Radiometal-cyclized Octerotide Derivatives for Oncology

描述(由申请人提供)：放射性标记的生长抑素类似物正在被开发为癌症成像和放射治疗药物，以靶向生长抑素受体阳性的肿瘤。这项建议的总体目标是合成、表征和评价分别用于癌症诊断成像和靶向放射治疗的~(99)T和~(188)Re-环化生长抑素多肽衍生物。需要解决的假设是，对生长抑素类似物进行结构修饰以增加肿瘤中的放射性保留，将导致改善肿瘤成像对比度，并在较低剂量下获得更有效的治疗，从而避免非靶组织。简而言之，本方案的目的是(1)合成和表征直接结合在多肽二硫键上的非放射性Re、Re-188、Tc-99m和Tc-99多肽；(2)将Re和Tc-99络合物的体外受体结合亲和力与其三维溶液相结构相关联；(3)评价具有高受体结合的Te-99m和Re-188环化多肽的体内分布和肿瘤靶向性；以及(4)评估最佳Re-188配位多肽在小鼠胰腺癌模型中的放射治疗潜力。

DESCRIPTION (provided by applicant): Radiolabeled somatostatin analogues are being developed as cancer imaging and radiotherapy agents to target somatostatin receptor-positive tumors. The overall goal of this proposal is to synthesize, characterize and evaluate Tc-99m- and Re-188-cyclized somatostatin peptide derivatives for diagnostic imaging and targeted radiotherapy, respectively, of cancer. The hypothesis to be addressed is that structural modification of somatostatin analogues to increase retention of radioactivity in tumors will result in both improved tumor imaging contrast and more effective therapy at lower doses that would spare the non-target tissues. The objectives of this proposal, in brief, are (1) to synthesize and characterize somatostatin receptor-targeting peptides with non-radioactive Re, Re-188, Tc-99m and Tc-99 incorporated directly into the peptide disulfide bond; (2) to correlate the in vitro receptor binding affinities of the Re and Tc-99 complexes to their three dimensional solution phase structures; (3) to evaluate the in vivo distributions and tumor-targeting properties of the Tc-99m- and Re-188-cyclized peptides with high receptor binding; and (4) to assess the radiotherapeutic potential of the optimal Re-188-coordinated peptide in a mouse model of pancreatic cancer.