Talbot Peter S, Laruelle Marc
Department of Psychiatry and Radiology, Columbia University College of Physicians and Surgeons and New York State Psychiatric Institute, New York, NY 10032, USA.
Eur Neuropsychopharmacol. 2002 Dec;12(6):503-11. doi: 10.1016/s0924-977x(02)00099-8.
This paper reviews the contribution of human PET and SPECT neuroreceptor occupancy studies to the understanding of drug action in psychiatric illness, and how they can aid the development of new drugs. All effective antipsychotics show significant D(2) receptor occupancy. However, at least for atypical antipsychotics, there is no clear relationship between occupancy and clinical response. The mechanisms underlying antipsychotic efficacy, and the minimal effective D(2) occupancy, remain to be elucidated, particularly for drugs with modest or transient occupancy. The low liability of some atypical antipsychotics for extrapyramidal side effects does not appear to be explained by their 5-HT(2A) antagonism, and the muscarinic receptor occupancy of some drugs may be partly explanatory. Previous reports of apparent 'limbic selectivity' of atypical antipsychotics may be in error, and may be due to technical differences in radiotracers. For SSRIs, high occupancies at the serotonin transporter (SERT) are achieved at therapeutic doses, although the minimum SERT occupancy required for therapeutic response remains undefined. Previous attempts to augment the antidepressant effect of SSRIs by pindolol have generally used daily doses which result in inadequate 5-HT(1A) receptor occupancy. For benzodiazepines, clinical doses would appear to leave a wide margin of unoccupied receptors. For methylphenidate and cocaine, typical doses occupy more than 50% of dopamine transporters, and their profiles are extremely similar. In therapeutic drug development, these techniques may be used to assess receptor occupancy profiles, likely drug dosages and dosing intervals which cannot be reliably assessed in humans by other methods.
本文综述了人类正电子发射断层扫描（PET）和单光子发射计算机断层扫描（SPECT）神经受体占有率研究对理解精神疾病中药物作用的贡献，以及它们如何有助于新药的开发。所有有效的抗精神病药物均显示出显著的D（2）受体占有率。然而，至少对于非典型抗精神病药物而言，占有率与临床反应之间没有明确的关系。抗精神病药物疗效的潜在机制以及最小有效D（2）占有率仍有待阐明，特别是对于占有率适中或短暂的药物。一些非典型抗精神病药物锥体外系副作用发生率低，似乎不能用其5-HT（2A）拮抗作用来解释，某些药物的毒蕈碱受体占有率可能部分具有解释作用。先前关于非典型抗精神病药物明显“边缘选择性”的报道可能有误，可能是由于放射性示踪剂的技术差异所致。对于选择性5-羟色胺再摄取抑制剂（SSRI），治疗剂量时可实现血清素转运体（SERT）的高占有率，尽管治疗反应所需的最小SERT占有率仍未明确。先前试图通过吲哚洛尔增强SSRI抗抑郁作用的尝试，通常使用的日剂量导致5-HT（1A）受体占有率不足。对于苯二氮䓬类药物，临床剂量似乎会留下大量未被占据的受体。对于哌甲酯和可卡因，典型剂量占据多巴胺转运体的比例超过50%，且它们的情况极为相似。在治疗药物开发中，这些技术可用于评估受体占有率情况、可能的药物剂量和给药间隔，而这些在人体中无法通过其他方法可靠评估。
