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 1 . Both tritium and carbon-11 radioisotopologues are generally necessary for in vitro and in vivo characterization of radioligands 2 , 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 [ 11 C]UCB-J and [ 11 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. A versatile and rapid metallaphotoredox catalytic method of making 3 H- and 11 C-labelled tracer compounds for use in positron emission tomography (PET) is reported.

中文翻译：

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用于 PET 配体发现的金属光氧化还原芳基和烷基放射性甲基化

正电子发射断层扫描 (PET) 放射性配体（放射性标记的示踪化合物）对于中枢神经系统候选药物、神经退行性疾病和众多肿瘤学目标 1 的体内表征非常有用。氚和碳 11 放射性同位素体通常对于放射性配体 2 的体外和体内表征都是必需的，但几乎没有用于合成任何一种的放射性标记协议，从而抑制了 PET 放射性配体的发展。由于碳 11 的半衰期短，此类放射性配体的合成也需要非常快速。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，用于通过甲基化带有芳基溴和烷基溴的药物前体将氚和碳 11 后期安装到所需的化合物中。甲基是生物活性分子中最普遍的结构元素之一，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，我们进行了 20 种氚化和 10 种碳 11 标记的复杂药物和 PET 放射性配体的快速合成，包括临床使用的化合物 [ 11 C]UCB-J 和 [ 11 C]PHNO。我们进一步概述了该协议在临床前 PET 成像中的直接效用，并将其转化为用于人类临床成像中常规放射性示踪剂生产的自动放射合成。我们还展示了该协议，用于安装其他多种和药学上有用的同位素，包括碳 14、碳 13 和氘。