Endothelin Receptor Imaging with PET

描述(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对内皮素受体进行成像。该项目的目标是开发和测试一种用于对癌症中的内皮素受体进行成像的放射性药物。为了实现这一目标，人们发展了分子生物学和免疫组织化学方法，并将其应用于有限数量的组织和细胞系样本，并获得了关于受体表达的定量数据。首次建立了同时生长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。本项目的具体目的是：1)系统、定量研究肿瘤组织中ETAR(ET A亚型受体)和ETBR(ET B亚型受体)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)开发和测试一种用于PET应用的特定的、乙酸乙酯选择性的放射性配体。辐射剂量测定和生物分布实验将在一个小动物模型中进行，估计的辐射暴露将外推到人类身上。有限的药理学研究将通过PET在小动物体内进行，并与体外组织标本上测定的受体表达相关。小动物成像实验将在CD-1小鼠身上进行，常规的PET/CT成像实验将在狒狒身上进行，以开发示踪剂动力学模型。3)对不同程度表达Etar的移植瘤动物进行PET成像。我们将用PET/CT对携带不同肿瘤移植瘤的SCID小鼠进行研究，以确定放射性配基的分布模式，并建立量化配基结合的示踪动力学模型。PET扫描结果将与体外研究相比较，以确认Etar密度和占有率。这项拟议的研究旨在建立一种体内成像的定量方法。它们有可能改善内皮素拮抗剂治疗癌症患者的选择。

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.