MIBG ANALOGUE RADIOPHARMACEUTICALS

描述（改编自申请人的摘要）： 间碘苄胍（MIBG）已被用于检测和治疗 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剂，但结果 MIBG治疗是不够的。 该提案的目标是制定一项 代谢更稳定的药剂，从正常组织中清除更快， 但仍被隔离并保留在肿瘤中。 的初步目标 该建议是开发用于制备 各种放射性碘标记和[At-211]标记的MIBG衍生物，以及 系统地评价了它们在体外和体内的作用。 结构性 计划的改造包括引入氯、溴、碘、硝基 和在MIBG的苯环中的4-位上的磺酸部分， 用吡啶环取代苯环本身。 固相 将开发有前途的试剂的合成方法。 的摄取和 体外保留动力学和几种药物的作用 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， 已经在几种人髓母细胞瘤细胞中证实了MIBG摄取 线，该肿瘤非常适合[At-211]治疗。 的 这些新的[I-131]和[At-211]标记的MIBG的治疗潜力 类似物将使用胸苷摄取和克隆形成试验进行评价， 单层和球体模型。 这些药物的组织分布将 在正常小鼠和具有神经母细胞瘤的无胸腺小鼠中测定， 嗜铬细胞瘤和髓母细胞瘤异种移植物。 增强战略 将研究肿瘤与正常组织的比率。 这场 这项研究应该有助于改善神经内分泌肿瘤的腔内放射治疗， 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.