Bantick R Alexander, Rabiner Eugenii A, Hirani Ella, de Vries Michiel H, Hume Susan P, Grasby Paul M
Cyclotron Building, CSC, The Hammersmith Hospital, Imperial College London, London, UK.
Neuropsychopharmacology. 2004 May;29(5):847-59. doi: 10.1038/sj.npp.1300390.
Drugs acting on the 5-HT1A receptor are used in the treatment of depression, generalized anxiety disorder, and schizophrenia. This study investigated 5-HT1A receptor occupancy by the 5-HT1A agonist drugs flesinoxan (a highly selective probe for the 5-HT1A receptor) and ziprasidone (a novel atypical antipsychotic drug). Using a within-subject design, 14 healthy volunteers each received two positron emission tomography scans using the selective 5-HT1A antagonist radiotracer [11C]WAY-100635. One scan constituted a baseline, while the other followed either 1 mg flesinoxan or 40 mg ziprasidone orally. In addition, rats were pretreated with intravenous flesinoxan at doses ranging from 0.001 to 5 mg/kg then [11C]WAY-100635 binding measured ex vivo. Cerebral cortical and hippocampal regions of interest, and cerebellar reference regions were sampled to estimate 5-HT1A receptor occupancy (inferred from reductions in specific radioligand binding). In man, occupancy was not significant despite volunteers experiencing side effects consistent with central serotonergic activity. The mean cerebral cortex occupancy (+/- 1 SD) for flesinoxan was 8.7% (+/- 13%), and for ziprasidone 4.6% (+/- 17%). However, in rats, flesinoxan achieved significant and dose-related occupancy (17-57%) at 0.25 mg/kg and above. We conclude that 5-HT1A receptor agonists produce detectable occupancy only at higher doses that would produce unacceptable levels of side effects in man, although lower doses are sufficient to produce pharmacological effects. The development of agonist radiotracers may increase the sensitivity of detecting agonist binding, as 5-HT1A antagonists bind equally to low- and high-affinity receptor states, while agonists bind preferentially to the high-affinity state.
作用于5-羟色胺1A（5-HT1A）受体的药物用于治疗抑郁症、广泛性焦虑症和精神分裂症。本研究调查了5-HT1A激动剂药物氟辛克生（一种对5-HT1A受体具有高度选择性的探针）和齐拉西酮（一种新型非典型抗精神病药物）对5-HT1A受体的占有率。采用受试者自身对照设计，14名健康志愿者每人接受两次正电子发射断层扫描，使用选择性5-HT1A拮抗剂放射性示踪剂[11C]WAY-100635。一次扫描作为基线，另一次在口服1mg氟辛克生或40mg齐拉西酮后进行。此外，对大鼠静脉注射剂量范围为0.001至5mg/kg的氟辛克生进行预处理，然后离体测量[11C]WAY-100635的结合情况。对大脑皮质和海马的感兴趣区域以及小脑参考区域进行采样，以估计5-HT1A受体占有率（根据特异性放射性配体结合的减少推断）。在人体中，尽管志愿者出现了与中枢5-羟色胺能活性一致的副作用，但占有率并不显著。氟辛克生的平均大脑皮质占有率（±1标准差）为8.7%（±13%），齐拉西酮为4.6%（±17%）。然而，在大鼠中，氟辛克生在0.25mg/kg及以上剂量时达到了显著的、与剂量相关的占有率（17%-57%）。我们得出结论，5-HT1A受体激动剂仅在较高剂量时才会产生可检测到的占有率，而这些剂量在人体中会产生不可接受的副作用水平，尽管较低剂量足以产生药理作用。激动剂放射性示踪剂的开发可能会提高检测激动剂结合的灵敏度，因为5-HT1A拮抗剂与低亲和力和高亲和力受体状态的结合能力相同，而激动剂则优先与高亲和力状态结合。
