Endothelin Receptor Imaging with PET

描述（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，但目前还没有令人满意的方法在体内成像内皮素受体。该项目的目标是开发和测试一种放射性药物，用于成像肿瘤中的内皮素受体。为了实现这一目标，分子生物学和免疫组织化学方法已经发展起来，并应用于有限数量的组织和细胞系样本，并获得了受体表达的定量数据。建立了首个同时生长ETAR阳性和ETAR阴性肿瘤的异种移植SCID小鼠模型。用非选择性内皮素受体配体[C-11]L-753,037进行了实验。该项目的具体目的是：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计划患者体内ETAR受体的PET成像研究。2)开发和测试用于PET应用的特定ETAR选择性放射配体。将在小型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量外推到人类身上。有限的药理学研究将在小动物体内使用PET进行，并与体外组织标本上确定的受体表达相关。在CD-1小鼠中进行小动物成像实验，在狒狒中进行常规PET/CT成像实验，建立示踪剂动力学模型。3)对不同程度表达ETAR的异种肿瘤移植动物进行PET成像。我们将利用PET/CT对携带多种异种肿瘤移植的SCID小鼠进行研究，以确定放射配体的分布模式，并建立一个量化配体结合的示踪动力学模型。PET扫描结果将与体外研究结果进行比较，以确定ETAR密度和占用率。本研究旨在建立一种定量的ETAR体内成像方法。它们有可能改善癌症患者使用内皮素拮抗剂治疗的选择。

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.