New imaging agents for studying gene expression

用于研究基因表达的新型成像剂

• 批准号: 7230205
• 负责人: Hank F Kung
• 金额: $ 18.48万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230205
• 关键词: Abbreviations; Biological Assay; Cell Line; Cell membrane; Cells; Chemical Structure; Deoxyuridine; Disease; Doxycycline; Enzyme Kinetics; Enzymes; Figs - dietary; Ganciclovir; Gene Expression; Genes; Glioma; Herpes Simplex Infections; Herpesvirus 1; Human; Image; Implant; In Vitro; Kinetics; Label; Measures; Metabolic; Nucleosides; Nucleotides; Nude Mice; Patients; Positron; Positron-Emission Tomography; Preparation; Probability; Process; Property; Proteins; Purpose; Pyrimidine; Pyrimidine Nucleosides; Pyrimidines; Radiochemistry; Radiolabeled; Rattus; Reporter; Series; Signal Transduction; Simplexvirus; Suicide Gene Therapy; Supplementation; Surrogate Markers; System; TK Gene; Testing; Thymidine; Thymidine Kinase; Tracer; Transgenes; Tumor Tissue; Viral; X-Ray Computed Tomography; analog; base; cancer therapy; design; desire; fialuridine; gene therapy; human TK2 protein; imaging probe; improved; in vivo; mutant; neoplastic cell; novel; nucleoside analog; radiotracer; single photon emission computed tomography; tumor; uptake

DESCRIPTION (provided by applicant): We propose to develop F-18 and 1-123 labeled nucleosides as selective substrates of herpes simplex thymidine kinase (HSV1-TK) in conjunction with positron computed tomography (PET). Introduction of HSV1- TK in tumor followed by gancyclovir (GCV) treatment has been successfully tested as a suicide gene therapy for cancer therapy. Labeled nucleosides (such as [1-123/124]FIAU and [F-18JFHBG) selectively targeting the HSV1-TK enzyme are useful as reporter probes for measuring HSV1-tk gene expression in vivo by PET or SPECT imaging. Based on this approach, HSV1-tk gene expression can also be used as a surrogate marker gene for expression of other genes (transgenes) determined by the labeled nucleosides as in vivo imaging probes. The objective of this project is to design, synthesize and characterize a series of novel labeled nucleosides, 2'-deoxyuridine and FIAU analogs (group A and B), as superior imaging agents for measuring in vivo gene expression. Currently, [F-18]FIAU is more effective for imaging HSV1-TK; but the synthesis of this F-18 probe is very long and difficult. [F-18]FHBG is easier to prepare, but only effective for imaging a mutant HSV1-TK(sr39). The purposes of developing these novel nucleosides are: 1) to prepare F-18 radiolabeled group A and B nucleosides 2). to identify improved F-18 nucleoside probes with desired in vivo kinetics for higher target to non-target ratio and a higher selectivity between the human TK vs viral HSV1-TK enzyme and 3) to test the correlation between gene expression and probe-uptake in a doxycycline inducible HSV1-TK expressing cell line. It is likely that the new probes can be selectively phosphorylated by the viral enzyme, as such they may be superior for measuring the concentration of HSV1-TK enzyme levels in the tumor cells. They will have several useful properties: ability to cross the cell membrane and a minimum influence from other metabolic steps of nucleosides and nucleotides. Efforts will be made to select tracers predominantly trapped in the targeted cells by the native HSV1-TK only, and confounding signals from other processes from native hTK1 and hTK2 enzymes are minimized. In conjunction with PET, these new imaging agents may enhance our ability to measure tk gene expression in vivo; thus, they may enhance the probability of developing new gene therapy approaches for various diseases.

描述（由申请人提供）：我们建议将F-18和1-123标记为核苷作为疱疹单纯胸腺胸苷激酶（HSV1-TK）的选择性底物与正电子计算机断层扫描（PET）。在肿瘤中引入HSV1-TK，然后进行Gancyclovir（GCV）治疗，已成功测试是一种自杀基因治疗癌症治疗。标记的核苷（例如[1-123/124] FIAU和[F-18JFHBG）选择性地靶向HSV1-TK酶是通过PET或SPECT Imaging在体内测量体内测量HSV1-TK基因表达的报告探针。基于这种方法，HSV1-TK基因表达也可以用作由标记的核苷作为体内成像探针确定的其他基因（转基因）表达的替代标记基因。该项目的目的是设计，合成和表征一系列新型标记的核苷，2'-脱氧尿苷和FIAU类似物（A组和B组），是用于测量体内基因表达的优质成像剂。目前，[F-18] FIAU对于成像HSV1-TK更有效。但是该F-18探针的合成非常长且困难。 [F-18] FHBG更容易准备，但仅对成像突变的HSV1-TK（SR39）有效。开发这些新型核苷的目的是：1）制备F-18辐射标记的A组和B核苷2）。为了确定所需的体内动力学的改进的F-18核苷探针，以提高目标与非目标比，并在人TK与病毒性HSV1-TK酶和3之间具有更高的选择性，以测试在多Xycycycycycycycycycy-cycycy-cycy-cycy-cycy-cycy-cycy-cycy-cycy-cycy-cycy-cycy-cycy-cycy-cycy-cy-cy-cyplible-lible-cycy-cycy-cycy-cycy-cy-cy-cy-cy-cy-cy-cy-cy-cyplible piptage之间的相关性。新探针可能会被病毒酶选择性地磷酸化，因此，它们对于测量肿瘤细胞中HSV1-TK酶水平的浓度可能是优越的。它们将具有几种有用的特性：越过细胞膜的能力，以及核苷和核苷酸其他代谢步骤的最小影响。仅由天然HSV1-TK选择主要将目标细胞捕获到目标细胞中的示踪剂，并将来自天然HTK1和HTK2酶的其他过程的混淆信号最小化。与PET结合使用，这些新成像剂可能会增强我们在体内测量TK基因表达的能力。因此，它们可能会增加开发各种疾病的新基因治疗方法的可能性。

项目成果

5-[18F]Fluoroalkyl pyrimidine nucleosides: probes for positron emission tomography imaging of herpes simplex virus type 1 thymidine kinase gene expression.

• DOI: 10.1016/j.nucmedbio.2008.10.009
• 发表时间: 2009-01
• 期刊: NUCLEAR MEDICINE AND BIOLOGY
• 影响因子: 3.1
• 作者: Chacko, Ann-Marie;Blankemeyer, Eric;Lieberman, Brian P.;Qu, Wenchao;Kung, Hank F.
• 通讯作者: Kung, Hank F.