Synthesis and evaluation of mefway analogs as ligands for serotonin 5HT1A receptors


18F-Mefway (N-{2-[4-(2′-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(4′-18F-fluoro-methylcyclohexane)carboxamide) was developed and evaluated for use as a PET ligand for imaging 5-HT1A receptors. Ongoing studies of 18F-Mefway have shown it to be an effective PET radiotracer. We have synthesized isomers of Mefway by changing the position of the methyl group in attempts to evaluate stability for imaging purposes. 2-Methyl-, 3-methyl-, and 4-methyl-cyclohexane-1-carboxylic acids and 3-carbomethoxy-, 4-carbomethoxycyclohexane-1-carboxylic acids were coupled with WAY-100634 to provide the methylcyclohexyl derivatives (2-, 3-, and 4-methyl). Mefway and 3-Mefway analogs were prepared by reduction of carbomethoxy- derivatives followed by fluorination. In vitro binding affinities for the methylated derivatives in rat brain homogenates were found to be 10.4 nM (2-methyl), 77 nM (3-methyl), and 21.5 nM (4-methyl). Binding affinity of 3-Mefway and 4-Mefway was found to be 17.4 nM and 6.26 nM, respectively. Our results suggest that 3-methyl/3-fluoromethyl substituent has approx. threefold lower affinities compared to the 4-methyl/4-fluoromethyl substituent.

DOI: 10.1007/s00044-014-1238-z

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@article{Thio2014SynthesisAE, title={Synthesis and evaluation of mefway analogs as ligands for serotonin 5HT1A receptors}, author={Joanne P. Thio and Christopher Liang and Alisha K. Bajwa and Dustin W. Wooten and Bradley T. Christian and Jogeshwar Mukherjee}, journal={Medicinal Chemistry Research}, year={2014}, volume={24}, pages={1480-1486} }