Targeted Molecular Probes for Tumor Imaging

用于肿瘤成像的靶向分子探针

• 批准号: 6654481
• 负责人: Henry F. VanBrocklin
• 金额: $ 39.34万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-05 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654481
• 关键词: SDS polyacrylamide gel electrophoresis; athymic mouse; epidermal growth factor; growth factor receptors; high performance liquid chromatography; imaging /visualization /scanning; neoplasm /cancer; pharmacokinetics; polymerase chain reaction; positron emission tomography; protein tyrosine kinase; radiotracer; receptor binding; technology /technique development; thin layer chromatography

DESCRIPTION (provided by applicant): The goal of this R01, a competing continuation of our R21, is to further develop and validate labeled probes as imaging agents for the epidermal growth factor receptor (EGFR). Growth factor receptors are important diagnostic and prognostic indicators as well as significant therapeutic targets. EGFR, one of the first growth factors discovered and the basis for many current therapeutic drug development programs, is a member of the ErbB family of receptor tyrosine kinases. Overexpression of these cell surface receptors plays a significant role in the progression of a variety of human tumors of the breast, ovary, lung and prostate. EGFR, over expressed in nearly 45% of breast tumors, ranges in concentration from 0-3600 fmol/mg membrane protein compared to 0- 1500 fmol/mg cytosol for the estrogen receptor. Additionally, tumor EGFR concentration is up to 100 times that of normal tissue, providing good target-to-background selectivity. Many active drug screening programs have identified potent small molecule inhibitors of the EGFR intracellular tyrosine-kinase domain. This is currently the only growth factor receptor where nM and sub-nM small molecule inhibitors have been found. Our approach is to synthesize receptor-binding molecules for the intracellular tyrosine-kinase domain as well as for the extra cellular binding domain, suitable for labeling with positron-emitting isotopes. The binding characteristics, specificity, lipophilicity and stability will be measured in vitro. Based on the in vitro characteristics, select compounds will be radiolabeled. Measures of hepatocyte metabolism will be performed in vitro using the labeled compounds. The biodistribution of select labeled probes will be carried out in tumor-bearing mice. These xenografts will have varying concentrations of EGFR. The uptake of labeled probe in the tumor tissues will be correlated with receptor content and probe metabolism will be determined. Small animal imaging will be used to follow the distribution time course and to obtain dosimetry information for the potential translation of some of these agents to human studies (not part of this proposal). These EGFR tracers may ultimately be important diagnostic probes, but more than likely they will be I invaluable tools for the development of new therapeutic drugs.

描述（由申请人提供）：R01 是 R21 的竞争延续，其目标是进一步开发和验证标记探针作为表皮生长因子受体 (EGFR) 的成像剂。生长因子受体是重要的诊断和预后指标以及重要的治疗靶点。 EGFR 是最早发现的生长因子之一，也是当前许多治疗药物开发项目的基础，是受体酪氨酸激酶 ErbB 家族的成员。这些细胞表面受体的过度表达在乳腺、卵巢、肺和前列腺等多种人类肿瘤的进展中发挥着重要作用。 EGFR 在近 45% 的乳腺肿瘤中过度表达，其浓度范围为 0-3600 fmol/mg 膜蛋白，而雌激素受体的浓度范围为 0-1500 fmol/mg 胞质溶胶。此外，肿瘤 EGFR 浓度高达正常组织的 100 倍，提供良好的靶点与背景选择性。许多活跃的药物筛选项目已经鉴定出 EGFR 胞内酪氨酸激酶结构域的有效小分子抑制剂。这是目前唯一发现的nM和亚nM小分子抑制剂的生长因子受体。 我们的方法是合成细胞内酪氨酸激酶结构域以及细胞外结合结构域的受体结合分子，适合用正电子发射同位素标记。将在体外测量结合特性、特异性、亲脂性和稳定性。根据体外特征，选择的化合物将被放射性标记。将使用标记的化合物在体外进行肝细胞代谢的测量。选择的标记探针的生物分布将在荷瘤小鼠中进行。这些异种移植物将具有不同浓度的 EGFR。肿瘤组织中标记探针的摄取将与受体含量相关并确定探针代谢。小动物成像将用于跟踪分布时间过程并获取剂量测定信息，以便将其中一些药物转化为人类研究（不是本提案的一部分）。 这些 EGFR 示踪剂最终可能成为重要的诊断探针，但它们更有可能成为开发新治疗药物的宝贵工具。