Chemoselective pre-conjugate radiohalogenation of unprotected mono- and multimeric peptides via oxime formation

Thorsten Poethko, Margret Schottelius, Georgette Thumshirn, Michael Herz, Roland Haubner, Gjermund Henriksen, Horst Kessler, Markus Schwaiger, Hans Jürgen Wester

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As part of our ongoing efforts in the development of new 18F-labeled peptides for clinical PET imaging, a new two-step 18F-labeling methodology based on the chemoselective oxime formation between an unprotected aminooxy-functionalized peptide and a 18F-labeled aldehyde was investigated and optimized. 4-[ 18F]Fluorobenzaldehyde ([18F]FB-CHO) was prepared by direct n.c.a. fluorination of 4-formyl-N,N,N-trimethylanilinium triflate and purified by radio-HPLC or a strong-cation-exchange/reverse phase cartridge system. The aminooxyacetic acid (Aoa) modified model peptide LEF-NH2 (Leu-Glu-Phe-NH2) and monomeric, dimeric and tetrameric RGD-containing cyclopeptides were synthesized by solid phase peptide synthesis. Radiochemical yields of N-(4-[18F]fluorobenzylidene)-oxime-formation ([18F]FBOA) with the Aoa-modified unprotected peptides were investigated. Optimized reaction conditions (60 °C, 0.5 mM peptide, 15 min, aqueous solution, pH 2.5) resulted in 70%-90% conjugation yields for all unprotected peptides studied. Chemoselectivity was demonstrated in competition experiments with amino acid mixtures. Biodistribution in M21 melanoma bearing mice showed improved tumor uptake and excretion behaviour in the series c(RGDfE)HEG-Dpr-[18F]FBOA < (c(RGDfE)HEG)2K-Dpr-[ 18F]FBOA < ((c(RGDfE)HEG)2K)2K-Dpr-[ 18F]FBOA. Two hours p.i. the fraction of intact c(RGDfE)HEG-K-Dpr- [18F]FBOA in blood, liver, kidney and tumor was > 90%, indicating high in vivo stability of the oxime linkage. Initial PET studies with ((c(RGDfE)HEG)2-K)2-K-Dpr-[18F]FBOA showed excellent imaging of M21-melanomas in mice. In conclusion, the new two-step chemoselective 18F-labeling fulfills all requirements for large scale syntheses of peptides in clinical routine. This methodology is also adaptable to other radioisotopes (e.g. radiohalogenation in general) and will thus offer a broad field of application.

Original languageEnglish
Pages (from-to)317-327
Number of pages11
JournalRadiochimica Acta
Issue number4-6
StatePublished - 2004


  • Chemoselective labeling
  • Fluorine-18
  • PET
  • Peptide labeling
  • Radiohalogenation


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