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

铜介导的富电子芳烃的后期放射性氟化

• 批准号: 9144955
• 负责人: MELANIE S. SANFORD
• 金额: $ 35.69万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144955
• 关键词: Acids; Address; Biological Sciences; Boronic Acids; Cardiac; Catalysis; Chemistry; Chloride Ion; Chlorides; Clinical; Collaborations; Communities; Copper; Cyclic GMP; Detection; Development; Dose; Drug Industry; Electrons; Equipment; Fluorides; Foundations; GABA Transporter 1; Gases; Generations; Goals; Grant; Growth; Image; Imaging Techniques; Iodides; Label; Mediating; Mediator of activation protein; Medical Imaging; Methodology; Methods; Michigan; Mitochondria; Monitor; Nerve; Neuroendocrine Tumors; Octreotide; Pathway interactions; Patients; Physiological Processes; Positron; Positron-Emission Tomography; Process; Production; Radiochemistry; Radioisotopes; Radiolabeled; Radiology Specialty; Reaction; Research; Route; Salts; Serotonin Receptor 5-HT1A; Side; Staging; Structure; Sympathetic Nervous System; Time; Tracer; Transition Elements; Translating; Translations; Universities; Ursidae Family; Work; beta-site APP cleaving enzyme 1; density; disease diagnosis; disorder prevention; dopamine D3 receptor; drug discovery; functional group; hypocretin; imaging agent; in vivo; innovation; interest; manufacturing facility; molecular imaging; novel; personalized medicine; physical science; poly(L-glutamic acid(60)-L-alanine(30)-L-tyrosine(10)); pre-clinical; radiotracer; rapid technique; receptor; sensor; somatostatin receptor 2; stannane; voltage

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.

项目概要：含有[18F]标记的富电子芳环的放射性示踪剂是最重要的放射性示踪剂之一。 备受追捧的 PET 显像剂，例如 6-[18F]氟- 的临床合成的开发。 20 多年来，左旋多巴一直是 PET 界具有挑战性且备受瞩目的目标。 由于[18F]标记的富电子芳烃非常重要，因此放射合成方法很少 访问这些结构是建立在物理科学之间现有合作的基础上的。 密歇根大学（化学，桑福德）和生命科学（放射学/医学成像，斯科特）， 拟议研究的总体目标是利用他们的集体专业知识来解决这个问题。 通过开发亲核放射性氟化方法来满足这一迫切需求，这些方法 (a) 使放射化学家能够 18F-标记富电子芳环起始于容易获得的、稳定的前体分子，并且(b)可以是 自动化、验证并转化为放射化学制造设施，供非化学家使用 合成临床放射性示踪剂剂量。该应用的中心假设是铜介导的。 放射性氟化方法将使该团队能够实现这些研究目标。 将开发用于放射性标记（异三叉基）（芳基）碘鎓盐（目标 1 和 2）以及芳基的 Cu 介导方法 碘化物、芳基硼酸和芳基锡烷（目标 3）与 18F– 的结合 这项工作意义重大，因为它需要进行。 开发合成以前无法获得（或难以获得）的 18F 标记的新方法 具有临床意义的 PET 放射性示踪剂：4-[18F]氟-间羟基苯乙基胍 ([18F]4F-MHPG；心脏 区域神经密度）、6-[18F]氟-L-DOPA（[18F]F-DOPA；多巴胺能通路）、[18F]2'-甲氧基苯基- (N-2'-吡啶基)-对氟-苯甲酰胺乙基哌嗪（[18F]MPPF；5-HT1A 受体），（4- [18F]氟苯基）三苯基氯化磷（[18F]BFPET；线粒体电压传感器）、[18F]奥曲肽 （[18F]TOC；生长抑素 2 受体，例如神经内分泌肿瘤）；临床前兴趣：新 GAT-1 GABA 转运蛋白和多巴胺 D3 受体的放射性示踪剂，以及感兴趣的目标 制药工业（BACE，食欲素受体）将通过多种方式实现。 创新包括：(a) 开发新型铜介导的亲核方法 富电子芳烃的放射性氟化（包括产生和利用 Ag18F 的新方法），(b) 这些新的放射性氟化反应的机械驱动优化以及（c）这些反应的转化 临床验证的放射合成方法（自动合成符合 cGMP 的临床剂量）。 总体而言，该项目将提供四种新颖的铜介导方法来合成 18F 标记的放射性示踪剂和 众多重要放射性示踪剂的经过验证的临床合成将扩大其用途。 PET 成像用于疾病的检测、治疗和预防。