Wilson A A, Inaba T, Fischer N, Dixon L M, Nobrega J, DaSilva J N, Houle S
PET Centre, Clarke Institute of Psychiatry, Toronto, Ontario, Canada.
Nucl Med Biol. 1998 Nov;25(8):769-76. doi: 10.1016/s0969-8051(98)00020-1.
Analogues of the potent and selective 5-HT1A ligand, WAY 100635, were synthesized and examined as potential candidates for imaging 5-HT1A receptors by positron emission tomography (PET). Several of the analogues displayed nanomolar affinity for the 5-HT1A receptor, comparable to WAY 100635. Three of these were examined in a model of human liver metabolism vis-à-vis WAY 100635. All showed a markedly lower propensity for amide hydrolysis than WAY 100635. Radiolabelling of these three potential PET radiotracers with carbon-11 was readily achieved from [11C]-iodomethane, and the newly synthesized radioligands were tested in vivo in rats for binding to 5-HT1A receptors. Whereas two of the ligands failed to bind to 5-HT1A receptors in vivo, one was successful. The latter, [11C]-7 [4-(2'-methoxyphenyl)-1-[2'-[N-(2'-pyridinyl)-2-bicyclo[2.2.2]octanec arboxamido]ethyl]-piperazine], showed good brain penetration, hippocampal:cerebellar ratios of 10:1 at 45 min postinjection. Blocking studies with a variety of drugs demonstrated that the binding of [11C]-7 in vivo was selective for 5-HT1A receptors. [11C]-7 is a promising candidate as a ligand for imaging 5-HT1A receptors by PET.
合成了强效且具选择性的5-HT1A配体WAY 100635的类似物，并作为正电子发射断层扫描（PET）成像5-HT1A受体的潜在候选物进行了研究。其中几种类似物对5-HT1A受体表现出纳摩尔亲和力，与WAY 100635相当。相对于WAY 100635，在人类肝脏代谢模型中对其中三种进行了研究。所有这些类似物的酰胺水解倾向均明显低于WAY 100635。利用[11C]-碘甲烷可轻松实现这三种潜在PET放射性示踪剂的碳-11放射性标记，并在大鼠体内对新合成的放射性配体与5-HT1A受体的结合情况进行了测试。其中两种配体在体内未能与5-HT1A受体结合，而有一种成功了。后者，即[11C]-7 [4-(2'-甲氧基苯基)-1-[2'-[N-(2'-吡啶基)-2-双环[2.2.2]辛烷甲酰胺基]乙基]-哌嗪]，显示出良好的脑渗透性，注射后45分钟时海马体与小脑的比值为10:1。用多种药物进行的阻断研究表明，[11C]-7在体内的结合对5-HT1A受体具有选择性。[11C]-7是一种有前景的PET成像5-HT1A受体配体候选物。
