Yokoi Fuji, Gründer Gerhard, Biziere Kathleen, Stephane Massoud, Dogan Ahmet S, Dannals Robert F, Ravert Hayden, Suri Ajit, Bramer Steven, Wong Dean F
Department of Radiology, Division of Nuclear Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
Neuropsychopharmacology. 2002 Aug;27(2):248-59. doi: 10.1016/S0893-133X(02)00304-4.
Aripiprazole (OPC 14597) is an antipsychotic drug that has high affinity for dopamine D2 and D3 receptors and the dopamine autoreceptor. It is being developed for treatment of patients with schizophrenia. The purpose of this study was to determine whether a dose response following graduated doses of aripiprazole could be quantified and correlated with its occupancy of the D2 and D3 dopamine receptors in the brain of living humans. Dopamine D2 and D3 receptor occupancy in fifteen normal male human brains was measured using positron emission tomography (PET) with [11C]raclopride. PET studies were performed before and after two weeks of administration of aripiprazole. The dopamine D2 receptor occupancy was quantified with two kinetic modeling methods without using a blood input function. Administration of aripiprazole for 14 days resulted in a dose-dependent receptor occupancy between 40 - 95% after the administration of 0.5mg, 1 mg, 2 mg, 10 mg, and 30 mg per day. These results suggest that an adequate occupancy can be obtained, and this may be useful to predict an appropriate therapeutic dose for an individual patient. Interestingly, even at striatal D2 receptor occupancy values above 90%, which occurred with the higher doses, extrapyramidal side effects (EPS) were not observed. This underlines aripiprazole's unique mechanism of action as a partial dopamine receptor agonist, which might become a novel principle in the treatment of schizophrenia.
阿立哌唑（OPC 14597）是一种抗精神病药物，对多巴胺D2和D3受体以及多巴胺自身受体具有高亲和力。它正被开发用于治疗精神分裂症患者。本研究的目的是确定阿立哌唑递增剂量后的剂量反应是否可以量化，并与其在活体人类大脑中对D2和D3多巴胺受体的占有率相关联。使用[11C]雷氯必利正电子发射断层扫描（PET）测量了15名正常男性人类大脑中的多巴胺D2和D3受体占有率。在给予阿立哌唑两周前后进行了PET研究。使用两种动力学建模方法在不使用血液输入函数的情况下对多巴胺D2受体占有率进行了量化。每天给予0.5mg、1mg、2mg、10mg和30mg阿立哌唑14天后，受体占有率呈剂量依赖性，介于40% - 95%之间。这些结果表明可以获得足够的占有率，这可能有助于预测个体患者的合适治疗剂量。有趣的是，即使在较高剂量下纹状体D2受体占有率值超过90%时，也未观察到锥体外系副作用（EPS）。这突出了阿立哌唑作为部分多巴胺受体激动剂的独特作用机制，并可能成为精神分裂症治疗的新原则。
