Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Al Hussainy R, Verbeek J, van der Born D, Booij J, Herscheid JK (2011) Design, synthesis and in vitro evaluation of bridgehead fluoromethyl analogs of N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridine-2-yl)cycloheannecarboamide (WAY-100635) for the 5-HT1A receptor. Eur J Med Chem 46:5728–5735
Bajwa A, Hillmer A, Wooten D, Saigal N, Christian B, Mukherjee J (2014) 18F-Mefway: efficacy as a PET imaging agent for serotonin 5HT1A receptors. J Nucl Med 55(suppl):553
Billard T, De Bars D, Zimmer L (2014) PET radiotracers for molecular imaging of serotonin 5-HT1A receptors. Curr Med Chem 21:70–81
Choi JY, Kim CH, Kim JY, Ha H, Ryu YH (2010) An Efficient Synthesis of trans-N-{2 [4(2-Methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(4-tosyloxymethylcyclohexane)-carboxamide, A Precursor of [18F]Mefway for Imaging 5-HT1A Receptor. Bull Korean Chem Soc 31:2371–2374
Kennedy SE, Zubiet J-K (2004) Neuroreceptor imaging of stress and mood disorders. CNS Spectr 9:292–301
Kumar JSD, Mann JJ (2007) PET tracers for 5-HT1a receptors and uses thereof. Drug Discov Today 12:748–756
Lang L, Jagoda E, Ma Y, Sassaman MB, Eckelman WC (2006) Synthesis and in vivo biodistribution of F-18 labeled 3-cis-, 3-trans-, 4-cis-, and 4-trans-fluorocyclohexane derivatives of WAY 100635. Bioorg Med Chem 14:3737–3748
Ma Y, Lang L, Kiesewetter D, Jagoda E, Eckelman WC (2006) Species differences in metabolites of PET ligands — serotonergic 5-HT1A receptor antagonists, 3-trans and 3-cis-FCWAY. Nucl Med Biol 33:1013–1019
Pike VW, Halldin C, McCarron JA, Lundkvist C, Hirani E, Olsson H, Hume SP, Karlsson P, Osman S, Swahn CG, Hall H, Wikstrom H, Mensonidas M, Poole KG, Farde L (1998) [carbonyl-11C]Desmethyl-WAY-100635 (DWAY) is a potent and selective radioligand for central 5-HT1A receptors in vitro and in vivo. Eur J Nucl Med 25:338–346
Saigal N, Pichika R, Easwaramoothy B, Collins D, Christian BT, Shi B et al (2006) Synthesis and biologic evaluation of a novel serotonin 5-HT1A receptor radioligand, 18F-labeled mefway, in rodents and imaging by PET in a nonhuman primate. J Nucl Med 47(10):1697–1706
Saigal N, Bajwa AK, Faheem SS, Coleman R, Pandey SK, Constantinescu CC, Fong V, Mukherjee J (2013) Evaluation of serotonin 5HT1A receptors in rodent models using 18F- mefway PET. Synapse 67:596–608
Thio J, Liang C, Bajwa A, Wooten D, Hillmer A, Mukherjee J (2013) Positional isomers of Mefway for imaging serotonin 5HT1a receptors. J Nucl Med 54(suppl):1104
Wooten D, Hillmer A, Murali D, Barnhart T, Bonab A, Normandin M, Schneider ML, Thio JP, Bajwa AK, Mukherjee J, Christian BT (2014) An in vivo comparison of 3- and 4-trans-[18F]Mefway in the nonhuman primate. Am J Nucl Med Mol Imaging 4(5):483–489
Wooten DW, Moraino JD, Hillmer AT, Engle JW, Dejesus OJ, Murali D, Barnhart TE, Nickles RJ, Davidson RJ, Schneider ML, Mukherjee J, Christian BT (2011a) In vivo kinetics of [F-18]MEFWAY: a comparison with [C-11]WAY100635 and [F-18]MPPF in the nonhuman primate. Synapse 65:592–600
Wooten DW, Hillmer AT, Murali D, Barnhart T, Schneider ML, Mukherjee J, Christian BT (2011b) An in vivo comparison of cis- and trans-18F-Mefway in the nonhuman primate. Nucl Med Biol 38:925–932
Wooten DW, Hillmer AT, Moraino JD, Ahlers EO, Slesarev M, Barnhart T, Mukherjee J, Schneider ML, Christian BT (2012) Measurement of 5-HT1A receptor density and in vivo binding parameters of 18F-Mefway in the nonhuman primate. J Cereb Blood Flow Metab 32:1546–1558
Zhang XY, Yasuno F, Zoghbi SS, Liow JS, Hong J, McCarron JA, Pike VW, Innis RB (2007) Quantification of serotonin 5-HT1A receptors in humans with [11C]-(-)-RWAY: radiometabolite(s) likely confound brain measurements. Synapse 61:469–477
Acknowledgment
This research was financially supported by a Grant from National Institutes of Health, R21/R33 AG 030524.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Thio, J.P., Liang, C., Bajwa, A.K. et al. Synthesis and evaluation of mefway analogs as ligands for serotonin 5HT1A receptors. Med Chem Res 24, 1480–1486 (2015). https://doi.org/10.1007/s00044-014-1238-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-014-1238-z