Merck Center for Catalysis at Princeton University, Princeton, NJ, USA.
Labeled Compound Synthesis Group, Department of Process R&D, MRL, Merck & Co., Rahway, NJ, USA.
Nature. 2021 Jan;589(7843):542-547. doi: 10.1038/s41586-020-3015-0. Epub 2020 Nov 25.
Positron emission tomography (PET) radioligands (radioactively labelled tracer compounds) are extremely useful for in vivo characterization of central nervous system drug candidates, neurodegenerative diseases and numerous oncology targets. Both tritium and carbon-11 radioisotopologues are generally necessary for in vitro and in vivo characterization of radioligands, yet there exist few radiolabelling protocols for the synthesis of either, inhibiting the development of PET radioligands. The synthesis of such radioligands also needs to be very rapid owing to the short half-life of carbon-11. Here we report a versatile and rapid metallaphotoredox-catalysed method for late-stage installation of both tritium and carbon-11 into the desired compounds via methylation of pharmaceutical precursors bearing aryl and alkyl bromides. Methyl groups are among the most prevalent structural elements found in bioactive molecules, and so this synthetic approach simplifies the discovery of radioligands. To demonstrate the breadth of applicability of this technique, we perform rapid synthesis of 20 tritiated and 10 carbon-11-labelled complex pharmaceuticals and PET radioligands, including a one-step radiosynthesis of the clinically used compounds [C]UCB-J and [C]PHNO. We further outline the direct utility of this protocol for preclinical PET imaging and its translation to automated radiosynthesis for routine radiotracer production in human clinical imaging. We also demonstrate this protocol for the installation of other diverse and pharmaceutically useful isotopes, including carbon-14, carbon-13 and deuterium.
正电子发射断层扫描（PET）放射性配体（放射性标记示踪化合物）对于中枢神经系统候选药物、神经退行性疾病和许多肿瘤学靶标的体内特征描述非常有用。氚和碳-11 放射性同位素通常都是放射性配体进行体外和体内特征描述所必需的，但几乎没有用于合成这两种同位素的放射性标记方案，这抑制了 PET 放射性配体的发展。由于碳-11 的半衰期很短，因此此类放射性配体的合成也需要非常迅速。在这里，我们报告了一种通用且快速的金属光氧化还原催化方法，通过含有芳基和烷基溴化物的药物前体的甲基化，在晚期将氚和碳-11 掺入所需化合物中。甲基是生物活性分子中最常见的结构元素之一，因此这种合成方法简化了放射性配体的发现。为了证明该技术的广泛适用性，我们快速合成了 20 个氚化和 10 个碳-11 标记的复杂药物和 PET 放射性配体，包括一种用于临床使用的化合物 [C]UCB-J 和 [C]PHNO 的一步法放射性合成。我们进一步概述了该方案在临床前 PET 成像中的直接应用及其转化为自动化放射性合成，以常规生产人类临床成像中的放射性示踪剂。我们还展示了该方案在安装其他不同且具有药物用途的同位素方面的应用，包括碳-14、碳-13 和氘。
