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.

项目概述：含有[18F]标记的富电子芳环的放射性示踪剂是最多的 备受追捧的PET显像剂。例如，开发一种临床合成的6-[18F]氟- 20多年来，L-多巴一直是聚酯界一个具有挑战性且备受瞩目的目标。尽管 由于[18F]标记的富电子芳烃的重要性，目前很少有放射性合成方法用于 进入这些建筑。这笔赠款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)， 利用他们的集体专业知识来解决这个问题。拟议研究的总体目标是 通过开发亲核放射性氟化方法来满足这一迫切需要，这些方法：(A)使放射化学家能够 18F-标记富含电子的芳环，起始于容易获得的、稳定的前体分子和(B)可以 自动化、验证并转换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。这一应用的中心假设是铜介导的 放射性氟化方法将独一无二地使该团队能够实现这些目标。拟议的研究 将开发铜介导的放射性标记(甲苯基)(芳基)碘盐(目标1和2)以及芳基的方法 碘化物、芳基硼酸和芳基锡烷(目标3)与18F-。这项工作意义重大，因为它需要 开发合成先前无法接触(或难以获得)的18F标记化合物的新方法 临床使用的PET放射性示踪剂：4-[18F]-间羟基苯乙基胍([18F]4F-MHPG；心脏 区域神经密度)，6-[18F]氟-L-多巴([18F]F-多巴；多巴胺能通路)，[18F]2‘-甲氧基苯基- (N-2‘-pyridinyl)-p-fluoro-benzamidoethylpiperazine([18F]MPPF；5-HT1a受体)，(4- [18F]三苯基氯化膦([18F]BFPET；线粒体电压传感器)，[18F]奥曲肽 ([18F]TOC；神经内分泌肿瘤中的生长抑素2受体)；临床前兴趣：新 GAT-1 GABA转运体和多巴胺D3受体的放射性示踪剂以及 制药行业(BACE、食欲素受体)。这些目标将通过各种不同的 创新包括：(A)开发铜为亲核试剂的新方法 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的优化和(C)这些 方法进行临床验证的放射合成(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的铜介导的方法来合成18F标记的放射性示踪剂和 验证了许多重要放射性示踪剂的临床合成。这两个交付内容都将扩展实用程序 用于检测、治疗和预防疾病的PET成像。