Synthesis and Evaluation of Pyridyloxypyridyl Indole Carboxamides as Potential PET Imaging Agents for 5-HT2C Receptors.

Nine pyridyloxypyridyl indole carboxamides were synthesized and displayed high affinities for 5-HT2C receptors and high selectivity over 5-HT2A and 5-HT2B. Among them, 6-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]1H-indole-3-carboxamide (8) exhibits the highest 5-HT2C binding affinity (Ki = 1.3 nM) and high selectivity over 5-HT2A (∼1000 times) and 5-HT2B (∼140 times). [11C]8 was synthesized by palladium-catalyzed coupling reaction between pinacolboranate 16 and [11C]CH3I with an average radiochemical yield of 27 ± 4% (n = 8, decay-corrected from end of [11C]CH3I synthesis). MicroPET imaging studies in rhesus monkeys showed regional uptake of [11C]8 in the choroid plexus, whereas the bindings in all other brain regions were low. The specific binding in the choroid plexus was confirmed by administration of a blocking dose of 0.1 mg/kg of the 5-HT2C antagonist SB-242084.