Imaging Alterations in Endocannabinoid Metabolism in Schizophrenia

描述（由申请人提供）：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，确定它是该疾病的主要诱因，从而提供了大麻素与SCZ之间的第一个联系。内源性大麻素（eCBs）研究最多的是anandamide (AEA)，它作用于突触前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的急剧升高，在精神病消退后恢复正常。大脑中的AEA水平通过脂肪酸酰胺水解酶（FAAH）酶的水解受到严格调节。因此，FAAH为欧洲央行体系定下了基调。[11C]遏制，碳11标记形式的强效不可逆FAAH抑制剂URB694，最近由我们的CAMH放射化学团队合成，并对正电子发射断层扫描（PET）成像进行了表征。示踪剂表现出高脑吸收，反映已知FAAH密度的区域分布，以及在动物研究中建立的良好的药效学和药代动力学特性。此外，在健康志愿者（HV）中进行PET成像以建立概念验证，测试-再测试可重复性

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.