Two-step methodology for high-yield routine radiohalogenation of peptides: 18F-labeled RGD and octreotide analogs

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

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Routine application of 18F-labeled peptides for quantitative in vivo receptor imaging of receptor-expressing tissues and quantification of receptor status using PET is limited by the lack of appropriate radiofluorination methods for routine large-scale synthesis of 18F-labeled peptides. To satisfy this demand, a new 18F-labeling methodology based on the chemoselective oxime formation between an unprotected aminooxy-functionalized peptide and an 18F-labeled aldehyde or ketone was investigated and optimized with respect to peptide conjugation. Methods: 4-[18F]Fluorobenzaldehyde ([18F]FB-CHO) was prepared from the 4-formyl-N,N,N-trimethylanilinium precursor via direct no-carrier-added 18F-fluorination (dimethyl sulfoxide, 60°C, 15 min) and purified using a cation-exchange/reversed-phase cartridge system. Radiochemical yields (RCYs) of N-(4-[18F] fluorobenzylidene) oxime ([18F]FBOA) formation with various aminooxy-modified peptides such as minigastrin, RGD, and octreotate analogs were investigated as a function of reaction time and temperature, peptide concentration, and pH. Biodistribution studies were performed with an [ 18F]FBOA-RGD dimer ((c(RGDfE)-HEG)2-K-Dpr-[ 18F]FBOA, 60 and 120 min after injection) and a gylcosylated [ 18F]FB-Tyr3-octreotate (Gluc-S-Dpr([18F]FBOA)- TOCA), 10 and 60 min after injection) using M21 and M21L human melanoma and AR42J rat pancreatic tumor-bearing nude mice, respectively. Results: [ 18F]FB-CHO was obtained in a nonoptimized RCY of 50% within 30 min. At low peptide concentrations (0.5 mmol/L), optimal [18F]FBOA- labeling efficiencies (60%-80%) were obtained within 15 min at 60°C and pH 2-3, independently of the peptide used, affording the [18F]FBOA- peptides in overall RCYs of up to 40% (from end of bombardment) after purification. Both (c(RGDfE)HEG)2-K-Dpr-[18F]FBOA and Gluc-S-Dpr([18F]FBOA)TOCA showed pharmacokinetics suitable for early (≤60 min) high-contrast PET imaging, high tumor uptake (2.48 ± 0.15 %ID/g [RGD] and 21.8 ± 1.4 %ID/g [TOCA] at 60 min after injection, where %ID/g = percentage injected dose per gram), and tumor-to-organ ratios that compared well with the corresponding [18F]fluoropropionyl analogs [18F] Galacto-RGD and Gluc-Lys([18F]FP)TOCA, which are prepared via multistep procedures. Conclusion: Oxime formation between aminooxy-functionalized peptides and an 18F-labeled aldehyde or ketone - in this case, [18F]FB-CHO - combines fast 1-step, high-yield synthesis of an 18F-labeled prosthetic group stable against in vivo defluorination with rapid, 1-step chemoselective conjugation to unprotected peptides under mild conditions. Thus, it allows fast and straightforward large-scale production of 18F-labeled peptides for clinical routine PET application. Furthermore, it opens new perspectives to peptide radiohalogenation in general, permitting labeling of the same precursor both with diagnostic (18F, 124I, 120gI, 123I) and therapeutic (211At, 131I) radiohalogens.

Original languageEnglish
Pages (from-to)892-902
Number of pages11
JournalJournal of Nuclear Medicine
Issue number5
StatePublished - 1 May 2004


  • F
  • PET
  • Peptides
  • Radiohalogenation


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