Chelator development for improved scandium theranostic agents

改进钪治疗诊断剂的螯合剂开发

• 批准号: 9888372
• 负责人: Melissa A Deri
• 金额: $ 16.5万
• 依托单位: HERBERT H. LEHMAN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-06 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888372
• 关键词: Acids; Acute; Amino Acids; Animals; Autoradiography; Behavior; Binding; Biodistribution; Biological; Biological Assay; Biological Models; Cations; Characteristics; Chelating Agents; Chemistry; Clinic; Clinical; Collaborations; Complex; Computer Models; Development; Diagnosis; Diagnostic Imaging; Disease; Drug Kinetics; Evaluation; Geometry; Goals; Gold; Half-Life; High temperature of physical object; Human; Image; In Vitro; Inorganic Chemistry; Investigation; Isotopes; Kinetics; Label; Lead; Ligand Binding; Ligands; Malignant Neoplasms; Medical; Memorial Sloan-Kettering Cancer Center; Metals; Modeling; Monitor; Mus; Neuroendocrine Tumors; Octreotide; Peptide Synthesis; Peptides; Pharmaceutical Preparations; Positron; Positron-Emission Tomography; Property; Radiation therapy; Radioactive; Radioactive metal; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Reaction Time; Research; Safety; Scandium; Series; Somatostatin; Structure; System; Targeted Radiotherapy; Thermodynamics; Tissues; Translations; Work; X-Ray Computed Tomography; base; biomaterial compatibility; bone; cancer radiation therapy; chelation; clinically relevant; density; design; imaging agent; imaging study; immunoreactivity; improved; in vivo; in vivo imaging; mouse model; nanoparticle; novel; personalized medicine; radiochemical; radiotracer; receptor; theories; theranostics; trend; tumor; unnatural amino acids; uptake; vector

Project Summary/Abstract Scandium-44 (44Sc) is a positron emitting radionuclide with a half-life of 3.97 h that is well-suited for use in positron emission tomography (PET) imaging. Scandium-47 (47Sc) is a beta emitter with a half-life of 3.345 d appropriate for targeted radiotherapy. When combined, 44Sc and 47Sc present an ideal radioisotope pair for use in theranostic agents meant to both diagnosis and treat disease. As radiometals, both isotopes of Sc require the use of a bifunctional chelator to attach the radioactive metal cation to a targeting vector that dictates the specific localization of the drug conjugate. Since 44Sc and 47Sc are both up and coming radionuclides for medical applications, there is a need for further chelator development for Sc-based radiopharmaceuticals. The most widely used chelator for Sc(III) is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); however as a macrocylic chelator, DOTA requires harsh radiolabeling conditions (high temperatures and long reaction times) to form the Sc-DOTA complex that are incompatible with sensitive biological molecules often used as targeting vectors in the drug conjugates. This research aims to investigate and develop an acyclic chelator for stably complexing Sc(III) under biologically compatible radiolabeling conditions to facilitate the use of Sc radioisotopes in targeted radiopharmaceuticals. To achieve these goals, this proposal aims to investigate the chelation chemistry of Sc(III) through the synthesis of small peptides as model systems to probe the effects of denticity, cavity size, and binding moiety on chelate stability, both experimentally and computationally. A series of tripeptides and tetrapeptides comprised of natural and non-natural amino acids will be synthesized and complexed with non-radioactive Sc(III). Selected Sc-peptide complexes will be further studied using density functional theory (DFT) calculations to probe the structure and geometry of the complexes. The trends observed with the peptide systems will inform the selection of promising acyclic chelators to be complexed with non-radioactive Sc and radioactive 44Sc. The acyclic chelators will be assessed based on their ability to readily chelate Sc under mild conditions with high purity, and on complex stability. The lead radiolabeled Sc-chelates will then be evaluated in vivo in mouse models through a collaboration with Memorial Sloan Kettering Cancer Center. PET imaging and biodistribution studies will be carried out to determine the in vivo stability and utility of the acyclic chelators in comparison with the current gold standard DOTA chelator. 44Sc-chelator complexes will be studied in healthy mice while 44Sc-chelator-octreotate (Y3-TATE) bioconjugates will be studied in tumor-bearing mice to monitor targeting to the somatostatin subtype 2 receptor (SSTr2) that are upregulated in neuroendocrine tumors. The development of acyclic chelators for rapid complexation of Sc radionuclides under mild conditions will lead to the development of a novel class of Sc-based radiopharmaceuticals for imaging and treating cancer.

项目摘要/摘要 Scandium-44（44SC）是一个正电子放射性核素，半衰期为3.97 h，非常适合用于 正电子发射断层扫描（PET）成像。 Scandium-47（47SC）是Beta发射极，半衰期为3.345 D 适用于靶向放射疗法。合并后，44SC和47SC会提供理想的放射性同位素对 在疗法剂中，既要诊断又治疗疾病。作为放射线仪，SC的两个同位素都需要 使用双功能螯合剂将放射性金属阳离子连接到决定靶向载体 药物结合物的特定定位。由于44SC和47SC既启动又是放射性核素 医疗应用，需要进一步开发基于SC的放射性药物。这 SC（III）使用的最广泛使用的螯合剂为1,4,7,10-TetraazacyClododecane-1,4,7,7,10-乙酸（DOTA）； 但是，作为大环螯合剂，DOTA需要严格的放射性标记条件（高温和长 反应时间）形成与敏感生物分子不兼容的SC-DOTA复合物 用作药物缀合物中的靶向向量。这项研究旨在调查和开发无环 在生物学上兼容的放射性标记条件下，用于稳定络合SC（III）的螯合剂以促进使用 靶向放射性药物中的SC放射性同位素。 为了实现这些目标，该提案旨在调查SC（III）的螯合化学 小肽作为模型系统的合成，以探测牙齿，腔体大小和结合部分的影响 在实验和计算上，螯合稳定性。一系列三肽和四肽 由天然和非天然氨基酸组成，将与非放射性活性合成并复杂化 SC（iii）。选定的SC肽复合物将使用密度功能理论（DFT）计算进一步研究 探测复合物的结构和几何形状。肽系统观察到的趋势将 告知选择有希望的无环螯合剂与非放射性SC和放射性的复合 44SC。无环螯合剂将根据其在轻度条件下容易螯合SC的能力进行评估 具有较高的纯度和复杂的稳定性。然后，将在体内评估铅辐射标记的SC螯合物 小鼠模型通过与纪念Sloan Kettering癌症中心合作。宠物成像和 将进行生物分布研究以确定无环螯合剂在体内稳定性和实用性 与当前的金标准DOTA螯合剂进行比较。将研究44SC示波子复合物 小鼠将在肿瘤的小鼠中研究44SC-氯酸二酸酯（Y3-TATE）生物缀合物以监测 靶向在神经内分泌肿瘤中上调的生长抑素亚型2受体（SSTR2）。这 在轻度条件下开发以快速络合SC放射性核素的无环螯合剂将导致 用于成像和治疗癌症的新型基于SC的放射性药物的开发。