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

ABSTRACT: 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.

SUBMITTER: Zeng F

PROVIDER: S-EPMC5846131 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

Zeng Fanxing F Nye Jonathon A JA Voll Ronald J RJ Howell Leonard L Goodman Mark M MM

ACS medicinal chemistry letters 20180205 3

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). [11 ...[more]

PMID: 29541358

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Project description:A series of indole derivatives was designed and synthesised to improve on activity and circumvent pharmacokinetic limitations experienced with the structurally related compound, ladostigil. The compounds consisted of a propargylamine moiety (a known MAO inhibitor and neuroprotector) at the N1 position and a ChE inhibiting diethyl-carbamate/urea moiety at the 5 or 6 position of the indole ring. In order to prevent or slow down the in vivo hydrolysis and deactivation associated with the carbamate function of ladostigil, a urea moeity was incorporated into selected compounds to obtain more metabolically stable structures. The majority of the synthesised compounds showed improved MAO-A inhibitory activity compared to ladostigil. The compounds possessing the propargylamine moiety showed good MAO-B inhibitory activity with 6 and 8 portraying IC50 values between 14-20 fold better than ladostigil. The ChE assay results indicated that the compounds have non-selective inhibitory activities on eeAChE and eqBuChE regardless of the type or position of substitution (IC50: 2-5 μM). MAO-A and MAO-B docking results showed that the propargylamine moiety was positioned in close proximity to the FAD cofactor suggesting that the good inhibitory activity may be attributed to the propargylamine moiety and irreversible inhibition as confirmed in the reversibility studies. Docking results also indicated that the compounds have interactions with important amino acids in the AChE and BuChE catalytic sites. Compound 6 was the most potent multifunctional agent showing better inhibitory activity than ladostigil in vitro on all enzymes tested (hMAO-A IC50 = 4.31 μM, hMAO-B IC50 = 2.62 μM, eeAChE IC50 = 3.70 μM, eqBuChE IC50 = 2.82 μM). Chemical stability tests confirmed the diethyl-urea containing compound 6 to be more stable than its diethyl-carbamate containing counterpart compound 8. Compound 6 also exerted significant neuroprotection (52.62% at 1 μM) against MPP+ insult to SH-SY5Y neural cells and has good in silico predicted ADMET properties. The favourable neuronal enzyme inhibitory activity, likely improved pharmacokinetic properties in vivo and the potent neuroprotective ability of compound 6 make it a promising compound for further development.

Dataset Information

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

Publications

Synthesis and Evaluation of Pyridyloxypyridyl Indole Carboxamides as Potential PET Imaging Agents for 5-HT<sub>2C</sub> Receptors.

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