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 Sc-44(44Sc)是一种发射正电子的放射性核素，半衰期为3.97小时，非常适合用于 正电子发射断层扫描(PET)成像。Sc-47(47Sc)是一种半衰期为3.345天的β辐射体 适用于靶向放射治疗。结合使用时，44Sc和47Sc是一对理想的放射性同位素对 在用于诊断和治疗疾病的治疗药物中。作为放射性金属，Sc的两种同位素都需要 使用双功能螯合剂将放射性金属阳离子连接到靶向载体上，该载体指示 药物结合物的特定定位。由于44Sc和47Sc都是正在和即将到来的放射性核素 为了满足医疗应用的需要，需要进一步开发基于SC的放射性药物的螯合剂。这个 应用最广泛的Sc(Ⅲ)络合剂是1，4，7，10-tetraazacyclododecane-1，4，7，10-tetraacetic酸； 然而，作为一种大环络合剂，DOTA需要苛刻的放射性标记条件(高温和长时间 反应时间)以形成通常与敏感生物分子不相容的SC-DOTA络合物 在药物结合物中用作靶向载体。本研究的目的是研究和开发一种非循环的 用于在生物相容的放射性标记条件下稳定络合Sc(III)的螯合剂，便于使用 靶向放射性药物中Sc放射性同位素的含量。 为了实现这些目标，这项建议旨在通过研究Sc(III)的螯合化学 合成小肽作为模型体系探讨致密性、空腔大小和结合部分的影响 无论是从实验还是从计算上来说，都是关于螯合稳定性的。一系列三肽和四肽 由天然和非天然氨基酸组成的合成并与非放射性络合 SC(III)。选定的SC-肽化合物将使用密度泛函理论(DFT)计算进行进一步研究 探索络合物的结构和几何构型。用多肽系统观察到的趋势将 选择有前景的无环络合剂与非放射性Sc和放射性Sc络合 44Sc.非环络合剂将根据它们在温和条件下容易螯合SC的能力进行评估 具有较高的纯度，且对络合物稳定。铅放射性标记的SC-螯合物随后将在体内进行评估 通过与纪念斯隆·凯特琳癌症中心的合作建立老鼠模型。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的稳定性和实用性。 与目前的金标DOTA络合剂进行比较。44Sc-络合物将在健康人体内进行研究 小鼠同时用44Sc-螯合剂-奥曲酸(Y3-Tate)生物结合物在荷瘤小鼠中进行监测 靶向神经内分泌肿瘤中上调的生长抑素亚型2受体(SSTR2)。这个 在温和的条件下开发用于Sc放射性核素快速络合的非环络合剂将导致 一类新型的基于SC的放射性药物的开发，用于肿瘤的成像和治疗。