McCarron Julie A, Marchais-Oberwinkler Sandrine, Pike Victor W, Tarkiainen Jari, Halldin Christer, Sóvagó Judit, Gulyas Balàzs, Wikström Hakan V, Farde Lars
MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Ducane Road, London, W12 0NN, UK.
Mol Imaging Biol. 2005 May-Jun;7(3):209-19. doi: 10.1007/s11307-005-4127-5.
[carbonyl-11C]N-(2-(1-(4-(2-methoxyphenyl)-piperazinyl)ethyl)-N-pyridinyl)cyclohexanecarboxamide ([carbonyl-11C]WAY-100635) is an effective radioligand for imaging brain 5-HT1A 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 [11C]WAY-100635.
Ligands with a methyl group on the alpha carbon of the cyclohexyl group (SWAY) or the alpha carbon of the C2H4 linker ((R,S)-JWAY) were synthesized and tested for binding affinity and intrinsic activity at 5-HT1A receptors. SWAY was labeled with carbon-11 (t1/2 = 20.4 minutes; beta+ = 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-HT1A receptors. After injection of [11C]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-HT1A 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 11C-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-HT1A receptor-rich brain regions was markedly greater than in cerebellum. In another PET experiment, the monkey was predosed with WAY-100635 before 11C-JWAY injection. At 90 minutes after injection, the ratio of radioactivity in 5-HT1A receptor-rich regions to that in cerebellum was reduced to near unity. Radioactivity represented by parent radioligand in plasma was 12% at 45 minutes.
11C-JWAY, but not [11C]SWAY, gives a sizeable 5-HT1A 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.
[羰基 - 11C]N - (2 - (1 - (4 - (2 - 甲氧基苯基) - 哌嗪基)乙基) - N - 吡啶基)环己烷甲酰胺([羰基 - 11C]WAY - 100635)是一种用于正电子发射断层扫描(PET)成像脑5 - HT1A受体的有效放射性配体。然而，这种放射性配体在推导相对区域受体密度方面存在一些缺点，包括快速代谢，这不利于为房室模型准确定义动脉输入函数，以及在脑中非常低的非特异性结合，这会降低通过简化参考组织(小脑)方法进行建模的准确性。在此，为了寻找一种克服这些限制的放射性配体，我们研究了在[11C]WAY - 100635中酰胺键的α碳原子之一上引入单个甲基的效果。
合成了在环己基的α碳上带有甲基的配体(SWAY)或在C2H4连接子的α碳上带有甲基的配体((R,S) - JWAY)，并测试了它们对5 - HT1A受体的结合亲和力和内在活性。SWAY在其O - 甲基上用碳 - 11标记(t1/2 = 20.4分钟；β+ = 99.8%)，(R,S) - JWAY在其羰基上用碳 - 11标记。通过PET实验在食蟹猴中评估每种放射性配体。
发现SWAY和(R,S) - JWAY是5 - HT1A受体的高亲和力拮抗剂。将[11C]SWAY注射到猴子体内后，脑中的放射性摄取在4.5分钟时达到最大值3%，并在72分钟时降至0.7%。然而，在实验的时间跨度内，富含5 - HT1A受体的脑区中的放射性浓度仅略高于小脑。血浆中母体放射性配体在45分钟时的放射性占比为39%。单独注射11C - JWAY后，脑中的放射性摄取在2.5分钟时达到最大值4.8%，并在90分钟时降至1.2%。此时，富含5 - HT1A受体的脑区中的放射性浓度明显高于小脑。在另一个PET实验中，猴子在注射11C - JWAY之前预先给予WAY - 100635。注射后90分钟，富含5 - HT1A受体区域与小脑中的放射性比值降至接近1。血浆中母体放射性配体在45分钟时的放射性占比为12%。
11C - JWAY而非[11C]SWAY在猴子中产生了可观的5 - HT1A受体选择性PET信号。SWAY或(R,S) - JWAY中酰胺键相邻的C - 甲基的存在未能对抗代谢。
