MIBG ANALOGUE RADIOPHARMACEUTICALS

描述(摘自申请者摘要)：放射性药物 间碘苯甲基胍(MIBG)已被用于药物的检测和治疗 神经内分泌肿瘤，尤其是神经母细胞瘤和嗜铬细胞瘤。 虽然它是一种令人满意的诊断应用试剂，但结果是 MIBG治疗的有效性是不够的。这项提议的目标是开发一种 代谢物更稳定，从正常组织中清除更快， 但仍被隔离并保留在肿瘤中。的初始目标 这项建议是为了开发合成方法来制备 各种放射性碘标记和[AT-211]标记的MIBG衍生物和TO 对其进行体内外系统评价。结构性的 计划的改造包括引入氯、溴、碘、硝基 和MIBG苯环4-位上的磺酸基团和 用吡啶环取代苯环本身。固相 将开发有前景的试剂的合成方法。摄取和 几种药物的体外滞留动力学及作用 将使用一组神经母细胞瘤、嗜铬细胞瘤和 髓母细胞瘤细胞系。虽然不是神经内分泌肿瘤，但特异性 已证实几种人髓母细胞瘤细胞摄取MIBG 这种肿瘤非常适合[At-211]-治疗。这个 这些新的[I-131]和[AT-211]标记MIBG的治疗潜力 类似物将通过胸腺嘧啶核苷摄取和克隆形成试验在 单层和椭球体模型。这些药物的组织分布将是 在正常小鼠和携带神经母细胞瘤的无瘤小鼠中测定， 嗜铬细胞瘤和髓母细胞瘤异种移植。增强功能的策略 将调查肿瘤与正常组织的比例。这样做的结果是 研究应有助于改善神经内分泌肿瘤的内放射治疗 可能是髓母细胞瘤。

DESCRIPTION (Adapted from Applicant's Abstract): The radiopharmaceutical meta-iodobenzylguanidine (MIBG) has been used in the detection and therapy of neuroendocrine tumors, especially neuroblastoma and pheochromocytoma. Although it is a satisfactory agent for diagnostic applications, the outcome of MIBG therapy is inadequate. The goal of this proposal is to develop an agent which is metabolically more stable, clears faster from normal tissues, and yet is sequestered and retained in tumor. The initial objectives of this proposal are to develop synthetic methods for the preparation of various radioiodinated and [At-211]-labeled MIBG derivatives and to systematically evaluate them in vitro and in vivo. The structural alterations planned include introduction of chlorine, bromine, iodine, nitro and sulfonic acid moieties at the 4-position in the benzene ring of MIBG and replacement of the benzene ring itself with a pyridine ring. Solid-phase synthetic methods will be developed for promising agents. The uptake and retention kinetics in vitro and the effect of several pharmacological agents will be studied using a panel of neuroblastoma, pheochromocytoma and medulloblastoma cell lines. Although not a neuroendocrine tumor, specific uptake of MIBG has been demonstrated in several human medulloblastoma cell lines, and this neoplasm is well suited for [At-211]-therapy. The therapeutic potential of these new [I-131]- and [At-211]-labeled MIBG analogues will be evaluated using thymidine uptake and clonogenic assays in monolayer and spheroid models. Tissue distribution of these agents will be determined in normal mice and athymic mice hosting neuroblastoma, pheochromocytoma, and medulloblastoma xenografts. Strategies to augment tumor-to-normal tissue ratios will be investigated. The outcome of this study should help improve the endoradiotherapy of neuroendocrine tumors and possibly of medulloblastoma.