LABELED THYMIDINE--DEVELOPMENT AS A PET IMAGING AGENT

我们研究的最终目标是了解 癌症对治疗的反应使用DNA测量 合成途径的正电子发射断层扫描成像 （PET）。 我们想让细胞增殖的成像 可获得并且通常有用，因为FDG成像已经用于细胞 能量学 对细胞增殖进行有效的测量 使用PET，我们正在开发标记的核苷， 详细的生化和动力学模型，他们的新陈代谢。 我们 研究帮助开发了获得PET所需的技术， 用[C-11]胸苷成像，胸苷被掺入DNA中， 可以用来推断细胞增殖。 虽然胸苷是 证明临床上有用，但它不是理想的示踪剂，因为它 快速降解 为了改善成像扩散，我们提出了一种 一种新的方法，专注于胸苷激酶-1（TK 1）， 在体内降解稳定的胸苷类似物。 TK 1是 外源性胸苷掺入的起始酶。 是 在进行DNA的细胞中受到严格调控并升高10-15倍 合成. TK 1的核苷底物被转化为 不渗透的细胞内核苷酸磷酸和保持在 DNA途径。 我们已经研究了一些胸苷类似物 并确定最佳候选药物是AZT和FLT， 以前用于人类的药物。 标记胸苷保留 类似物，由TK 1介导，应该类似于测量 己糖激酶活性与FDG。 我们的初步结果表明， 这两种化合物及其在组织中的吸收和保留的研究 培养和动物肿瘤系统。 这将包括定量 在荷瘤狗中成像和建模。 作为替代 我们将继续研究增殖细胞成像的方法 FFUdR，我们发现它保留在肿瘤中。 最近 在细胞培养中的研究表明，FFUdR也可以用于 衡量基因治疗的成功。 我们将进一步研究这一点 和相关化合物，BVFRU和BVFddU，以确定其 评估基因治疗的能力。 选择性保留这些示踪剂 是基于疱疹的底物特异性改变 单纯病毒胸苷激酶（HSVtk），TK 1的病毒同工酶， 用于基因治疗。 这部分的长期目标是 该项目的目的是开发一种成像剂， 切除肿瘤进行“自杀标记”基因治疗。

The ultimate goal of our research is to develop an understanding of the response of cancer to therapy using measurements of DNA synthetic pathways as imaged by positron emission tomography (PET). We want to make imaging cellular proliferation as widely available and generally useful as FDG imaging has been for cellular energetics. To make valid measurements of cellular proliferation using PET, we are developing labeled nucleosides and producing detailed biochemical and kinetic models of their metabolism. Our studies have helped develop the techniques needed to obtain PET images with [C-11]thymidine, which is incorporated into DNA and can be used to infer cellular proliferation. While thymidine is proving clinically useful, it is not an ideal tracer because of its rapid degradation. To improve imaging proliferation, we propose a new approach focusing on thymidine kinase-1 (TK1) and using thymidine analogs that are stable to degradation in vivo. TK1 is the initial enzyme in the incorporation of exogenous thymidine. It is tightly regulated and elevated 10-15 fold in cells undertaking DNA synthesis. TK1"s nucleoside substrates are converted to impermeable intracellular nucleotide phosphates and held within the DNA pathway. We have examined a number of thymidine analogs and have determined that the best candidates are AZT and FLT, drugs previously used in humans. Retention of labeled thymidine analogs, mediated by TK1, should be analogous to measuring hexokinase activity with FDG. Our preliminary results indicate that both compounds and the study of their uptake and retention in tissue culture and animal tumor systems. This will include quantitative imaging and modeling in tumor bearing dogs. As an alternative method of imaging proliferating cells we will continue to study FFUdR, which we have found to be retained in tumors. Recent studies in cell culture indicate that FFUdR may also be useful in measuring the success of gene therapy. We will further study this and related compounds, BVFRU and BVFddU, to determine their ability to evaluate gene therapy. Selective retention of these tracers in cells is based on the altered substrate specificity of herpes simplex virus thymidine kinase (HSVtk), the viral isozyme of TK1, which is used in gene therapy. The long range goal of this portion of the project is to develop an imaging agent for visualizing durable transection of tumors for "suicide-marker" gene-therapy.