Journal Article

Two C-Methyl Derivatives of super(11)CWAY-100635 - Effects of an Amido a-Methyl Group on Metabolism and Brain 5-HT sub(1A) Receptor Radioligand Behavior in Monkey

Sovago, Judit, McCarron, Julie A, Marchais-Oberwinkler, Sandrine, Wikstroem, Hakan V, Halldin, Christer, Pike, Victor W, Gulyas, Balazs, Tarkiainen, Jari, Farde, Lars

2005

Overview

[carbonyl- super(11)C]N-(2-(1-(4-(2-methoxyphenyl)-piperazinyl)ethyl)- N-pyridinyl)cyclohexanecarboxamide ([carbonyl- super(11)C]WAY-1006 35) 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 [ super(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; b super(+) = 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 [ super(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 [ super(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 [ super(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. [ super(11)C](R,S)- JWAY, but not [ super(11)C]SWAY, gives a sizeable 5-HT sub(1A) receptor-selective PET signal in monkey. The presence of a C-methyl group adjacent to the amide bond in SWAY or (R,S)-JWAY fails to counter metabolism.

• Subject: Cynomolgus