MIBG ANALOGUE RADIOPHARMACEUTICALS

MIBG 模拟放射性药物

• 批准号: 2733354
• 负责人: GANESAN VAIDYANATHAN
• 金额: $ 21.77万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-08 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2733354
• 关键词: analog; antineoplastics; athymic mouse; drug design /synthesis /production; guanidines; halogens; medulloblastoma; neoplasm /cancer pharmacology; neuroblastoma; pharmacokinetics; pheochromocytoma; radionuclides; radiopharmacology; tissue /cell culture

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.

描述（改编自申请人的摘要）：放射性药物 间碘苄基胍（MIBG）已用于检测和治疗 神经内分泌肿瘤，特别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 MIBG 治疗还不够充分。 该提案的目标是开发一个 代谢更稳定的药剂，从正常组织中清除得更快， 但仍被隔离并保留在肿瘤中。 最初的目标 该提案旨在开发合成方法来制备 各种放射性碘标记和 [At-211] 标记的 MIBG 衍生物以及 在体外和体内系统地评估它们。 结构性 计划的改变包括引入氯、溴、碘、硝基 MIBG 苯环 4 位上有磺酸基团， 用吡啶环取代苯环本身。 固相 将为有前景的药物开发合成方法。 吸收率和 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，但具有特异性 MIBG 的摄取已在几种人髓母细胞瘤细胞中得到证实 线，并且这种肿瘤非常适合 [At-211] 治疗。 这 这些新的 [I-131] 和 [At-211] 标记的 MIBG 的治疗潜力 将使用胸苷摄取和克隆形成测定来评估类似物 单层和球体模型。 这些药剂的组织分布将是 在正常小鼠和患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。 增强策略 将研究肿瘤与正常组织的比率。 这件事的结果 研究应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。