SEROTONIN 1A RECEPTOR & METABOLIC IMAGING IN DEPRESSION

产品说明：（申请人摘要）多条证据表明，在重度抑郁症（MDD）中，降钙素1A（5 HT 1A）受体功能异常，并且躯体抗抑郁治疗影响与治疗功效相关的5 HT 1A受体功能变化。支持这些假设的数据已获得通过评估神经内分泌和温度反应的5 HT 1A激动剂在MDD科目，测量5 HT 1A受体结合在脑组织中获得死后的MDD科目的小样本，并检查在5 HT 1A受体结合在大鼠抗抑郁药（AD）管理后的变化。然而，还没有直接的证据表明，中央5 HT 1A受体异常或抗抑郁药治疗对5 HT 1A受体药理学的影响在生活抑郁症受试者。用于正电子发射断层扫描（PET）成像的高选择性5-HT 1A受体放射性配体[羰基-11 C]- WAY-100635的开发，最近使直接、无创探索MDD中的中枢5-HT 1A受体结合潜力（BP）成为可能。为了进一步了解MDD的神经生物学和AD治疗机制，将使用PET和[羰基-11 C]WAY-100635比较MDD和健康对照受试者之间以及MDD受试者治疗前和治疗后状况之间的5 HT 1A受体BP。将在同一扫描过程中采集18 F-氟脱氧葡萄糖（FDG）摄取图像，以评价局部5 HT 1A受体BP与先前在MDD中确定的葡萄糖代谢异常之间的关系。在成像之前还检查皮质醇分泌的内分泌评估，以确定海马5 HT 1A受体的下调是否响应于与MDD相关的皮质醇增多而发生，如在实验动物中在应激和糖皮质激素施用期间所发生的那样。影像学和内分泌测量在8周间隔后重复，在此期间抑郁症患者用抗抑郁药舍曲林治疗。飞行员成像数据表明，未经药物治疗的抑郁症患者和对照组之间的5 HT 1A受体BP的差异是强大的中颞叶皮层和腹外侧和腹内侧前额叶皮层（PFC）。如果在MDD中建立了近中颞叶皮质（包括海马）中5 HT 1A受体BP降低与皮质醇分泌异常之间的联系，则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，5 HT 1A受体BP的异常降低的幅度成比例地大于先前在MDD中这些区域中显示的代谢和灰质体积的异常，这表明5 HT 1A受体成像测量可以提供灵敏的病理标记物，可以指导未来的MDD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.