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被开发为针对生长抑素受体阳性肿瘤的癌症成像和放疗药物。本提案的总体目标是合成、表征和评价Tc-99m-和re -188环化生长抑素肽衍生物分别用于癌症的诊断成像和靶向放疗。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放射性的保留，将导致肿瘤成像对比度的改善和更有效的低剂量治疗，从而避免非靶组织。简而言之，本提案的目标是：(1)合成和表征非放射性Re， Re-188， Tc-99m和Tc-99直接结合到肽二硫键中的生长抑素受体靶向肽；(2) Re和Tc-99配合物的体外受体结合亲和力与其三维固相结构的相关性；(3)评价Tc-99m-和re -188环化高受体结合肽的体内分布和肿瘤靶向特性；(4)评估最佳re -188协同肽在胰腺癌小鼠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.