DEVELOPMENT OF CANCER IMAGING AGENTS

描述：(改编自申请人的摘要)： 本项目目标是演示和验证已标记的 酪氨酸激酶抑制剂可用作肿瘤的显像剂 过度表达这些受体相关的酶。申请者有 概述了一种发展独特正电子和单光子的范例 利用表皮生长因子受体发射放射性药物 酪氨酸激酶(EGFRtk)和乳腺癌作为模型系统。许多 受体酪氨酸激酶家族的成员与肿瘤有关 细胞信号转导通路，是有用的预后指标。 EGFR在45%的乳腺肿瘤中过度表达。它的流行已经 与激素治疗的反应差和差有关 患者预后。一系列氨基喹唑啉衍生物， 在结构上类似于已知在微微到纳米级抑制EGFRtk的那些 适用于氟-18，碳-11标记的摩尔浓度， 将合成溴-76或碘-123。抑制的能力 EGFRtk活性将在体外全细胞中进行测试 自动磷酸化试验。特异性将通过测试 喹唑啉类药物对erbB-2和erbB-3酪氨酸激酶的抑制作用 活动。有效的抑制剂随后将被放射性标记为NO 添加氟-18、碳-11或溴-76的载体 回旋加速器或来自amersham的碘-125。积累了大量的 肿瘤细胞中的标记示踪剂(MDA-435、MCF-7、MDA-231、MDA-568) 拥有不同水平的EGFR表达将在体外进行评估 细胞培养实验；特异性和非特异性结合 量过了。细胞系中EGFR的含量将由一个 分离法，并与摄取相关。分布和分布 将对所选放射性示踪剂的代谢特性进行评估 在荷瘤小鼠身上。来自相同细胞系的肿瘤细胞 细胞培养实验将被植入并在小鼠身上生长。示踪剂 分布、有效性和受体介导的摄取将被确定 在小鼠模型中。同样，肿瘤中的摄取将与 直接测量EGFR滴度。证明自己有能力 使用EGFRtk显像剂可视化乳腺癌将具有双重功能 冲击力。这不仅将扩大我们的特工队伍， 乳房病变的诊断和分期，但它也将验证 以酪氨酸激酶为基础的显像剂用于靶向其他肿瘤 纸巾。此外，它将提供进入新领域的机会 药物发现和治疗干预方面的研究。

DESCRIPTION: (Adapted from applicant's abstract): The goal of this project is to demonstrate and validate that labeled tyrosine kinase inhibitors can be used as imaging agents for tumors overexpressing these receptor associated enzymes. The applicants have outlined a paradigm to develop unique positron and single photon emitting radiopharmaceuticals using the epidermal growth factor receptor tyrosine kinase (EGFRtk) and breast cancer as model systems. Many members of the receptor tyrosine kinase family are involved in tumor cell signal transduction pathways and are useful prognostic indicators. EGFR is overexpressed in 45 percent of breast tumors. Its prevalence has been correlated with poor responsiveness to hormonal therapy and poor patient prognosis. A series of aminoquinazoline derivatives, structurally similar to those know to inhibit EGFRtk at pico- to nano- molar concentration suitable for labeling with fluorine-18, carbon-11, bromine-76 or iodine-123 will be synthesized. The ability to inhibit EGFRtk activity will be tested in an in vitro whole cell autophosphorylation assay. Specificity will be determined by testing the quinazolines ability to inhibit erbB-2 and erbB-3 tyrosine kinase activity. Potent inhibitors will be subsequently radiolabeled with no carrier added fluorine-18, carbon-11 or bromine-76 produced in their cyclotron or with iodine-125 from Amersham. The accumulation of the labeled tracers in tumor cells (MDA-435, MCF-7, MDA-231, MDA-568) possessing various levels of EGFR expression will be assessed in vitro cell culture experiments; specific and non-specific binding will be measured. The amount of EGFR in the cell lines will be determined by a separate method and correlated with the uptake. The distribution and metabolic characteristics of the selected radiotracers will be evaluated in tumor-bearing mice. Tumor cells from the same cell lines used in the cell culture experiments will be implanted and grown in mice. Tracer distribution, efficacy and receptor-mediated uptake will be determined in the mouse model. Again, uptake in the tumors will be correlated with a direct measure of EGFR titer. Demonstration of the ability to visualize breast cancer with EGFRtk imaging argents will have dual impact. Not only will this expand our armamentarium of agents for the diagnosis and staging of breast lesions but it will also validate the use of tyrosine kinase-based imaging agents to target tumors in other tissues. Additionally, it will provide inroads into new areas of research in drug discovery and therapeutic intervention.