美国普林斯顿大学默克催化中心David W. C. MacMillan研究小组经过不懈努力，通过金属光氧化还原催化的芳基/烷基放射性甲基化反应，实现了一系列正电子发射成像（PET）分子的快速高效合成。相关论文于2020年11月25日发表在《自然》杂志上。
研究团队报道了一种广泛适用的金属光氧化还原催化反应，该反应可用于在合成后期向溴代芳基/烷基药物分子前体安装氚代或含11C的甲基，从而简化了放射性配体的发现过程。为证明该技术广泛的应用范围，研究人员进行了20种氚代和10种11C标记的复杂药物和PET放射性配体的快速合成，包括临床中使用的[11C]UCB-J和[11C]PHNO的一步放射性合成。
研究人员还进一步概述了该方法在临床前PET成像中的直接应用，以及该方法在自动化放射合成用于人体临床成像示踪剂的日常生产中的转化应用。另外，该方法还可以拓展到其他多种同位素，包括14C，13C和氘的安装中，非常有利于新药项目的开发。
据悉，正电子发射断层扫描（PET）的放射性配体是一种可用于在体内对中枢神经系统、药物候选分子、神经退行性病变以及许多肿瘤靶点成像的高度先进的示踪手段。尽管体外或体内的放射性配体示踪普遍需要氚代或含11C的放射性同位素，但目前几乎没有用于合成这两者的同位素标记方法，限制了PET放射性配体的发展。
附：英文原文
Title: Metallaphotoredox aryl and alkyl radiomethylation for PET ligand discovery
Author: Robert W. Pipal, Kenneth T. Stout, Patricia Z. Musacchio, Sumei Ren, Thomas J. A. Graham, Stefan Verhoog, Liza Gantert, Talakad G. Lohith, Alexander Schmitz, Hsiaoju S. Lee, David Hesk, Eric D. Hostetler, Ian W. Davies, David W. C. MacMillan
Issue&Volume: 2020-11-25
Abstract: Positron emission tomography (PET) radioligands are highly enabling tracers which facilitate in vivo characterization of central nervous system (CNS) drug candidates, neurodegenerative diseases, and numerous oncology targets. While both tritium and carbon-11 radioisotopologs are generally necessary for in vitro and in vivo characterization of radioligands, there exist few radiolabeling protocols for the synthesis of either, inhibiting the development of PET radioligands. Here, we report a broadly useful metallaphotoredox-catalyzed method for late-stage installation of both tritium and carbon-11 via methylation of pharmaceutical precursors bearing aryl and alkyl bromides, simplifying radioligand discovery. To demonstrate the breadth of applicability of this technology, the rapid synthesis of 20 tritiated and 10 carbon-11-labeled complex pharmaceuticals and PET radioligands has been conducted, including a one-step radiosynthesis of clinically utilized [11C]UCB-J and [11C]PHNO. We have further outlined the direct utility of this protocol for preclinical PET imaging and its translation to automated radiosynthesis for routine radiotracer production in human clinical imaging. Last, this protocol has been expanded to the installation of other diverse isotopes, including carbon-14, carbon-13, and deuterium, an enabling feature for the development of pharmaceutical programs.
DOI: 10.1038/s41586-020-3015-0
Source: https://www.nature.com/articles/s41586-020-3015-0