Abstract
The excesses of reagents used in protein chemistry are often incompatible with the reduced or even inverse stoichiometries used for efficient radiolabeling. Analysis and screening of aqueous Pd(0) ligand systems has revealed the importance of a guanidine core and the discovery of 1,1-dimethylguanidine as an enhanced ligand for aqueous Suzuki–Miyaura cross-coupling. This novel Pd catalyst system has now allowed the labeling of small molecules, peptides, and proteins with the fluorine-18 prosthetic [18F]4-fluorophenylboronic acid. These findings now enable site-specific protein 18F-labeling under biologically compatible conditions using a metal-triggered reaction.
Highlights
P eptides and proteins have been increasingly applied as substrates for positron emission tomography (PET) tracers, but such tracers remain difficult to create.[1−6] Their application requires practical methods to incorporate positron emission nuclides
Using a “tag-and-modify” approach[26] in our research in protein post-translational modification, we have demonstrated efficient Suzuki−Miyaura coupling (SMC) on proteins under biologically compatible conditions.[27−31] Suitable aryl iodidecontaining “tag” residues may be site- introduced into proteins either by chemical modification[27] or in a genetically encoded manner[28,29,31] with great site flexibility, making this a useful strategy for metal-mediated protein-labeling
We describe the development of an enhanced aqueous Pd ligand system that enables Pdmediated protein and peptide 18F-labeling
Summary
To probe the limits of the SMC, and so test its possible utility under such stringent conditions, we explored key parameters. Palladium catalyst was scavenged by 3mercaptopropionic acid[28] before the protein product 14 was purified by size-exclusion chromatography down to levels as low as 1 ppm Pd (as measured by ICP-OES, see SI) Even under these conditions, detection of radiolabeled protein was confirmed by HPLC (Scheme 3c) with a RCY of ∼2−5% from boronic acid 1 (decay-corrected);[49] addition of 2 equiv of carrier [19F]1 did not improve the yield. Pd-catalyzed cross-coupling reactions under extreme conditions (biomacromolecules, biocompatible aqueous context, low concentrations and excesses, and short time frames dictated by isotope half-life) to allow detectable 18F-protein-labeling This was enabled by the discovery of the enhanced, readily available Pd ligand L3.
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