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This report describes a copper-mediated radiocyanation of aryl halides that is applicable to complex molecules. This transformation tolerates an exceptionally wide range of functional groups, including unprotected amino acids. As such, it enables the site-specific introduction of (11)C[CN] into peptides at an iodophenylalanine residue. The use of a diamine-ligated copper(I) mediator is crucial for achieving high radiochemical yield under relatively mild conditions, thus limiting racemization and competing side reactions of other amino acid side chains. The reaction has been scaled and automated to deliver radiolabeled peptides, including analogues of adrenocorticotropic hormone 1–27 (ACTH) and nociceptin (NOP). For instance, this Cu-mediated radiocyanation was leveraged to prepare >40 mCi of [(11)C]cyano-NOP to evaluate biodistribution in a primate using positron emission tomography. This investigation provides preliminary evidence that nociceptin crosses the blood-brain barrier and shows uptake across all brain regions (SUV >1 at 60 min post-injection), consistent with the known distribution of NOP receptors in the rhesus brain.

Positron emission tomography (PET) is an important non-invasive tool to help guide the drug discovery and development process. Positron-emitting–radiolabeled drug candidates represent an important tool for drug hunters to gain insight into a drug's biodistribution and target engagement of exploratory biologic targets of interest. Recently, there have been several drug candidates that incorporate an acryloyl functional group due to their ability to form a covalent bond within the biological target of interest through Michael addition. Methods to incorporate a carbon-11 radionuclide into acrylamide derivatives remain challenging given the reactive nature of this moiety. Herein, we report the improved radiosynthesis of carbon-11–containing acrylamide drug candidates, [11C]ibrutinib, [11C]tolebrutinib, and [11C]evobrutinib, using [11C]CO and a novel “in-loop” 11C-carbonylation reaction. [11C]Ibrutinib, [11C]tolebrutinib, and [11C]evobrutinib were reliably synthesized, generating 2.2-7.1 GBq of these radiopharmaceuticals in radiochemical yields ranging from 3.3 to 12.8% (non-decay corrected; relative to starting [11C]CO2) and molar activities of 281-500 GBq/μmol (7.5-13.5 Ci/μmol), respectively. This study highlights an improved method for incorporating carbon-11 into acrylamide drug candidates using [11C]CO within an HPLC loop suitable for clinical translation using simple modifications of standard automated synthesis modules used for cGMP manufacture of PET radioligands.