4-Nitrophenyl activated esters are superior synthons for indirect radiofluorination of biomolecules

Abstract

<p>A comparative study of PNP- and TFP-activated esters of radiolabelled prosthetic groups demonstrates the superiority of PNP esters in terms of stability and yields for use in one-step radiolabelling of small molecules and peptides.</p>

DNAzymes for amine and peptide lysine acylation

“…We then performed in vitro selection experiments with acyl donor oligonucleotides activated in situ from their 5-carboxylic acid (5-CO2H) precursors using two common amide-forming coupling reagents, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4methylmorpholinium chloride (DMT-MM) 67 or the combination of the water-soluble 1-ethyl-3-(3dimethylaminopropyl)carbodiimide (EDC) and 2,3,5,6-tetrafluorophenol (TFP). [68][69][70][71] Before performing in vitro selection, the resulting DMT and TFP esters (here abbreviated DMTE and TFPE; structures in Figure 1C) were assayed for their uncatalyzed background reactivities, using a DNA splint complementary to the DNA-anchored acyl donor and the simple DNA-anchored amine nucleophile (DNA-C3-NH2; Figure 2A,B). Both DMTE and TFPE led to relatively high uncatalyzed background reactivity, with substantial formation of acylation product; e.g., 34% amide formation in 0.5 min (DMTE) and 15% amide formation in 0.5 min (TFPE), each assessed at pH 7.0.…”

Radiolabelled Peptides: Optimal Candidates for Theranostic Application in Oncology

“…We have recently developed pre-activated 4-nitrophenyl esters as superior intermediates that can facilitate radiofluorination at elevated temperatures (1008C), while still activated enough to acylate peptides quantitatively at room temperature. [190] This methodology was adopted to prepare 4-nitrophenyl 2-[ 18 F]fluoropropionate [190,191] and analogues of the most useful prosthetic groups, N-succinimidyl 4-[ 18 F]fluorobenzoate and 2,3,5,6-tetrafluorophenyl 6-[ 18 F]fluoronicotinate, in one step [191] (Fig. 17).…”

“…These developments constitute a major breakthrough for the indirect radiofluorination of peptides. [191,192] More recently, the notion that peptides are unamenable to direct radiofluorination, necessitating the use of F-18 labelled prosthetic groups, has been challenged. Both F-18 labelled PSMA analogues PSMA-1007 and DCFPyl (discussed above) are now being routinely prepared by direct radiofluorination of the fully unprotected peptide with a pyridine quaternary ammonium salt precursor (Fig.…”

“…Bottom panel: shows our improved methods for preparing these prosthetic groups in one-step, mediated by the enhanced stability of the p-Nitrophenyl (PNP) activated ester (labelled blue). [190,191] remains unknown. As such there is a need for intensive research to understand and optimise the factors that govern direct radiofluorination of peptides and to evaluate its adaptability to diverse peptide scaffolds.…”

“…Top panel: shows the chemical structures of the common acylating prosthetic groups (labelled blue). Bottom panel: shows our improved methods for preparing these prosthetic groups in one-step, mediated by the enhanced stability of the p-Nitrophenyl (PNP) activated ester (labelled blue) [190,191].…”