Astatine 211 & Radioiodine Labeled Octreotide Conjugates

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（SST 2）在许多肿瘤类型中发现。Ii这个 建议，我们将重点放在放射性卤代奥曲肽的发展 作为放射诊断和治疗的缀合物和相关肽 髓母细胞瘤最近的研究表明， 人髓母细胞瘤上的SST 2非常高，甚至高于人髓母细胞瘤上的SST 2。 神经内分泌肿瘤髓母细胞瘤是最常见的中枢神经系统肿瘤， 儿童系统肿瘤预后不佳。尚无有效的治疗方法 对于这种疾病，使发展更具体和选择性 对髓母细胞瘤的诊断和治疗具有重要的临床意义。 最后，髓母细胞瘤似乎是一个理想的临床环境， a粒子的放射生物学优势，如211 At Ou发射的粒子 假设是奥曲肽缀合物及其标记方法 最大化肿瘤细胞内放射性卤素捕获的肽 将增强肿瘤保留和肿瘤与正常器官的比率， 提高了它们作为诊断和治疗剂的临床潜力。我们 具体的目标是：1）合成L he 2“At标记的奥曲肽类似物 [N-（3-[211 At]阿司他苯甲酰基）-D-phe 1]奥曲肽和5[211 [At] astato-nicotinoylD-phe 1]octreotide，并将它们的性质与 相应的碘代类似物; 2）标记糖化奥曲肽和奥曲肽 具有放射性碘核素和211 At的缀合物;葡萄糖的肽缀合物， 麦芽糖和麦芽三糖进行研究; 3）采用两种策略 最初开发用于标记Intemalizini抗体-D-氨基酸 带有极性取代基的连接剂和酰化剂-用于标记 奥曲肽类似物与211 At和放射性碘核素; 有希望的211奥曲肽缀合物的潜在效用与 它们的放射性碘标记的类似物作为诊断和治疗 放射性药物拟定的体外研究包括表征 结合、内化和催化;拟议的体内研究包括 组织分布、剂量测定、放射性活度以及治疗性 功效

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.