99mTc and 188Re Complexes for Conjugation to Peptides

用于与肽缀合的 99mTc 和 188Re 复合物

• 批准号: 6772207
• 负责人: LYNN CAROL FRANCESCONI
• 金额: $ 16.49万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6772207
• 关键词: antibody; chelating agents; chemical conjugate; circular dichroism; drug design /synthesis /production; heavy metals; high performance liquid chromatography; immunoconjugates; peptide chemical synthesis; radiopharmacology; radiotracer; stereoisomer; technetium

DESCRIPTION (provided by applicant): Targeted technetium ( 99m Tc) and rhenium ( 188 Re) radiopharmaceuticals consist of a targeting vector that determines the specificity for the target (receptor, biochemical process) and is linked to an organic ligand that forms a complex (or chelate) with the radiometal. Our long-range goal is to design new conjugates consisting of the 99m Tc/ 188 Re chelate and the targeting vector (Figure 1) that will have exceptional stability, targeting ability and rapid elimination of unbound radioactivity. The objective of this proposal is to design, synthesize and test simple Tc/Re complexes (chelates) based on two Tc/Re "cores", [M v =O] 3+ and M I (CO)3 + , M= 99m Tc, 188 Re, and complementary peptide ligand systems. (Aims 1 and 2) The peptide ligands are chosen to provide an understanding of the factors (structure, lipophilicity, stereochemistry) that lead to 1) the formation of one major product (two, in the case of stereoisomers) upon radiolabeling, 2) the metal chelates remaining intact in in vivo and in vitro assays (high stability) and 3) elimination of the intact metal chelates in the urine via the kidneys (renal system). This understanding is key to the design of targeted 99m Tc and 188 Re radiopharmaceuticals because we hypothesize that the metal chelate has a profound effect on the stability of the radiometal and the biodistribution of the entire molecule. The chelates designed in this project can be easily conjugated to target vectors (biomolecules) by standard solid phase peptide synthesis (SPPS) techniques for further in vivo testing for specificity to the target and application as imaging or radiotherapy agents. Aim 3, a collaborative effort with New York University School of Medicine proposes to conjugate the best chelates from Aims 1 and 2 to a 13 amino acid peptide that is the active site of the HU177 antibody. Both the peptide and the antibody bind to an antigen of collagen type IV that is exposed when collagen unravels in the vicinity of tumors as part of angiogenesis. The 99m Tc and 188 Re conjugates will be tested for in vivo tracking of the peptide and antibody and for applications in imaging and therapy.Our proposed study differs from other Tc and Re radiopharmaceutical studies because we will work with both the tracer ( 99m Tc, 188 Re, [10[ -10] -10[ -12] M]) and the macroscopic ( 99 Tc and Re [10[-2] -10[-3] M]) species. This is critical to gain a complete understanding of the structure, speciation and chemistry of the radiopharmaceutical. In this effort we employ techniques that have not been used for 99m Tc and 188 Re radiopharmaceutical studies and will provide important information on structures and chemistry. These techniques include, but are not limited to, preparative HPLC to prepare the 99 Tc macroscopic analogs, that can be related to the tracer species, and the use of Circular Dichroism and 17 O NMR Spectroscopy.

描述（由申请人提供）：针对性的Technetium（99m TC）和Rhenium（188 RE） 放射性药物由靶向矢量组成，该靶向矢量决定了目标的特异性 （受体，生化过程），并与有机配体相连，该配体形成具有辐射量的复合物（或螯合物）。我们的远程目标是设计由99m TC/ 188螯合物和靶向向量（图1）组成的新偶联物，这些偶像将具有出色的稳定性，靶向能力和快速消除未结合的放射性。该建议的目的是设计，合成和测试简单的TC/RE复合物（螯合物），基于两个TC/RE“内核”， [M V = O] 3+和M I（CO）3 +，M = 99m TC，188 RE和互补的肽配体系统。 （目的1和2）选择肽配体以了解导致1）形成一种主要产物（两种立体异构体的形成）的因素（结构，亲脂性，立体化学）），对放射性标签的形成，2），2）将金属螯合物保持在体内的稳定性和较高的稳定性（3），并以3杆的形式消除了整体的构成和3个构成的构成。通过肾脏（肾脏系统）。这种理解是针对目标99m TC和188次放射性药物的设计的关键，因为我们假设金属螯合物对放射线的稳定性和整个分子的生物分布具有深远的影响。该项目中设计的螯合物可以通过标准的固相肽合成（SPP）技术很容易地与靶向载体（生物分子）结合在一起 目标和应用为成像或放射治疗剂。 AIM 3，与纽约大学医学院的合作努力提议将最佳的螯合物从AILS 1和2到13个氨基酸肽，这是HU177抗体的活跃部位。肽和抗体都与胶原型抗原的抗原结合，当胶原蛋白在肿瘤附近脱离时，它是血管生成的一部分。将测试99m TC和188个偶联物的体内跟踪肽和抗体，并在成像和治疗中应用。 示踪剂（99m TC，188 RE，[10 [-10] -10 [-12] M]）和宏观（99 TC和RE [10 [-2] -10 -10 [-3] M]）物种。这对于完全了解放射性药物的结构，物种和化学是至关重要的。在这项工作中，我们采用了尚未用于99m TC和188种放射性药物研究的技术，并将提供有关结构和化学的重要信息。这些技术包括但不限于制备HPLC，以制备可能与示踪剂物种有关的99个TC宏观类似物，以及使用圆形二色性和17 O NMR光谱的使用。