Synthesis of Intrinsically Disordered Fluorinated Peptides for Modular Design of High‐Signal ¹⁹F MRI Agents

Abstract

19F MRI is valuable for in vivo imaging due to the only trace amounts of fluorine in biological systems. Because of the low sensitivity of MRI however, designing new fluorochemicals remains a significant challenge for achieving sufficient 19F signal. Here, we describe a new class of high-signal, water-soluble fluorochemicals as 19F MRI imaging agents. A polyamide backbone is used for tuning the proteolytic stability to avoid retention within the body, which is a limitation of current state-of-the-art perfluorochemicals. We show that unstructured peptides containing alternating N-ε-trifluoroacetyllysine and lysine provide a degenerate 19F NMR signal. 19F MRI phantom images provide sufficient contrast at micromolar concentrations, showing promise for eventual clinical applications. Finally, the degenerate high signal characteristics were retained when conjugated to a large protein, indicating potential for in vivo targeting applications, including molecular imaging and cell tracking.

Lithium hexamethyldisilazide initiated superfast ring opening polymerization of alpha-amino acid N-carboxyanhydrides

“…Synthetic polypeptides are biocompatible and have a broad range of applications including protein/peptide mimicking 1–4 , antimicrobial agents and materials 5–14 , drug, and gene delivery 15–18 , tissue engineering and other biomaterial applications 19–25 . Polypeptides can be synthesized from the polymerization of α -amino acid N -carboxyanhydride (NCA), the Leuchs’ anhydride discovered in 1906 by Hermann Leuchs 26–28 .…”

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

“…Depending on the research target, 19 F NMR measurements can be used to study ligand–protein [ 12 ] and protein–protein interactions [ 13 ]; membrane proteins [ 14 – 16 ] and membrane-associated peptides [ 17 – 18 ]; equilibria among conformations of RNA [ 19 ], DNA [ 20 ], and peptide nucleic acids (PNA) [ 21 ]; and many others. Particularly recent is the development of peptide-based contrast agents for 19 F imaging [ 22 ].…”

Partially Fluorinated Copolymers as Oxygen Sensitive 19F MRI Agents

“…As imilarc oncept was recently expanded to disordered peptides by Pomerantz and co-workers. [64] Despite these advances, the water-soluble copolymer 19 FMRI agents studied to date do not have adequate sensitivity for use on clinically relevantt hree Te sla( T) instruments, which requires am inimum 126 mm local concentration of chemically equivalent 19 Fn uclei. [65] For example, the highest performing reported TFEA copolymer achieves ac oncentration of 100 mm local [ 19 F] at ac opolymer concentration of 20 mg mL À1 .…”