Two C-Methyl Derivatives of [11C]WAY-100635 - Effects of an Amido [alpha]-Methyl Group on Metabolism and Brain 5-HT1A Receptor Radioligand Behavior in Monkey

[carbonyl-^sup 11^C]N-(2-(1-(4-(2-methoxyphenyl)-piperazinyl)ethyl)-N-pyridinyl)cyclohexanecarboxamide ([carbonyl-^sup 11^C]WAY-100635) is an effective radioligand for imaging brain 5-HT^sub 1A^ receptors with positron emission tomography (PET). However, this radioligand has some drawbacks for deriving relative regional receptor densities, including rapid metabolism, which acts against accurate definition of an arterial input function for compartmental modeling, and very low nonspecific binding in brain, which detracts from the accuracy of modeling by a simplified reference tissue (cerebellum) approach. Here, in a search for a radioligand that overcomes these limitations, we investigated the effects of introducing a single methyl group at either of the carbon atoms alpha to the amide bond in [^sup 11^C]WAY-100635. Ligands with a methyl group on the alpha carbon of the cyclohexyl group (SWAY) or the alpha carbon of the C^sub 2^H^sub 4^ linker ((R,S)-JWAY) were synthesized and tested for binding affinity and intrinsic activity at 5-HT^sub 1A^ receptors. SWAY was labeled with carbon-11 (t^sub 1/2^ = 20.4 minutes; β^sup +^ = 99.8%) in its O-methyl group and (R,S)-JWAY in its carbonyl group. Each radioligand was evaluated by PET experiments in cynomolgus monkey. SWAY and (R,S)-JWAY were found to be high-affinity antagonists at 5-HT^sub 1A^ receptors. After injection of [^sup 11^C]SWAY into monkey, radioactivity uptake in brain reached a maximum of 3% at 4.5 minutes and decreased to 0.7% at 72 minutes. However, over the time span of the experiment, radioactivity concentrations in 5-HT^sub 1A^ receptor-rich brain regions were only fractionally higher than in cerebellum. Radioactivity represented by parent radioligand in plasma was 39% at 45 minutes. After injection of [^sup 11^C](R,S)-JWAY alone, radioactivity uptake in brain reached a maximum of 4.8% at 2.5 minutes and decreased to 1.2% at 90 minutes. At this time, radioactivity concentration in 5-HT^sub 1A^ receptor-rich brain regions was markedly greater than in cerebellum. In another PET experiment, the monkey was predosed with WAY-100635 before [^sup 11^C](R,S)-JWAY injection. At 90 minutes after injection, the ratio of radioactivity in 5-HT^sub 1A^ receptor-rich regions to that in cerebellum was reduced to near unity. Radioactivity represented by parent radioligand in plasma was 12% at 45 minutes. [^sup 11^C](R,S)-JWAY, but not [^sup 11^C]SWAY, gives a sizeable 5-HT^sub 1A^ receptor-selective PET signal in