New PET tracers for neuroimaging of FAAH in endocannabinoid signaling

描述(由申请人提供)：K01研究的目标是帮助申请人在神经和精神疾病的PET示踪剂开发和神经成像方面建立一个独立且具有竞争力的研究计划，主要重点是开发一种用于对药物成瘾的内源性大麻(ECB)信号中的脂肪酸酰胺水解酶(FAAH)进行PET成像研究的最佳放射性药物。FAAH是一种负责分解内源性大麻素的酶，如花生胺。因此，它在为人脑中的大麻素系统定调方面发挥着重要作用。FAAH的抑制被认为是一个有吸引力的药物和成像靶点。此外，有大量证据表明，FAAH在成瘾以及其他精神和神经疾病中发挥着重要作用。测量活着的人脑中FAAH水平的能力将非常有用。不仅可以直接测量潜在的FAAH抑制剂药物的疗效，而且可以将FAAH在某些人群中的作用与正常人群进行比较(例如，吸毒者与非吸毒者相比)，从而深入了解这种重要的酶在正常和疾病受试者中的作用。FAAH可以通过医学成像技术-正电子发射断层扫描(PET)在人脑中测量，该技术可以创建体内发生的生化过程的图像。几种放射性示踪剂已被开发用于FAAH的PET成像。到目前为止，只有由Neil Vasdev博士开发的碳-11(11C；半衰期=20.4分钟)标记的放射性示踪剂[11C]STRET已经在人体试验中进行了测试和验证。[11C]CRED的试验数据证明了FAAH成像的可行性和临床潜力。为了克服基于PK的[11C]抑制的局限性，开发了第一种放射性标记的氟-18(18F；半衰期=109.7分钟)FAAH抑制剂[18F]DOPP。在非人类灵长类动物中对[18F]DOPP的初步评估表明，该放射性示踪剂是一种有前途的铅放射性示踪剂，值得进一步优化和评估，以用于对ECB信号通路在疾病表现上的急性变化的特异性成像。这项建议涉及对一名初级教员进行PET神经成像研究的培训，从工作台到床边，并为放射性药物科学领域做出贡献；该领域严重缺乏高素质的人才。申请者还将利用世界级的教育资源、在科学研究和指导方面拥有成功记录的教职员工以及一流的研究设施来进行拟议的研究。本K01提案的具体目的是设计、合成和开发动力学优化的氟化FAAH抑制剂，用18F放射性标记最有希望的先导化合物，并在非人类灵长类动物中对这些化合物进行评估。我们将确定18F标记的FAAH抑制剂的分布、特异性结合和动力学模型，这将使我们能够研究FAAH连接的内源性大麻素对成瘾的调节机制。相关性：这项提议有可能改善公共健康，并通过使用18F标记的FAAH示踪剂改进PET神经成像来帮助患有毒瘾的患者。

DESCRIPTION (provided by applicant): The goal of the K01 research is to help the applicant to establish an independent and highly- competitive research program in the PET tracer development and neuroimaging for neurologic and psychiatric illnesses, with a major focus of developing an optimal radiopharmaceutical for PET imaging study of fatty acid amide hydrolase (FAAH) in the endocannabinoid (eCB) signaling of drug addiction. FAAH is the enzyme responsible for hydrolysing endocannabinoids such as anandamide. As such it plays a major role in setting the tone of the cannabinoid system in the human brain. Inhibition of FAAH is seen as an attractive pharmaceutical and imaging target. In addition there is substantial evidence that FAAH plays a major role in addiction, and in other psychiatric and neurological illnesses. The ability to measure the levels of FAAH in the living human brain would be extremely useful. Not only could the efficacy of potential FAAH inhibitor drugs be measured directly, but the role of FAAH in certain populations could be compared to normal populations (e.g. drug users compared to non-users), affording insights into the role of this important enzyme in normal and diseased subjects. FAAH could be measured in the human brain by the medical imaging technique, positron emission tomography (PET), which creates images of biochemical processes occurring in vivo. Several radiotracers have been developed for PET imaging of FAAH. To date, only carbon-11 (11C; half-life = 20.4 min) labeled radiotracer, [11C]CURB developed by Dr. Neil Vasdev, has been tested and validated in human trials. Pilot data with [11C]CURB demonstrated both the feasibility, and clinical potential, of imaging FAAH. To overcome the PK-based limitations of [11C]CURB, the first fluorine-18 (18F; half-life = 109.7 min) radiolabeled FAAH inhibitor [18F]DOPP was developed. Preliminary evaluation of [18F]DOPP in nonhuman primates showed that this radiotracer is a promising lead radiotracer worthy of further optimization and evaluation for specific imaging of acute changes in eCB signaling pathways on disease presentation. This proposal involves training a junior faculty member in PET neuroimaging studies from bench to bedside and contributing to the field of radiopharmaceutical sciences; a field suffering from a critical shortage of highly qualified personnel. The applicant will also take advantage of the world-class educational resources, faculty members with successful track-records in scientific research and mentoring, and top-tier research facilities to conduct the proposed research. It is the specific aim of this K01 proposal t design, synthesize, and develop fluorinated FAAH inhibitors with optimized kinetics, radiolabel the most promising lead compounds with 18F and evaluate these compounds in nonhuman primates. We will determine the distribution, specific binding and kinetic model of 18F-labeled FAAH inhibitor that will enable us to study mechanisms for FAAH-linked endocannabinoid regulation of addiction. Relevance: This proposal has the potential to improve public health and help patients suffering from addiction through advancement of PET neuroimaging using 18F-labeled FAAH tracer.