Direct ¹¹CN-Labeling of Unprotected Peptides via Palladium-Mediated Sequential Cross-Coupling Reactions

Abstract

A practical procedure for 11CN-labeling of native peptides has been developed. The process involves two sequential Pd-mediated cross-coupling reactions at the cysteine residue of a peptide and operates under mild conditions. The method was shown to be highly chemoselective for cysteine over other potentially nucleophilic residues and the radiolabelled products were synthesized and purified in less than 15 minutes. Appropriate for biomedical applications, the method could be used on extremely small scale (20 nmol) with high radiochemical yield. The success of the protocol stems from the use of a Pd-reagent based on a dihaloarene, which enables direct “nucleophile-nucleophile” coupling of the peptide and [11C]-cyanide by temporal separation of nucleophile addition.

Arylation Chemistry for Bioconjugation

“…[171] Later in 2018, Buchwald and Pentelute created palladiumbased bi-functional linkers for both inter-and intra-molecular crosslinking of cysteine and lysine residues in peptides and proteins. [171] Later in 2018, Buchwald and Pentelute created palladiumbased bi-functional linkers for both inter-and intra-molecular crosslinking of cysteine and lysine residues in peptides and proteins.…”

Site‐Specific Deoxyfluorination of Small Peptides with [18F]Fluoride

“…[6b] There are several examples of the introduction of smaller labeled prosthetic groups to peptides,which can be expected to alter the properties of the peptides to as maller extent. [10] Unnatural peptides have been labeled through biorthogonal 1,3-dipolar cycloaddition with [ 18 F]-containing alkynes ( Figure 1C). [10] Unnatural peptides have been labeled through biorthogonal 1,3-dipolar cycloaddition with [ 18 F]-containing alkynes ( Figure 1C).…”

Chemistry for Positron Emission Tomography: Recent Advances in 11C‐, 18F‐, 13N‐, and 15O‐Labeling Reactions

“…[12] Representative examples of Pd-mediated reactions include the formation of [ 11 C]AZD9272 and of compounds derived from aryl-11 CN, such as [ 11 C]NAD-299. [67] Thef ormal "nucleophile-nucleophile coupling" provided 11 C-labeled peptides in high RCY (10-50 %). [66] These biaryl phosphine ligands,for example, t-BuXPhos or BrettPhos,were the key to stabilizing the Pd-aryl complex and accelerating the transmetalation and reductive elimination under mild reaction conditions.T hese authors further extended this concept to the labeling of cysteine-containing peptides by asequential Pd-mediated CÀSa nd CÀ 11 CN bonding formation in ao nepot reaction.…”