Centre for Human Drug Research, Zernikedreef 10, Leiden, The Netherlands.
J Psychopharmacol. 2012 Aug;26(8):1128-35. doi: 10.1177/0269881111435251. Epub 2012 Jan 30.
JNJ-37822681 is a novel, fast-dissociating dopamine D(2) receptor antagonist, currently in development as an antipsychotic drug candidate. A previous first-in-human study demonstrated mild central nervous system effects of JNJ-37822681 in healthy male volunteers. Significant but transient serum prolactin elevations were demonstrated, whereas other neurophysiological effects were relatively small. To investigate striatal dopamine D(2) receptor occupancy by variable single doses of JNJ-37822681, an open-label [(11)C]raclopride positron emission tomography study was performed in 12 healthy male volunteers, using the simplified reference tissue model with cerebellum as reference tissue. Oral administration of JNJ-37822681 resulted in dose-dependent dopamine D(2) receptor occupancy. Receptor occupancy increased from 9-19% at 2 mg doses to 60-74% at 20 mg doses of JNJ-37822681. Therefore, single oral doses of JNJ-37822681 can produce occupancy levels that are generally associated with clinical efficacy for registered antipsychotic drugs.
JNJ-37822681 是一种新型、快速解离的多巴胺 D2 受体拮抗剂，目前正在开发中作为一种抗精神病药物候选物。先前的首次人体研究表明，JNJ-37822681 在健康男性志愿者中具有轻度的中枢神经系统作用。研究表明，JNJ-37822681 会导致显著但短暂的血清催乳素升高，而其他神经生理效应则相对较小。为了研究不同剂量的 JNJ-37822681 对纹状体多巴胺 D2 受体的占有率，12 名健康男性志愿者进行了一项开放标签的[(11)C]raclopride 正电子发射断层扫描研究，使用简化的参考组织模型，以小脑作为参考组织。JNJ-37822681 经口服给药，可产生剂量依赖性的多巴胺 D2 受体占有率。JNJ-37822681 的 2 毫克剂量组的受体占有率从 9-19%增加到 20 毫克剂量组的 60-74%。因此，JNJ-37822681 的单次口服剂量可以产生通常与已注册的抗精神病药物的临床疗效相关的占有率水平。
