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

Abstract

Indirect radiolabelling has for a long time been the mainstay strategy for radiofluorination of biomolecules. Acylation of biomolecules through the use of an ¹⁸F-labelled activated ester is a standard method for indirect radiolabelling. However, the preparation of ¹⁸F-labelled activated esters is typically a complex and multistep procedure. Herein, we describe the use of 4-nitrophenyl (PNP) activated esters to rapidly prepare ¹⁸F-labelled acylation synthons in one step. Furthermore, we present a comparative study of PNP activated esters and the commonly utilised 2,3,5,6-tetrafluorphenyl (TFP) activated esters under direct radiofluorination conditions and demonstrate their relative acylation behaviour. We demonstrate the superiority of PNP esters under direct radiofluorination conditions with favourable acylation kinetics.

Fig. 1. [¹⁸F]-labelled acylating agents [¹⁸F]1, [¹⁸F]2 and [¹⁸F]3.

Fig. 2. Reported radiosynthesis of ester [¹⁸F]6 by direct radiofluorination using K₂₂₂·K[¹⁸F]F complex.

Fig. 3. The synthesis of precursors 16–19 from benzoic acid 8 and nicotinic acid 9.

Fig. 4. Radiofluorination of esters 16–19 to form the corresponding synthons [¹⁸F]2, [¹⁸F]6, [¹⁸F]20 and [¹⁸F]21. Yields of [¹⁸F]20 and [¹⁸F]21 presented as average of n = 3 ± standard deviation. *Labelling attempted only once.

Fig. 5. Acylation of esters [¹⁸F]20, [¹⁸F]21 and [¹⁸F]2 with benzylamine 22 to afford amidated products [¹⁸F]23 and [¹⁸F]24. % yield is the average of n = 3 with standard deviation bars shown.

Fig. 6. Radiolabelling of c(RGDyK) peptide 25 with PNP esters [¹⁸F]20 and [¹⁸F]21.