Copper-mediated Late-Stage Radiofluorination of Electron-rich Arenes

项目概述：含有[18F]标记的富电子芳环的放射性示踪剂是目前研究最多的放射性示踪剂之一。 备受追捧的PET显像剂。例如，6-[18F]氟- 20多年来，L-DOPA一直是PET界具有挑战性和备受瞩目的目标。尽管 由于[18F]标记的富电子芳烃的重要性，很少有放射合成方法 访问这些结构。该补助金建立在物理科学之间现有的合作基础上 （化学，桑福德）和生命科学（放射学/医学成像，斯科特）在密歇根大学， 将他们的集体专业知识用于解决这一问题。拟议研究的总体目标是 通过开发亲核放射化学方法来解决这一关键需求，（a）使放射化学家能够 18 F-标记富电子芳环起始于容易获得的稳定前体分子，和（B）可以是 自动化，验证，并翻译到放射化学生产设施，供非化学家使用， 合成临床放射性示踪剂剂量。本申请的中心假设是铜介导的 无线电探测方法将使该小组能够实现这些目标。拟议研究 将开发用于放射性标记（均三甲苯基）（芳基）碘鎓盐（目标1和2）以及芳基碘鎓盐的Cu介导方法。 碘化物、芳基硼酸和芳基锡烷（Aim 3）与18F-。这项工作意义重大，因为它需要 开发用于合成以前无法获得（或难以获得）的18F标记的 临床感兴趣的PET放射性示踪剂：4-[18 F]氟-间羟基苯乙基胍（[18 F]4F-MHPG;心脏 局部神经密度）、6-[18 F]氟-L-多巴（[18 F]F-DOPA;多巴胺能通路）、[18 F] 2 '-甲氧基苯基- (N-2 1 '-吡啶基）-对氟-苯甲酰氨基乙基哌嗪（[18F]MPPF; 5-HT 1A受体），（4- [18 F]氟苯基）三苯基氯化鏻（[18 F]BFPET;线粒体电压传感器），[18 F]奥曲肽 （[18 F]TOC;生长抑素2受体，例如，神经内分泌肿瘤）;临床前兴趣：新 用于GAT-1 GABA转运蛋白和多巴胺D3受体的放射性示踪剂，以及靶向GAT-1 GABA转运蛋白和多巴胺D3受体的目标。 制药行业（BACE，食欲素受体）。这些目标将通过各种方式实现， 创新包括：（a）开发新的铜介导的亲核方法 富电子芳烃的放射性氢化（包括Ag 18 F的产生和利用的新方法），（B） 这些新的放射性同位素反应的机械驱动的优化和（c）这些反应的转化 临床验证的放射合成方法（符合cGMP的临床剂量的自动合成）。 总的来说，该项目将提供四种新的铜介导的方法来合成18F标记的放射性示踪剂， 许多重要的放射性示踪剂的有效临床合成。这两个可交付成果都将扩展实用程序 PET成像用于疾病的检测、治疗和预防。

Project Summary: Radiotracers containing [18F]-labeled electron-rich aromatic rings are among the most highly sought-after PET imaging agents. For example, the development of a clinical synthesis of 6-[18F]fluoro- L-DOPA has been a challenging and high-profile target in the PET community for more than 20 years. Despite the great importance of [18F]-labeled electron rich arenes, there are very few radiosynthesis methods for accessing these structures. The grant builds on an existing collaboration between the physical sciences (Chemistry, Sanford) and life sciences (Radiology/Medical Imaging, Scott) at the University of Michigan, bringing their collective expertise to bear on this problem. The overall objective of the proposed research is to address this critical need by developing nucleophilic radiofluorination methods that (a) enable radiochemists to 18F-label electron rich aromatic rings starting from readily available, stable precursor molecules and (b) can be automated, validated, and translated to radiochemistry manufacturing facilities for use by non-chemists to synthesize clinical radiotracer doses. The central hypothesis of this application is that copper mediated radiofluorination methods will uniquely enable this team to achieve these objectives. The proposed research will develop Cu-mediated methods for radiolabeling (mesityl)(aryl)iodonium salts (Aims 1 and 2) as well as aryl iodides, aryl boronic acids and aryl stannanes (Aim 3) with 18F–. The work is significant because it entails development of novel methods for the synthesis of previously inaccessible (or difficult to access) 18F-labeled PET radiotracers of clinical interest: 4-[18F]fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG; cardiac regional nerve density), 6-[18F]fluoro-L-DOPA ([18F]F-DOPA; dopaminergic pathway), [18F]2'-methoxyphenyl- (N-2'-pyridinyl)-p-fluoro-benzamidoethylpiperazine ([18F]MPPF; 5-HT1A receptor), (4- [18F]fluorophenyl)triphenylphosphonium chloride ([18F]BFPET; mitochondrial voltage sensor), [18F]octreotide ([18F]TOC; somatostatin 2 receptors in, for example, neuroendocrine tumors); pre-clinical interest: new radiotracers for the GAT-1 GABA transporter and dopamine D3 receptor, and targets of interest to the pharmaceutical industry (BACE, orexin receptors). These goals will be accomplished through a variety of innovations including: (a) the development of novel copper-mediated methods for the nucleophilic radiofluorination of electron rich arenes (including new methods for the generation and utilization of Ag18F), (b) the mechanistically-driven optimization of these new radiofluorination reactions and (c) translation of these methods to clinically validated radiosyntheses (automated synthesis of cGMP-compliant clinical doses). Overall, this project will deliver four novel Cu-mediated methods for synthesizing 18F-labeled radiotracers and validated clinical synthesis of numerous important radiotracers. Both of these deliverables will expand the utility of PET imaging for the detection, treatment, and prevention of disease.