Synthesis of Radiofluorinated PET Imaging Agents

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疗效至关重要。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允许对特定生化活性区域进行成像。发射正电子的放射性示踪剂可以设计成定位于特定的组织类型，如肿瘤，或者它们可以给出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）和相对较短的正电子扩散距离（1毫米）；这些特征使得从[18F]氟化放射性示踪剂获得的相对高分辨率图像能够快速获得，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。本研究计划的目标是发展无载流子（n.c.a）富电子芳香环放射性氟化的一般方法。[18F]氟，并通过开发与现有商业自动化放射性示踪剂合成平台无缝对接的化学物质，促进该方法的普遍使用。这种全新的能力将极大地扩展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是开发一种新的、通用的、高效的方法，用于用n.c.a. [18F]氟化物对功能化的富电子芳香化合物进行碘介导的单步放射性氟化。拟议的工作将建立在机理研究的基础上，这些研究描述了从还原消除二芳基氟化碘盐中产生芳基氟化物的高产率。具体目标2是开发一种通用的合成方法，使高功能化芳香化合物能够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易保护基团化学来扩大这种合成化学的范围。

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. PUBLIC HEALTH RELEVANCE: Noninvasive, in vivo imaging of biological processes is essential for identifying disease states and progression, and for assessing the efficacy of treatment regimens. This research will address the need for new positron emission tomography (PET) imaging agents by developing a novel methodology for their synthesis. The outcomes of this research program will be new diagnostic techniques to identify disease states and a general and facile means to access a wide variety of new and existing imaging agents; these compounds and procedures will provide the physician with new opportunities to probe, diagnose and assess human disorders.