A new approach for a C-11-C bond formation: Synthesis and biodistribution studies of 17a-(3'-[11C]prop-1-ynyl)-3-methoxy-3,17b-estradiol

AIMS: To expand the scope of 11C-labelled compounds, novel 11C-C bond forming reactions gain more and more attention. In this context, technically simple, high-yielding and functional group tolerating reactions are of particular interest. The Sonogashira copper-palladium catalysed coupling of terminal alkynes with aromatic and vinylic halides represents such a reaction. To the best of our knowledge, the Sonogashira-reaction has not yet been employed in 11C-chemistry. In this work we describe a modified Sonogashira-like reaction for labelling the terminal alkyne group of the potent contra-ceptive steroid mestranol with [11C]methyl iodide and biodistribution studies of the title compound.
METHODS: Pd2(dba)3/AsPh3/TBAF as catalyst/co-ligand/base combination was used to form the desired cross-coupling product in sufficient radiochemical yield. The labelling position was verified by the synthesis of the corresponding 13C-labelled compound using the same cross-coupling protocol. Biodistribution studies were performed with immature female Wistar rats. One group of animals was pre-treated with 1 mg/kg body weight 17a-ethynyl-estradiol 10 minutes before injecting the 11C-labelled compound. Radioactivity distribution in organs of interst was studies after 5 and 60 minutes after injection. Blood plasma samples were taken for metabolite analysis by means of radio-HPLC.
RESULTS: A new approach for a 11C-C bond formation via a Sonogashira-like cross-coupling reaction of terminal acetylenes with [11C]MeI was exemplified by the synthesis of 17a-(3'-[11C]prop-1-ynyl)-3-methoxy-3,17b-estradiol. Classical conditions of the Sonogashira reaction (Pd0, CuI and TEA or DIPA as the base) can not be employed for 11C-labelling with [11C]methyl iodide due to the rapid quaternization of the amine base. Using optimized alternative reaction conditions (Pd2(dba)3/AsPh3/TBAF/[11C]MeI/ steroid in THF, 5 minutes at 60°C) the title compound was obtained in decay-corrected radiochemical yields of 27-47% (n=8) based on [11C]MeI within 21-27 minutes after EOB. In a typical synthesis, 1-2 GBq of 17a-(3'-[11C]prop-1-ynyl)-3-methoxy-3,17b-estradiol could be synthesized in radiochemical purity >99%. The specific activity ranged between 10-19 GBq/µmol, and the labeling position was verified by the synthesis of the corresponding 13C-labeled compound. Biodistribution studies after 5 min. and 60 minutes exhibited no specific binding in target organs (uterus, ovaries). The highest uptake of radioactivity was observed in the fat (4.7% ID/g tissue nomalized to 100 g body weight at 60 minutes). The compound was fast metabolized and biliary eliminated.
CONCLUSION: We developed a new method for a 11C-C bond formation employing the cross-coupling of terminal alkynes with [11C]methyl iodide via a Sonogashira-like reaction in sufficient radiochemical yields. The biodistribution data of the title compound are consistent with the high lipophilicity of the compound.