Astatine 211 & Radioiodine Labeled Octreotide Conjugates

说明(申请人提供)：生长抑素受体，特别是 生长抑素受体亚型2(Sst2)在多种肿瘤类型中均有表达。二、这个 建议，我们将重点开发放射性卤代奥曲肽 作为放射诊断和治疗的结合物和相关多肽 髓母细胞瘤。最近的研究表明，精矿的浓度 Sst2对人髓母细胞瘤的抑制率极高，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系统肿瘤。 儿童系统肿瘤，预后不佳。没有有效的治疗方法 对于本病，使其发展更具特异性和选择性 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开发的理想临床环境。 ~(211)Au等a粒子的放射生物学优势 假设是奥曲肽与这些物质的结合和标记方法 最大限度地将放射性卤素捕获到肿瘤细胞内的多肽 将增加肿瘤滞留和肿瘤与正常器官的比率，从而 提高它们作为诊断和治疗药物的临床潜力。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]Astatenzoyl)-D-phe1]奥曲肽和5[211 并将它们的性质与奥曲肽进行比较。 相应的碘类似物；2)标记甘氨酸、奥曲肽和奥曲肽 与放射性碘核素和~(211)At的结合物；葡萄糖的多肽结合物， 将对麦芽糖和麦芽糖进行研究；3)采取两种策略 最初是为标记Intemalizini抗体-D-氨基酸而开发的 标记用含极性取代基的连接物和酰化剂 奥曲肽类似物与~(211)At和放射性核素；4)评价 211种有前景的奥曲肽结合物的潜在用途 它们的放射性碘化类似物作为诊断和治疗 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；拟议的活体研究包括 评价组织分布、剂量学、分解代谢和治疗 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.