DEVELOPMENT OF GRP RECEPTOR AVID RADIOPHARMACEUTICALS

GRP 受体 AVID 放射性药物的开发

• 批准号: 2895792
• 负责人: Wynn A Volkert
• 金额: $ 18.53万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-03 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2895792
• 关键词: athymic mouse; bombesin; drug design /synthesis /production; gastrin releasing peptide; high performance liquid chromatography; neuropeptide receptor; peptide analog; peptide chemical synthesis; radionuclides; radiotracer; receptor binding; synthetic peptide; technetium; tissue /cell culture

DESCRIPTION: Proposal describes the design of new conjugates of synthetic bombesin (BBN) analogues that form high specific activity site-directed radio-pharmaceuticals for specific in vivo targeting of neoplastic cells that express gastric releasing peptide (GRP) receptors (including small cell lung cancer - SCLC). Radiopharmaceuticals that result from this research would be labeled with Tc-99m, Re-188 or I-123/125. All of these radionuclides are available in no-carrier added (NCA) levels and have half-lives that are compatible for preparing radiopharmaceuticals based on relatively small biomolecular targeting agents (e.g., peptides). The specific objectives of this research are to: 1) develop new synthetic BBN analogues, labeled with Tc-99m, Re-188 or I-123/125, that exhibit high specific binding affinities to cells expressing GRP receptors, 2) use normal and tumor bearing animal models to identify which of the promising radiolabeled peptides (identified using in vitro binding studies) also exhibit optimal tumor uptake and pharmacokinetic properties. The new BBN-analogue- conjugates, synthesized in-house, using an automated peptide synthesizer, will be purified and characterized and both tracer and macroscopic levels. Methods to prepare radiolabeled BBN-analogues specific to maximize activities and stability of the final drug product will be developed. Approaches and methods to conjugate or incorporate Tc-99m and Re-188 chelate receptor binding, as well as maintaining good in vitro and in vivo stability, will be developed. The most promising radiolabeled BBN analogues will be evaluated in athymic mice with tumors expressing GRP receptors, to assess their ability to specifically target SCLC's or other GRP expressing neoplasms. The pharmacokinetic studies (including clearance of radioactivity from blood and other non-target organs (e.g., kidneys)] will be performed in both normal and athymic mice to identify radiolabeled BBN-analogues that produce maximal target to non-target uptake rates. Ligand frameworks that form Tc-99m (r Re-188) chelates with a spectrum of physico-chemical properties will be conjugated at selected sites on BBN peptide analogues to determine which site-specific modifications will produce Tc-99m or Re-188 BBN analogues with optimal in vitro and in vivo properties. The results of these studies should provide radiolabeled BBN analogues that could be developed (via future clinical trials) into effective radiopharmaceuticals for treatment of patients with GRP-expressing neoplasms.

描述：提案描述了合成的新缀合物的设计 蛙皮素（BBN）类似物， 用于肿瘤细胞的特异性体内靶向的放射性药物 表达胃释放肽（GRP）受体（包括小细胞 肺癌- SCLC）。 这项研究的放射性药物 将用Tc-99 m、Re-188或I-123/125标记。 所有这些 放射性核素可在无载体添加（NCA）水平中获得，并且具有 与制备放射性药物相容的半衰期， 相对小的生物分子靶向剂（例如，肽）。 的 本研究的具体目标是：1）开发新的合成BBN 用Tc-99 m、Re-188或I-123/125标记的类似物， 对表达GRP受体的细胞的特异性结合亲和力，2）使用正常 和荷瘤动物模型，以确定哪些有前途的 放射性标记的肽（使用体外结合研究鉴定）还 表现出最佳的肿瘤摄取和药代动力学性质。 新 BBN-类似物-缀合物，使用自动化肽在内部合成 合成器，将被纯化和表征，示踪剂和 宏观层面。 制备放射性标记的BBN-类似物特异性的方法 为了最大化最终药物产品的活性和稳定性， 开发 缀合或掺入Tc-99 m和Tc-99 m的途径和方法 Re-188螯合受体结合，以及在体外和体内维持良好的 将开发体内稳定性。 最有前途的放射性标记BBN 类似物将在具有表达GRP的肿瘤的无胸腺小鼠中进行评价 受体，以评估其特异性靶向SCLC或其他 表达GRP的肿瘤。 药代动力学研究（包括清除率 来自血液和其他非靶器官的放射性（例如，肾）] 将在正常和无胸腺小鼠中进行，以鉴定放射性标记的 BBN-类似物，产生最大的靶向非靶向摄取率。 形成Tc-99 m（r Re-188）的配体框架与光谱螯合 将在BBN上的选定位点结合物理化学性质 肽类似物，以确定哪些位点特异性修饰将 在体外和体内以最佳方式生产Tc-99 m或Re-188 BBN类似物 特性. 这些研究的结果应提供放射性标记的BBN 类似物，可以开发（通过未来的临床试验）， 用于治疗表达GRP的患者的有效放射性药物 肿瘤。