Publications Repository - Helmholtz-Zentrum Dresden-Rossendorf

2 Publications
McMurry cyclization in 18F-labeling - radiosynthesis of a 2,3-diarylsubstituted COX-2 inhibitor
Laube, M.; Kniess, T.; Bergmann, R.; Steinbach, J.; Pietzsch, J.;
Cyclooxygenase-2 (COX-2) is an inducible enzyme overexpressed under inflammatory conditions and is assumed to play a key role in cancerogenesis. Functional imaging of COX-2 expression in vivo by means of COX-2 inhibitors radiolabeled with positron emitters is a challenging approach, e.g., for differentiation of inflammatory processes and cancer1. Despite of different attempts, up to now a suitable radiotracer for COX-2 expression is unavailable. We developed an 18F-labeled COX-2 inhibitor [18F]3 from the type of a 2,3-diarylsubstituted indole via the McMurry cyclization. Thereby, with this labeling approach we got access with [18F]fluoride to the indole system which is, in principle, poorly activated for a nucleophilic substitution.
The potent COX-2 inhibitor 3 (IC50=0.02 μmol) was synthesized as reference compound2. The labeling precursor 1 bearing a trimethylammonium leaving group was obtained in a six-step synthesis sequence. The radiolabeling reaction was performed as an one pot-two step procedure starting first by introduction of [18F]fluoride by a nucleophilic substitution at 1 followed by McMurry cyclization to form the indole core structure (Figure 1). The radiosynthesis was carried out with an automated nucleophilic synthesizer TracerLABFXN (GE) and has been optimized with respect of the base, solvent, and temperature. Purification of [18F]3 was performed by semi-preparative HPLC and SPE with C18 cartridges.
Considering a set of optimization experiments it turned out that for the McMurry cyclization the use of THF is inevitable. Hence, the radiolabeling was performed in acetonitrile at 110-120°C, the solvent was removed under vacuum, and the McMurry reaction was run in pure THF at 90-100°C. Under these conditions the intermediate [18F]2 was formed in 10-15% yield and the cyclization step provided the desired McMurry product [18F]3 in 50-82% yield. A typical module assisted radiosynthesis of [18F]3 starting with 8 GBq of [18F]fluoride and 15 mg precursor 1 yielded 490 MBq of [18F]3 (10% overall yield d.c.) within 80 min synthesis time. The radiochemical purity of [18F]3 after HPLC purification was > 98% and the specific activity was determined to be 74-91 GBq/μmol at end of synthesis.
A highly potent and selective COX-2 inhibitor from type of a 2,3-diarylsubstituted indole was labeled with fluorine-18 in a two step fully automated radiosynthesis giving a potential PET tracer for functional imaging of COX-2 in vivo. In best to our knowledge, this is the first time that McMurry cyclization was utilized in PET-chemistry as labeling approach to get access to poorly activated compounds by nucleophilic substitutions with [18F]fluoride. In vitro stability studies in rat plasma and blood and in vivo studies in rats showed high stability of [18F]3 over two hours. Cell uptake studies with [18F]3 in THP-1, FaDu, HT29, A2058 and A375 cell lines are under the way as well as small animal PET investigations in HT29 mouse xenograft models.
[1] Kuge et al., (2009), Nucl. Med. Biol., 36, 869-876,
[2] Hu et al., (2003), Bioorg. & Med. Chem.,11, 1153-1160
  • Lecture (Conference)
    19th International Symposium on Radiopharmaceutical Sciences, 28.08.-02.09.2011, Amsterdam, Niederlande
  • Abstract in refereed journal
    Journal of Labelled Compounds and Radiopharmaceuticals 54(2011), S73

Publ.-Id: 16256 - Permalink