Imaging Alterations in Endocannabinoid Metabolism in Schizophrenia

描述(申请人提供)：虽然多巴胺在精神分裂症阳性症状(SCZ)中的作用已经确立，但越来越多的人认识到大麻素信号也可能发挥关键作用。流行病学研究发现，早期使用大麻会使SCZ的发病率增加两倍，从而将其确定为疾病的主要触发因素，从而提供了大麻类物质与SCZ之间的第一个联系。研究最多的内源性大麻素(ECB)，anandamide(AEA)作用于突触前CB1受体，调节神经递质的释放。在精神病发作期间，SCZ患者的脑脊液中检测到AEA显著升高，精神病缓解后AEA恢复正常。大脑中的AEA水平通过脂肪酸酰胺水解酶(FAAH)的水解酶进行严格调节。因此，FAAH为欧洲央行体系定下基调。[11C]我们的CAMH放射化学团队最近合成了一种碳11标记形式的有效不可逆FAAH抑制剂URB694，并对其进行了正电子发射断层扫描(PET)成像表征。该示踪剂具有较高的脑摄取率、反映已知FAAH浓度的区域分布以及良好的药效学和药代动力学特性，如动物研究所证实的那样。此外，在健康志愿者(HV)中进行了PET成像，以建立概念验证、重测重复性 和全身剂量测量，并优化[11C]路缘量化的动力学建模。作为第一个能够在体内评估FAAH酶的放射性示踪剂，[11C]STRET首次提供了活体大脑中AEA/FAAH的指标，从而超越了量化CB1受体表达的范围。我们的目标是通过使用[11C]抑制PET在体内测量未服用抗精神病药物的SCZ患者的FAAH。我们假设，与HV相比，SCZ组[11C]抑制纹状体和背外侧前额叶皮质的结合程度将显著降低。此外，我们还旨在探讨地区性FAAH水平与SCZ的精神病理和认知缺陷之间的关系。34名参与者(SCZ组17名，HV组17名)将使用高分辨率研究断层扫描(HRRT)进行60分钟[11C]边缘PET扫描。如前所述，使用代谢产物校正的动脉血浆中的[11C]抑制放射性作为输入函数，[11C]抑制的动力学可以用一个不可逆的两组织隔室模型来描述，提供了可靠的结果度量？？K3。高分辨率磁共振成像(MRI)扫描将提供量化PET图像中局部示踪剂分布以及测量局部脑血流量所需的解剖相关性。这项拟议的研究将首次探索ECB信号在活体大脑中的变化，并首次评估SCZ中的AEA代谢。我们的研究很重要，因为它可能阐明大麻在SCZ发病中所起作用的神经化学机制。这一概念上的突破将对精神病领域产生重大影响，为SCZ的治疗和预防提供新的途径。

DESCRIPTION (provided by applicant): While the role of dopamine in positive symptoms of schizophrenia (SCZ) is well established, it is increasingly recognized that cannabinoid signaling may also play a key role. Epidemiological studies have detected a twofold increase in the incidence of SCZ with early cannabis use, identifying it as a major trigger for the disease and thus providing the first link between cannabinoids and SCZ. The most studied of endocannabinoids (eCBs), anandamide (AEA), acts on the presynaptic CB1 receptors to modulate the release of neurotransmitters. Dramatic elevations of AEA were detected in cerebrospinal fluid of patients with SCZ in the midst of a psychotic episode, which normalize after psychosis resolution. Levels of AEA in the brain are tightly regulated through hydrolysis by the fatty acid amide hydrolase (FAAH) enzyme. FAAH therefore sets the tone of the eCB system. [11C]CURB, a carbon-11-labelled form of the potent irreversible FAAH inhibitor URB694, has recently been synthesized by our CAMH radiochemistry team and characterized for positron emission tomography (PET) imaging. The tracer exhibits high brain uptake, regional distribution that reflects known FAAH density, and excellent pharmacodynamic and pharmacokinetic properties, as established in animal studies. Furthermore, PET imaging in healthy volunteers (HV) was carried out to establish proof-of- concept, test-retest reproducibility and full body dosimetry, and to optimize kinetic modeling for [11C]CURB quantification. As the first radiotracer capable of assessing FAAH enzyme in-vivo, [11C]CURB goes beyond quantifying CB1 receptor expression by providing for the first time an index of AEA/FAAH in the living brain. We aim to measure FAAH in vivo by using [11C]CURB PET in antipsychotic-naive patients with SCZ. We hypothesize that [11C]CURB binding in the striatum and dorsolateral prefrontal cortex will be significantly lower in SCZ, as compared to HV. Additionally, we aim to explore the relation between regional FAAH levels and psychopathology and cognitive deficits in SCZ. Thirty-four participants (17 in SCZ and 17 in HV group) will undergo a 60 min [11C]CURB PET scan using a high-resolution research tomograph (HRRT). As previously established, the kinetics of [11C]CURB can be described with an irreversible two-tissue compartment model using metabolite-corrected [11C]CURB radioactivity in arterial plasma as input function, providing the reliable outcome measure ?k3. High resolution Magnetic Resonance Imaging (MRI) scans will provide an anatomical correlation needed to quantify regional tracer distribution in the PET image, as well as to measure regional cerebral blood flow. The proposed research will be the first exploration of changes in eCB signaling in a living brain evaluating for the first time AEA metabolism in SCZ. Our research is important since it may elucidate the neurochemical mechanism behind the role of cannabis in the onset of SCZ. This conceptual breakthrough would have significant impact on the field of psychosis, providing a new approach to treatment and prevention of SCZ.