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 targets1. While both tritium and carbon-11 radioisotopologs are generally necessary for in vitro and in vivo characterization of radioligands2, 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.
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