18F-Trifluoromethanesulfinate Enables Direct C-H 18F-Trifluoromethylation of Native Aromatic Residues in Peptides.

Choon Wee Kee,Sven Macholl,Patrick G Isenegger,Juliette Chupin,Stefan Verhoog,Bart Cornelissen,Sharon Ashworth,Jan Passchier,Véronique Gouverneur,Christophe Plisson,Osman Tack,Thomas C Wilson,Michael C Willis,Florian Guibbal,Giulia Boscutti,Mateusz Imiołek,Roxana Kashani,Adeline W J Poh,Benjamin G Davis,Jane Sosabowski ,Michael J Tilby

doi:10.1021/jacs.9b11709

Abstract

18F labeling strategies for unmodified peptides with [18F]fluoride require 18F-labeled prosthetics for bioconjugation more often with cysteine thiols or lysine amines. Here we explore selective radical chemistry to target aromatic residues applying C–H 18F-trifluoromethylation. We report a one-step route to [18F]CF3SO2NH4 from [18F]fluoride and its application to direct [18F]CF3 incorporation at tryptophan or tyrosine residues using unmodified peptides as complex as recombinant human insulin. The fully automated radiosynthesis of octreotide[Trp(2-CF218F)] enables in vivo positron emission tomography imaging.

Highlights

18F labeling strategies for unmodified peptides with [18F]fluoride require 18F-labeled prosthetics for bioconjugation more often with cysteine thiols or lysine amines
Additional challenges imposed by radiochemistry include low reaction concentration, solvent compatibility, and the fact that cyclotron-produced 18F sources are limited to 18F-fluoride and [18F]F2
Formation of is known,[29−31] so the challenge was to validate a protocol that couples in situgenerated [18F]CF3− with SO2 (Scheme 1B)

Summary

SO and

Formation of is known,[29−31] so the challenge was to validate a protocol that couples in situgenerated [18F]CF3− with SO2 (or a surrogate of this gaseous and toxic reagent) (Scheme 1B). The synthesis time for the 18F-labeled peptide from [18F]CF3SO2NH4 was 90 min.[32] was performed in the presence of TBHP and Fe(NO3)3· 9H2O36 in DMSO/aqueous ammonium formate at 40 °C for 20 min (Scheme 3).32 18F-trifluoromethylation at C2 was detected in 2% RCC. These two regioisomers are separable by HPLC. This issue was solved by changing the difluorocarbene source to ClF2CCO2Me, a reagent activated with (2-biphenyl)di-tert-butylphosphine (JohnPhos), and the solvent to DMA; no change was required for NMM·SO2 With these modifications, starting from up to 45 GBq of [18F]fluoride, [18F]CF3SO2NH4 was produced in up to 6% ± 1% activity yield (non-decay-corrected, n = 2) after semipreparative HPLC (Am = 1.13 GBq/μmol, synthesis time = 40 min). Characterization of new compounds, automation protocol, and in vivo experiments (PDF)

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■ ACKNOWLEDGMENTS

Findings

■ REFERENCES