Synthesis and Evaluation of Pyridyloxypyridyl Indole Carboxamides as Potential PET Imaging Agents for 5-HT 2C 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]1 H -indole-3-carboxamide ( 8 ) exhibits the highest 5-HT2C binding affinity ( K i = 1.3 nM) and high selectivity over 5-HT2A (∼1000 times) and 5-HT2B (∼140 times). [11 C] 8 was synthesized by palladium-catalyzed coupling reaction between pinacolboranate 16 and [11 C]CH3 I with an average radiochemical yield of 27 ± 4% ( n = 8, decay-corrected from end of [11 C]CH3 I synthesis). MicroPET imaging studies in rhesus monkeys showed regional uptake of [11 C] 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.