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

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 was 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. 3-fold lower affinities compared to the 4-methyl/4-fluoromethyl substituent.

Comparative assessment of 18F‐Mefway as a serotonin 5‐HT1A receptor PET imaging agent across species: Rodents, nonhuman primates, and humans

“…This was similar to previous observations for other WAY analogs (Wilson et al, ; Lang et al, ). Additionally, the possibility of repositioning the fluoromethyl group at different carbons was explored in new series of Mefway analogs (Thio et al, ). The 3‐Mefway analog exhibited lower in vivo binding properties compared with the 4‐Mefway analog reported here (Wooten et al, ).…”

“…The 3‐Mefway analog exhibited lower in vivo binding properties compared with the 4‐Mefway analog reported here (Wooten et al, ). The 2‐Mefway analogs exhibited higher affinities, similar to those of 4‐Mefway, and may be promising in vivo (Thio et al, ). Thus, of the various Mefway analogs prepared thus far, the trans ‐4‐Mefway reported here appears to be most promising.…”

“…18 F‐fluoride ion was produced in an MC‐17 cyclotron, an RDS 112 cyclotron, or a GE PET Trace cyclotron using oxygen‐18‐enriched water ( 18 O to 18 F using p,n reaction). The Mefway tosylate precursor (>95% purity; trans ‐ N ‐{2‐[4‐(2′‐methoxyphenyl)piperazinyl]ethyl}‐ N ‐(2‐pyridyl)‐ N ‐(4′‐toluenesulfonyloxymethylcyclohexane)‐carboxamide) was prepared in house using reported methods (Saigal et al, ; Thio et al, ) or purchased from Isoflex (San Francisco, CA). 18 F‐Fluoride radioactivity was counted in a Capintec CRC‐15R dose calibrator.…”