Astatine 211 & Radioiodine Labeled Octreotide Conjugates

砹211

• 批准号: 6634072
• 负责人: Michael Rod Zalutsky
• 金额: $ 28.76万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634072
• 关键词: athymic mouse; autoradiography; chemical conjugate; chemical synthesis; diagnosis design /evaluation; drug metabolism; drug receptors; glucose; halogens; iodine; laboratory rat; maltose; medulloblastoma; neoplasm /cancer radionuclide diagnosis; neoplasm /cancer radionuclide therapy; nonhuman therapy evaluation; octreotide; pharmacokinetics; radionuclides; radiopharmacology; radiotracer; receptor binding; trioses

DESCRIPTION (Provided by Applicant): Somatostatin receptors, particularly the somatostatin receptor subtype 2 (sst2), are found on many tumor types. Ii this proposal, we shall focus on the development of radiohalogenated octreotide conjugates and related peptides as radiodiagnostics and therapeutics for medulloblastoma. Recent studies have demonstrated that the concentratior of sst2 on human medulloblastoma is extremely high, even higher than on neuroendocrine tumors. Medulloblastoma is the most frequent central nervous system tumor in children with dismal outcome. There is no effective treatment for this disease, making the development of more specific and selective diagnostics anc therapeutics for medulloblastoma of high clinical significance. Finally, medulloblastoma appears to be an idea clinical setting for exploiting the radiobiological advantages of a-particles such as those emitted by 211At Ou hypothesis is that octreotide conjugates and labeling methods for these peptides which maximize the trapping of the radiohalogen within the tumor cell will enhance tumor retention and tumor-to-normal organ ratios, thereby improving their clinical potential as diagnostic and therapeutic agents. Our specific aims are: 1) To synthesizL he2' 'At-labeled octreotide analogues [N-(3-[211 At]astatobenzoyl)-D-phe1]octreotide and 5[211 'At]astato-nicotinoylD-phe1]octreotide and compare their properties to the corresponding iodo analogues; 2) To label glycate octreotide and octreotate conjugates with radioiodine nuclides and 211At; peptide conjugates of glucose, maltose and maltotriose will be investigated; 3) To adapt two strategies originally developed for labeling intemalizini antibodies - D-amino acid linkers and acylation agents bearing polar substituents - for labeling octreotide analogue with 211At and radioiodine nuclides; 4) To evaluate the potential utility of promising 211 octreotide conjugates in comparison with their radioiodinated analogues as diagnostic and therapeutic radiopharmaceuticals. The proposed in vitro studies include characterization of binding, internalization and catabolism; the proposed in vivo studies include evaluation of tissue distribution, dosimetry, catabolism as well as therapeutic efficacy.

描述（由申请人提供）：生长抑素受体，特别是 生长抑素受体亚型 2 (sst2) 存在于许多肿瘤类型中。我这个 建议重点发展放射性卤代奥曲肽 缀合物和相关肽作为放射诊断和治疗剂 髓母细胞瘤。最近的研究表明，浓度 人髓母细胞瘤上的 sst2 非常高，甚至高于 神经内分泌肿瘤。髓母细胞瘤是最常见的中枢神经瘤 儿童系统肿瘤预后不佳。没有有效的治疗方法 针对这种疾病，使得开发更具特异性和选择性的 髓母细胞瘤的诊断和治疗具有很高的临床意义。 最后，髓母细胞瘤似乎是一个理想的临床环境，可以利用 a 粒子（例如 211At Ou 发射的粒子）的放射生物学优势 假设是奥曲肽缀合物和这些的标记方法 最大限度地捕获肿瘤细胞内放射性卤素的肽 将增强肿瘤保留和肿瘤与正常器官的比率，从而 提高其作为诊断和治疗剂的临床潜力。我们的 具体目标是： 1) 合成L he2' 'At标记的奥曲肽类似物 [N-(3-[211 At]astato苯甲酰基)-D-phe1]奥曲肽和 5[211 'At]astato-nicotinoylD-phe1]octreotide 并比较它们的特性 相应的碘类似物； 2) 标记糖酸奥曲肽和奥曲酸 与放射性碘核素和 211At 缀合物；葡萄糖的肽缀合物， 将调查麦芽糖和麦芽三糖； 3）适应两种策略 最初开发用于标记 intemalizini 抗体 - D-氨基酸 带有极性取代基的接头和酰化剂 - 用于标记 具有 211At 和放射性碘核素的奥曲肽类似物； 4）评估 有前途的 211 奥曲肽缀合物与 它们的放射性碘类似物作为诊断和治疗用途 放射性药物。拟议的体外研究包括表征 结合、内化和分解代谢；拟议的体内研究包括 组织分布、剂量测定、分解代谢以及治疗的评估 功效。