Imaging Alpha (v)beta(3) Integrin Expression

描述（由申请人提供）：与正常细胞和静止内皮细胞相比，肿瘤细胞和活化内皮细胞表面α (v) β(3)整合素的过表达意味着应用放射性标记的α (v) β(3)整合素拮抗剂成像α (v) β(3)阳性肿瘤中的α (v) β(3)表达水平。本研究的目标是开发铜-64 （t1/2 = 12.7 h）标记的α (v) β(3)整合素的RGD肽拮抗剂，用于通过正电子发射断层扫描（PET）靶向乳腺癌。我们假设RGD肽的偶联和放射性标记会对受体结合的亲和力和特异性以及这些放射性示踪剂的体内药代动力学产生显著影响。为了使示踪剂临床适用于基于α (v) β(3)整合素表达水平的患者分割，必须进行系统的研究以优化示踪剂，使示踪剂具有快速和高产率的放射性标记，体内抗转运稳定性，以及高受体结合亲和力和特异性。放射性示踪剂的设计还应具有令人满意的体内药代动力学，以获得高质量的成像：高肿瘤与正常组织的比例，快速循环清除率，低肾脏摄取和快速肾脏清除率，并避免肝胆排泄。本文拟开展以下研究：1)开发和优化铜-64标记的乳腺癌肿瘤靶向RGD肽；2)在临床前动物模型中，将肿瘤摄取的大小与肿瘤整合素密度水平联系起来。这项研究的成功将促进这项实验室工作迅速转化为临床应用，因为小动物PET成像研究的特点密切反映了人类临床PET研究的设置。我们预计，利用PET对α (v) β(3)表达和功能活性的无创系列研究将成为评估α (v) β(3)整合素在肿瘤进展和转移中的作用的重要工具。

DESCRIPTION (provided by applicant): Overexpression of alpha(v)beta(3) integrin on the surfaces of tumor cells and activated endothelial cells as compared to normal cells and rest endothelial cells implicates the application of radiolabeled alpha(v)beta(3) integrin antagonist for imaging of alpha(v)beta(3) expression levels in alpha(v)beta(3) positive tumors. The goal of this proposal is to develop copper-64 (t1/2 = 12.7 h) labeled RGD peptide antagonists of alpha(v)beta(3) integrin for breast cancer targeting by means of positron emission tomography (PET). We hypothesize that conjugation and radiolabeling of RGD peptides will have significant effect on the receptor binding affinity and specificity, as well as the in vivo pharmacokinetics of these radiotracers. To make the tracers clinically applicable for patient segmentation based upon alpha(v)beta(3) integrin expression levels, systematic studies have to be performed to optimize the tracer in such a way that the tracer will have fast and high yield radiolabeling, in vivo stability against transchelation, and high receptor binding affinity and specificity. The radiotracer should also be designed to have satisfactory in vivo pharmacokinetics for high quality imaging: high tumor-to-normal tissue ratio, fast circulation clearance, low kidney uptake and fast renal clearance, as well as avoiding hepatobiliary excretion. The research proposed here is to: 1) develop and optimize copper-64 labeled RGD peptides for breast cancer tumor targeting; and 2) correlate the magnitude of tumor uptake with tumor integrin density levels in preclinical animal models. The success of this research will facilitate the rapid translation of this laboratory work into clinical applications, since the features of small animal PET imaging studies closely reflect the settings of a clinical PET study for human beings. We anticipate that noninvasive serial studies of alpha(v)beta(3) expression and functional activity using PET will become an important tool to evaluate the role of alpha(v)beta(3) integrin during tumor progression and metastasis.