SEROTONIN 1A RECEPTOR & METABOLIC IMAGING IN DEPRESSION

（申请人摘要）多项证据表明，5 -羟色胺1a （5HT1A）受体功能在重度抑郁症（MDD）中异常，而躯体抗抑郁治疗对5HT1A受体功能的影响与治疗效果有关。通过评估MDD受试者对5HT1A激动剂的神经内分泌和温度反应，测量MDD受试者死后小样本脑组织中的5HT1A受体结合，以及检查抗抑郁药物（AD）给药后大鼠5HT1A受体结合的变化，获得了支持这些假设的数据。然而，目前还没有直接的证据表明5HT1A受体中枢异常或抗抑郁药物治疗对5HT1A受体药理学的影响。一种用于正电子发射断层扫描（PET）成像的高选择性5-HT1A受体放射配体[carbonyl-11C]- WAY-100635的开发，最近使得直接、无创伤地探测MDD的中枢5HT1A受体结合电位（BP）成为可能。为了进一步了解MDD的神经生物学和AD的治疗机制，我们将使用PET和[羰基- 11c]WAY-100635来比较MDD与健康对照者以及MDD受试者治疗前后的5HT1A受体BP。将在同一扫描过程中获得18f -氟脱氧葡萄糖（FDG）摄取图像，以评估区域5HT1A受体BP与先前在MDD中发现的葡萄糖代谢异常之间的关系。成像前也检查了皮质醇分泌的内分泌评估，以确定海马5HT1A受体的下调是否发生在与重度抑郁症相关的高皮质醇血症的反应中，就像实验动物在应激和糖皮质激素给药期间一样。在使用抗抑郁药物舍曲林治疗的8周间隔后，重复影像学和内分泌测量。初步成像数据表明，未服药的抑郁症患者与对照组之间的5HT1A受体BP在中颞叶皮层和腹外侧和腹内侧前额叶皮层（PFC）中存在显著差异。如果在重度抑郁症中，中颞叶皮层（包括海马）5HT1A受体BP降低与皮质醇分泌异常之间存在联系，那么在治疗期间，这种异常的正常化可能具有预后意义。在腹外侧和腹内侧PFC中，5HT1A受体BP异常降低的幅度比先前在MDD中这些区域显示的代谢和灰质体积异常大，这表明5HT1A受体成像测量可能提供敏感的病理标记，可以指导未来MDD的死后组织学和组织化学研究。

DESCRIPTION: (Applicant's abstract) Multiple lines of evidence suggest that serotonin1A (5HT1A) receptor function is abnormal in major depressive disorder (MDD) and that somatic antidepressant therapies effect changes in 5HT1A receptor function that are relevant to treatment efficacy. The data supporting these hypotheses have been obtained by assessing neuroendocrine and temperature responses to 5HT1A agonists in MDD subjects, measuring 5HT1A receptor binding in brain tissue acquired post mortem from small samples of MDD subjects, and examining changes in 5HT1A receptor binding in rats following antidepressant drug (AD) administration. However, there has been no direct demonstration of a central 5HT1A receptor abnormality or an effect of antidepressant treatment on 5HT1A receptor pharmacology in living depressed subjects. The development of a highly selective 5-HT1A receptor radioligand for positron emission tomography (PET) imaging, [carbonyl-11C]- WAY-100635, has recently made direct, noninvasive exploration of the central 5HT1A receptor binding potential (BP) possible in MDD. To advance knowledge regarding the neurobiology of MDD and the mechanisms of AD treatment, PET and [carbonyl-11C]WAY-100635 will be used to compare the 5HT1A receptor BP between MDD and healthy control subjects and between the pre-and post-treatment conditions in the MDD subjects. Images of 18F-fluorodeoxyglucose (FDG) uptake will be acquired in the same scan session to evaluate the relationship between regional 5HT1A receptor BP and the glucose metabolic abnormalities previously identified in MDD. Endocrine assessments of cortisol secret-ion are also examined prior to imaging to determine whether down-regulation of hippocampal 5HT1A receptors occurs in response to the hypercortisolism associated with MDD as it does in experimental animals during stress and glucocorticoid administration. The imaging and endocrine measures are repeated following an 8 week interval during which the depressives are treated with the antidepressant drug sertraline. Pilot imaging data suggest that the differences in the 5HT1A receptor BP between unmedicated depressives and controls are robust in the mesiotemporal cortex and the ventrolateral and ventromedial prefrontal cortex (PFC). If a link between reduced 5HT1A receptor BP in the mesiotemporal cortex (which includes the hippocampus) and abnormal cortisol secretion is established in MDD, then normalization of this abnormality during treatment may have prognostic implications. In the ventrolateral and ventromedial PFC, the magnitude of the abnormal reductions of 5HT1A receptor BP were proportionately larger than the abnormalities of metabolism and grey matter volume previously shown in these areas in MDD, suggesting the 5HT1A receptor imaging measures may provide sensitive markers of pathology that can guide future post mortem histological and histochemical studies of MDD.