Fast 18F-fluoroethylation without azeotropic drying in the radiosynthesis of cyclooxygenase-2 inhibitors


Fast 18F-fluoroethylation without azeotropic drying in the radiosynthesis of cyclooxygenase-2 inhibitors

Kniess, T.; Laube, M.; Pietzsch, J.; Steinbach, J.

Objectives: 18F-Fluoroethylation is a basic approach in PET labeling chemistry and 2-[18F]fluoroethyl tosylate ([18F]FETs) is one of the mostly used agents. Usual protocols with [18F]FETs are covering the azeotropic drying of [18F]fluoride, nucleophilic substitution, purification and 18F-fluoroethylation within 60-90 min synthesis time. We developed a fast 18F-fluoroethylation avoiding azeotropic drying to yield e.g. 18F-fluoroethylated cyclooxygenase-2 (COX-2) inhibitors within 25 min.
Methods: Our approach is based on the finding that [18F]fluoride trapped on SAX cartridges can be completely eluted by a mixture of K222/K2CO3/acetonitrile/2% water and is bsufficiently reactive for 18F-labeling. [1,2] [18F]Fluoride, trapped on the SAX cartridge is eluted with 0.7 mL K222/K2CO3/acetonitrile/H2O into a vial containing 20 μmol bis-tosylate precursor. The vial is heated 10 min at 100°C, than 20 μmol hydroxyl precursor and 40 μmol Cs2CO3 dissolved in 0.5 mL DMF are added. Additional heating for 10 min at 110°C yields the 18Ffluoroethylated COX-2 radiotracers, by almost complete consumption of [18F]FETs. We used three different precursors to build COX-2 inhibitors (Fig) as model compounds to elucidate 18F-fluoroethylation.
Results: By elution of the SAX cartridge (46 mg) with K222/K2CO3/acetonitrile/H2O (42 μmol, 21 μmol, 679 μL, 21 μL) the adsorbed activity could be tranferred nearly quantitatively (93-95%). [18F]FETs was formed in 79-88% rcy as confirmed by radio-TLC. Subsequent 18F-fluoroethylation of the corresponding hydroxyl precursors resulted in yields of 77-92% (n=7) in case of the cyclopentene (1), 54-65% (n=3) for the pyrazolo[1,5-b]pyridazine (2), and 44-70% (n=3) for the indomethacine (3).
Conclusions: The [18F]KF/K222/K2CO3/H2O complex, formed without azeotropic drying is highly reactive to form [18F]FETs in yields up to 88%. Hence the reaction time can be shortened resulting in fast 18F-fluoethylations with total radiochemical yields up to 92% as exemplified for three radiolabeled COX-2 inhibitors.
References
[1] Wessmann S.H. et al., Nuklearmedizin, 2012, 51, 1-8
[2] Kolb H.C. et al., J.Label.Compd.Radiopharm.,2011, 54, S518

  • Poster
    21st International Symposium on Radiopharmaceutical Sciences (ISRS), 26.-31.05.2015, Columbia/Missouri, USA
  • Open Access Logo Abstract in refereed journal
    Journal of Labelled Compounds and Radiopharmaceuticals 58(2015), S169
    DOI: 10.1002/jlcr.3302_2

Permalink: https://www.hzdr.de/publications/Publ-22087
Publ.-Id: 22087