验证成像， 我们正在继续研究TdR的生物化学和动力学 新陈代谢. 特别是，本提案将研究 胸苷的主要代谢产物，标记为CO2，及其组织固定。 这些信息正在被整合到动力学模型中。 我们更进一步 开发这样的模型来简化我们的数据分析方案， 产生DNA合成的图像。 虽然胸苷在临床上证明 有用的，我们已经开始寻找核苷类似物， 细胞增殖并具有改善的成像特性。 我们计划 检验两种二氟胸苷类似物的假设， 5-氟-1-（2 '-氟-2'-脱氧-β-D-呋喃核糖基）尿嘧啶（FFUdR）和 5-氟-1-（2 '-氟-2'-脱氧-β-达拉滨糖基）尿嘧啶（FFaraU），将 提供增加的肿瘤与血液的比率，并且在体内几乎不发生降解。 vivo. 当用F-18标记时，这种示踪剂可以大大简化成像 通过消除对分析代谢物的需要， 作为 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-双（羟甲基）-1-环丁基]腺嘌呤 （F-环丁-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 (CMV)感染小鼠，因为CMV是一个主要问题， 艾滋病和器官移植。

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.