Author
Listed:
- Robert W. Pipal
(Merck Center for Catalysis at Princeton University)
- Kenneth T. Stout
(Merck Center for Catalysis at Princeton University)
- Patricia Z. Musacchio
(Merck Center for Catalysis at Princeton University)
- Sumei Ren
(MRL, Merck & Co.)
- Thomas J. A. Graham
(University of Pennsylvania)
- Stefan Verhoog
(MRL, Merck & Co.)
- Liza Gantert
(MRL, Merck & Co.)
- Talakad G. Lohith
(MRL, Merck & Co.)
- Alexander Schmitz
(University of Pennsylvania)
- Hsiaoju S. Lee
(University of Pennsylvania)
- David Hesk
(MRL, Merck & Co.
RTI International)
- Eric D. Hostetler
(MRL, Merck & Co.)
- Ian W. Davies
(Merck Center for Catalysis at Princeton University)
- David W. C. MacMillan
(Merck Center for Catalysis at Princeton University)
Abstract
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 targets1. Both tritium and carbon-11 radioisotopologues are generally necessary for in vitro and in vivo characterization of radioligands2, 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 [11C]UCB-J and [11C]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.
Suggested Citation
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 & Eri, 2021.
"Metallaphotoredox aryl and alkyl radiomethylation for PET ligand discovery,"
Nature, Nature, vol. 589(7843), pages 542-547, January.
Handle:
RePEc:nat:nature:v:589:y:2021:i:7843:d:10.1038_s41586-020-3015-0
DOI: 10.1038/s41586-020-3015-0
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Citations
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Cited by:
- Mengjie Jiao & Jie Zhang & Minyan Wang & Hongjian Lu & Zhuangzhi Shi, 2024.
"Metallaphotoredox deuteroalkylation utilizing thianthrenium salts,"
Nature Communications, Nature, vol. 15(1), pages 1-11, December.
- Malek Y. S. Ibrahim & Milad Abolhasani, 2022.
"Recyclable cooperative catalyst for accelerated hydroaminomethylation of hindered amines in a continuous segmented flow reactor,"
Nature Communications, Nature, vol. 13(1), pages 1-13, December.
- Jian Rong & Ahmed Haider & Troels E. Jeppesen & Lee Josephson & Steven H. Liang, 2023.
"Radiochemistry for positron emission tomography,"
Nature Communications, Nature, vol. 14(1), pages 1-23, December.
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