Intramolecular Friedel-Crafts Acylation of [11C]Isocyanates Enabling the Radiolabeling of [carbonyl-11C]DPQ

Marius Ozenil; Lukas Kogler; Braeden A Mair; Marcus Hacker; Wolfgang Wadsak; Benjamin H Rotstein; Verena Pichler

doi:10.1002/chem.202400581

Intramolecular Friedel-Crafts Acylation of [¹¹C]Isocyanates Enabling the Radiolabeling of [carbonyl-¹¹C]DPQ

Chemistry. 2024 Mar 12:e202400581. doi: 10.1002/chem.202400581. Online ahead of print.

Authors

Marius Ozenil¹, Lukas Kogler^{2

3}, Braeden A Mair^{4

5}, Marcus Hacker¹, Wolfgang Wadsak^{1

3}, Benjamin H Rotstein^{4

5

6}, Verena Pichler²

Affiliations

¹ Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
² Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, University of Vienna, Josef-Holaubek-Platz 2, 1090, Vienna, Austria.
³ CBmed GmbH-Center for Biomarker Research in Medicine, Stiftingtalstraße 5, 8010, Graz, Austria.
⁴ Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie Curie Pvt, Ottawa, ON, K1 N 6 N5, Canada.
⁵ University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y 4 W7, Canada.
⁶ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8 M5, Canada.

PMID: 38470445
DOI: 10.1002/chem.202400581

Abstract

α,β-aromatic lactams are highly abundant in biologically active molecules, yet so far they cannot be radiolabeled with short-lived (t_1/2=20.3 min), β⁺-decaying carbon-11, which has prevented their application as positron emission tomography tracers. Herein, we developed, optimized, and applied a widely applicable, one-pot, quick, robust and automatable radiolabeling method for α,β-aromatic lactams starting from [¹¹C]CO₂ using the reagent POCl₃⋅AlCl₃. This method proceeds via intramolecular Friedel-Crafts acylation of in situ formed [¹¹C]isocyanates and shows a broad substrate scope for the formation of five- and six-membered rings. We implemented our developed labeling method for the radiosynthesis of the potential PARP1 PET tracer [carbonyl-¹¹C]DPQ in a clinical radiotracer production facility following the standards of the European Pharmacopoeia.

Keywords: PARP; PET tracer; carbon-11.