Non-peptide NK 1 receptor ligands based on the 4-phenylpyridine moiety

Abstract

The quinoline nucleus of the previously described 4-phenylquinoline-3-carboxamides NK 1 receptor ligands 7 has been transformed into either substituted or azole—(i.e., triazole or tetrazole) fused pyridine moieties of compounds 9 and 10, respectively, in order to obtain NK 1 receptor ligands showing lower molecular weight or higher hydrophilicity. The program of molecular manipulations produced NK 1 receptor ligands showing affinity in the nanomolar range. In particular, 4-methyl-1-piperazinyl derivative 9j showed an IC 50 value of 4.8 nM and was proved to behave as a NK 1 antagonist blocking Sar 9-SP-sulfone induced proliferation and migration of microvascular endothelial cells. Therefore, compound 9j has been labeled with [ 11C]CH 3I ( t 1/2 = 20.4 min, β + = 99.8%) starting from the corresponding des-methyl precursor 9i using with a radiochemical yield of about 10% (not decay corrected) and a specific radioactivity >1 Ci/μmol in order to be used as a radiotracer in next PET studies.