Lima L, Laporte A M, Gaymard C, Spedding M, Mocaër E, Hamon M
INSERM U. 288, Neuropsychopharmacologie moléculaire, cellulaire et fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
J Neural Transm (Vienna). 1997;104(10):1059-75. doi: 10.1007/BF01273319.
The tritiated derivative of the potent 5-HT1A receptor agonist S-14506 ¿1[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphtyl)pipera zine¿ was tested for its capacity to selectively label the serotonin 5-HT1A receptors both in vitro in the rat and the mouse brain, and in vivo in the mouse. In vitro studies showed that the pharmacological profile and the distribution of [3H]S-14506 specific binding sites (Kd = 0.15 nM) in different brain regions matched perfectly those of the prototypical 5-HT1A receptor ligand [3H]8-OH-DPAT. However, in the three regions examined (hippocampus, septum, cerebral cortex), the density of [3H]S-14506 specific binding sites was significantly higher (+66-90%) than that found with [3H]8-OH-DPAT. Whereas the specific binding of [3H]8-OH-DPAT was markedly reduced by GTP and Gpp(NH)p and increased by Mn2+, that of [3H]S-14506 was essentially unaffected by these compounds. In addition, the alkylating agent N-ethylmaleimide was much less potent to inhibit the specific binding of [3H]S-14506 than that of [3H]8-OH-DPAT. Measurement of in vivo accumulation of tritium one hour after i.v. injection of [3H]S-14506 to mice revealed marked regional differences, with about 2.5 times more radioactivity in the hippocampus than in the cerebellum. Pretreatment with 5-HT1A receptor ligands prevented tritium accumulation in the hippocampus but not in the cerebellum. Autoradiograms from brain sections of injected mice confirmed the specific in vivo labeling of 5-HT1A receptors by [3H]S-14506, therefore suggesting further developments with derivatives of this molecule for positron emission tomography in vivo in man.
强效5-HT1A受体激动剂S-14506（1-[2-(4-氟苯甲酰胺基)乙基]-4-(7-甲氧基萘基)哌嗪）的氚化衍生物，在大鼠和小鼠脑的体外实验以及小鼠的体内实验中，被测试其选择性标记5-羟色胺5-HT1A受体的能力。体外研究表明，[3H]S-14506特异性结合位点（Kd = 0.15 nM）在不同脑区的药理学特征和分布与典型的5-HT1A受体配体[3H]8-OH-DPAT完全匹配。然而，在所检测的三个脑区（海马体、隔区、大脑皮层）中，[3H]S-14506特异性结合位点的密度比[3H]8-OH-DPAT的密度显著更高（+66 - 90%）。[3H]8-OH-DPAT的特异性结合被GTP和Gpp(NH)p显著降低，被Mn2+增加，而[3H]S-14506的特异性结合基本不受这些化合物影响。此外，烷基化剂N-乙基马来酰亚胺抑制[3H]S-14506特异性结合的效力远低于抑制[3H]8-OH-DPAT特异性结合的效力。给小鼠静脉注射[3H]S-14506一小时后，对体内氚积累的测量显示出明显的区域差异，海马体中的放射性约为小脑的2.5倍。用5-HT1A受体配体进行预处理可阻止海马体中的氚积累，但不能阻止小脑中的氚积累。注射小鼠脑切片的放射自显影片证实了[3H]S-14506对5-HT1A受体的体内特异性标记，因此表明该分子的衍生物在人体正电子发射断层扫描的体内研究中有进一步发展的潜力。
