Endothelin Receptor Imaging of Cancer with PET

说明（由申请人提供）：内皮素受体拮抗剂在癌症和心血管疾病中的治疗应用正在迅速扩大，但还没有令人满意的方法来对内皮素受体进行体内成像。该项目的目标是开发和测试一种放射性药物，用于成像癌症中的内皮素受体。为了实现这一目标，分子生物学和免疫组织化学方法已被开发和应用于有限数量的组织和细胞系样品和受体表达的定量数据已经获得。已经建立了第一个ETAR阳性和ETAR阴性肿瘤同时生长的异种移植物SCID小鼠模型。已经用非选择性内皮素受体配体[C-11]L-753，037进行了实验。本课题的具体目的是：1）系统、定量地研究内皮素A亚型受体（ETAR）和内皮素B亚型受体（ETBR）在肿瘤组织中的表达。这些实验的结果将有助于规划患者体内ETAR受体的体内成像PET研究。2)开发和测试用于PET应用的特定ETAR选择性放射性配体。将在小动物模型中进行辐射剂量测定和生物分布实验，并将估计的辐射照射外推至人类。将使用PET在小动物体内进行有限的药理学研究，并与体外组织标本上测定的受体表达相关。将在CD-1小鼠中进行小动物成像实验，并在狒狒中进行常规PET/CT成像实验，以开发示踪剂动力学模型。3)对不同程度表达ETAR的肿瘤异种移植动物进行PET成像。将使用PET/CT研究携带各种肿瘤异种移植物的SCID小鼠，以确定放射性配体的分布模式，并开发用于定量配体结合的示踪剂动力学模型。将PET扫描结果与体外研究进行比较，以确认ETAR密度和占用率。拟定的研究旨在建立ETAR体内成像的定量方法。他们有潜力改善癌症患者的选择与内皮素拮抗剂治疗。

DESCRIPTION (provided by applicant): Therapeutic applications of endothelin receptor antagonists are rapidly expanding in cancer and cardiovascular diseases, but there is no satisfactory method to image the endothelin receptors in vivo. The goal of this project is to develop and test a radiopharmaceutical for imaging the endothelin receptors in cancer. To achieve that goal, molecular biology and immunohistochemistry methods have been developed and applied to a limited number of tissue and cell line samples and quantitative data on receptor expression have been obtained. The first xenograft SCID mouse model with simultaneous growth of ETAR positive and ETAR negative tumors has been established. Experiments with with the nonselective endothelin receptor ligand [C-11]L-753,037 have been performed. The specific aims of the project are: 1) To investigate the expression of the ETAR (endothelin A subtype receptor) and ETBR (endothelin subtype B receptor) in cancer tissues in a systematic and quantitative fashion. The results of these experiments will help plan in vivo imaging PET studies of the ETAR receptor in patients. 2) To develop and test a specific, ETAR selective radioligand for PET applications. Radiation dosimetry and biodistribution experiments will be performed in a small animal model and the estimated radiation exposure will be extrapolated to humans. Limited pharmacological studies will be performed in small animals in vivo with PET and correlated with receptor expression determined on tissue specimens in vitro. Small animal imaging experiments will be performed in CD-1 mice and regular PET/CT imaging experiments will be perfomed in baboons to develop a tracer kinetic model. 3) To perform PET imaging of animals with tumor xenografts that express the ETAR to various degrees. SCID mice bearing a variety of tumor xenografts will be investigated with PET/CT to define the distribution pattern of the radioligand and to develop a tracer kinetic model for quantification of ligand binding. PET scan findings will be compared with in vitro studies to confirm ETAR density and occupancy. The proposed studies are designed to establish a quantitative method for in vivo imaging of the ETAR. They have the potential to improve selection of cancer patients for treatment with endothelin antagonists.