¹⁸F-Fluoroglucosylation of peptides, exemplified on cyclo(RGDfK)

Oxime formation between an aminooxy-functionalized peptide and an ¹⁸F-labelled aldehyde has recently been introduced as a powerful method for the rapid one-step chemoselective synthesis of radiofluorinated peptides.

Here, the potential of using routinely produced and thus readily available [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) as the aldehydic prosthetic group was investigated using an aminooxyacetyl-conjugated cyclic RGD peptide (cyclo(RGDfK(Aoa-(Boc)) as a model peptide.

The use of [¹⁸F]FDG from routine production ([¹⁸F]FDGTUM) containing an excess of d-glucose did not allow the radiosynthesis of [¹⁸F]FDG-RGD in activities >37 MBq in reasonable yield, rendering the direct use of clinical grade [¹⁸F]FDG for the routine clinical synthesis of ¹⁸F-labelled peptides impossible. Using no-carrier-added (n.c.a.) [¹⁸F]FDG obtained via HPLC separation of [¹⁸F]FDGTUM from excess glucose, however, afforded [¹⁸F]FDG-RGD in yields of 56–93% (decay corrected) and activities up to 37 MBq. Suitable reaction conditions were 20 min at 120°C and pH 2.5, and a peptide concentration of 5 mM. In a preliminary in vivo biodistribution study in M21 melanoma-bearing nude mice, [¹⁸F]FDG-RGD showed increased tumour accumulation compared to the “gold standard” [¹⁸F]galacto-RGD (2.18 vs 1.49 %iD/g, respectively, at 120 min after injection), but also slightly increased uptake in non-target organs, leading to comparable tumour/organ ratios for both compounds.

These data demonstrate that chemoselective ¹⁸F-labelling of aminooxy-functionalized peptides using n.c.a. [¹⁸F]FDG represents a radiofluorination/glycosylation strategy that allows preparation of ¹⁸F-labelled peptides in high yield with suitable pharmacokinetics. As soon as the necessary n.c.a. preparation of [¹⁸F]FDG prior to reaction with the Aoa-peptide can be implemented in a fully automated [¹⁸F]FDG-synthesis, [¹⁸F]fluoroglucosylation of peptides may represent a promising alternative to currently used chemoselective one-step ¹⁸F-labelling protocols.