Targeted Molecular Probes for Tumor Imaging

描述（由申请人提供）：本R01的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）显像剂。该R01是我们R21的竞争延续。生长因子受体是重要的诊断和预后指标，也是重要的治疗靶点。EGFR是最早发现的生长因子之一，也是目前许多治疗药物开发项目的基础，它是ErbB受体酪氨酸激酶家族的成员。这些细胞表面受体的过表达在多种人类乳腺、卵巢、肺和前列腺肿瘤的发展中起着重要作用。EGFR在近45%的乳腺肿瘤中过表达，其膜蛋白浓度为0-3600 fmol/mg，而雌激素受体的细胞质浓度为0- 1500 fmol/mg。此外，肿瘤EGFR浓度高达正常组织的100倍，提供了良好的目标-背景选择性。许多活性药物筛选程序已经确定了EGFR细胞内酪氨酸激酶结构域的有效小分子抑制剂。这是目前唯一发现纳米和亚纳米小分子抑制剂的生长因子受体。

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.