Synthesis of Radiofluorinated PET Imaging Agents

放射性氟化 PET 显像剂的合成

• 批准号: 8666643
• 负责人: STEPHEN DIMAGNO
• 金额: $ 28.65万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666643
• 关键词: 2-Fluoro-2-deoxyglucose; Address; Alkaloids; Amines; Amino Acids; Aromatic Compounds; Benchmarking; Biochemical; Biological Process; Brain; Brain imaging; Cancerous; Cell Nucleus; Chemistry; Clinical; Clinical Research; Data; Development; Diagnosis; Diagnostic Imaging; Diagnostic Procedure; Diffusion; Disease; Drug Kinetics; Drug Receptors; Electrons; Enzymes; Fluorides; Foundations; Functional Imaging; Goals; Half-Life; Histocompatibility Testing; Human; Hydrogen Bonding; Image; Iodine; Isotopes; Label; Lead; Ligands; Location; Magnetic Resonance Imaging; Measures; Mediating; Metabolic; Methodology; Methods; Organ; Outcomes Research; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physicians; Positron; Positron-Emission Tomography; Preparation; Procedures; Production; Property; Protocols documentation; Radioactivity; Radiolabeled; Research; Research Project Grants; Resolution; Roentgen Rays; Salts; Solutions; Staging; Synthesis Chemistry; Time; Tissues; Tracer; Treatment Efficacy; Treatment Protocols; Tyrosine; Work; analog; cross reactivity; design; disease diagnosis; drug candidate; hazard; imaging modality; in vivo; in vivo imaging; innovation; interest; non-invasive imaging; novel; novel diagnostics; oncology; oxidation; pre-clinical; programs; radiologist; radiotracer; success; tertiary amine; tool; tumor

DESCRIPTION (provided by applicant): Noninvasive diagnostic imaging of tissues is essential for determining the identification and staging of diseases, and assessing the efficacy of treatment regimens. While most imaging methods provide structural information (CAT, X-Ray, MRI), positron emission tomography permits imaging of regions of specific biochemical activity. Positron emitting radiotracers may be designed to localize in specific tissue types, such as tumors, or they may give a measure of normal metabolic activity. The positron emitting nucleus 18F possesses an ideal half-life (110 minutes) and relatively short positron diffusion distance (1 mm); these features permit relatively high resolution images obtained from [18F]fluorinated radiotracers to be acquired rapidly, with little lingering radioactivity hazard for the patient. Unfortunately, preparation of many desirable [18F]fluoride-labeled radiotracers is stymied by the lack of highly efficient, broadly applicable aromatic radiofluorination methods. The goals of this research project are to develop general methodology to radiofluorinate electron rich aromatic rings with no-carrier-added (n.c.a.) [18F]fluoride and to facilitate general use of this methodology by developing chemistry that interfaces seamlessly with existing commercial automated radiotracer synthesis platforms. This wholly new capability will expand dramatically the types of diseases that can be imaged by PET, and will lead directly to innovative protocols for diagnostic imaging and tissue localization. The proposed research has three specific aims. Specific aim 1 is to develop new, general, highly efficient methodology for single-step iodine-mediated radiofluorination of functionalized, electron-rich aromatic compounds with n.c.a. [18F]fluoride. The proposed work will build on a foundation of mechanistic studies describing the high yield formation of aryl fluorides from the reductive elimination of diaryliodonium fluoride salts. Specific aim 2 is to develop a general synthetic methodology that permits highly functionalized aromatic compounds to be transformed into radiotracer precursors directly. Specific aim 3 is to expand the scope of this synthetic chemistry by providing facile protecting group chemistry that is compatible with late stage radiofluorination of alkaloids.

描述（由申请人提供）：组织的无创诊断成像对于确定疾病的识别和分期以及评估治疗方案的功效至关重要。虽然大多数成像方法提供结构信息（CAT、X 射线、MRI），但正电子发射断层扫描可以对特定生化活性区域进行成像。正电子发射放射性示踪剂可以设计用于定位特定的组织类型，例如肿瘤，或者它们可以提供正常代谢活动的测量。正电子发射核18F具有理想的半衰期（110分钟）和较短的正电子扩散距离（1毫米）；这些功能允许快速获取从[18F]氟化放射性示踪剂获得的相对高分辨率图像，对患者几乎没有残留的放射性危害。不幸的是，由于缺乏高效、广泛适用的芳香族放射性氟化方法，许多理想的[18F]氟化物标记放射性示踪剂的制备受到阻碍。该研究项目的目标是开发使用无载体添加（n.c.a.）[18F]氟化物对富电子芳环进行放射性氟化的通用方法，并通过开发与现有商业自动化放射性示踪剂合成无缝连接的化学物质来促进该方法的普遍使用平台。这种全新的功能将极大地扩展 PET 成像的疾病类型，并将直接导致诊断成像和组织定位的创新方案。拟议的研究有三个具体目标。具体目标 1 是开发新的、通用的、高效的方法，用于使用 n.c.a. 进行功能化、富电子芳香族化合物的一步碘介导的放射性氟化。 [18F]氟化物。拟议的工作将建立在机械研究的基础上，描述从二芳基碘鎓氟化物盐的还原消除中高产率形成芳基氟化物。具体目标2是开发一种通用合成方法，允许将高度官能化的芳香族化合物直接转化为放射性示踪剂前体。具体目标 3 是通过提供与生物碱后期放射性氟化相容的简便保护基化学来扩大这种合成化学的范围。