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）：放射线药物 元二苯甲胺（MIBG）已用于检测和治疗 神经内分泌肿瘤，尤其是神经母细胞瘤和嗜铬细胞瘤。 尽管它是诊断应用的令人满意的代理人，但结果 MIBG治疗的不足。 该建议的目的是开发 代谢上更稳定的药物可以从正常组织中清除速度， 但被隔离并保留在肿瘤中。 最初的目标 该建议是开发用于制备的合成方法 各种放射性固定剂和[AT-211]标记的MIBG衍生物以及 系统地在体外和体内评估它们。 结构 计划的更改包括引入氯，溴，碘，硝基 MIBG苯环的4位和磺酸部分和磺酸部分 用吡啶环代替苯环本身。 固相 将为有前途的药物开发合成方法。 吸收和 在体外保留动力学和几种药理剂的作用 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。 尽管不是神经内分泌肿瘤，但 在几个人类髓母细胞中已经证明了MIBG的摄取 线条，该肿瘤非常适合[AT-211]疗法。 这 这些新[I-131]和[AT-211]标记的MIBG的治疗潜力 类似物将使用胸苷的摄取和克隆生成测定评估 单层和球体模型。 这些药物的组织分布将是 在正常小鼠和宿主神经母细胞瘤的无胸腺小鼠中确定， 嗜铬细胞瘤和髓母细胞瘤异种移植物。 增强策略 将研究肿瘤与正常的组织比率。 结果的结果 研究应有助于改善神经内分泌肿瘤和 可能是髓母细胞瘤。