New PET tracers for neuroimaging of FAAH in endocannabinoid signaling

描述（由申请人提供）：K 01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的、具有高度竞争力的研究项目，主要关注开发一种最佳放射性药物，用于药物成瘾的内源性大麻素（eCB）信号传导中脂肪酸酰胺水解酶（FAAH）的PET成像研究。FAAH是负责水解内源性大麻素如大麻素的酶。因此，它在设定人类大脑中大麻素系统的基调方面发挥着重要作用。FAAH的抑制被视为有吸引力的药物和成像靶标。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起着重要作用。测量活体人脑中FAAH水平的能力将非常有用。不仅可以直接测量潜在FAAH抑制剂药物的功效，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酶在正常和患病受试者中的作用。FAAH可以通过正电子发射断层扫描（PET）医学成像技术在人脑中测量，该技术可以创建体内发生的生化过程的图像。已经开发了几种放射性示踪剂用于FAAH的PET成像。迄今为止，只有碳-11（11 C;半衰期= 20.4分钟）标记的放射性示踪剂，[11 C]CURB由Neil Vasdev博士开发，已在人体试验中进行了测试和验证。[11 C]CURB的初步数据证明了FAAH成像的可行性和临床潜力。为了克服[11 C]CURB的PK限制，开发了第一种氟-18（18 F;半衰期= 109.7 min）放射性标记的FAAH抑制剂[18 F]DOPP。[18 F]DOPP在非人灵长类动物中的初步评价表明，这种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价，用于疾病表现时eCB信号通路急性变化的特异性成像。该提案涉及培训一名初级教员从事PET神经成像研究，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。申请人还将利用世界一流的教育资源，在科学研究和指导方面具有成功记录的教师，以及顶级研究设施来进行拟议的研究。本K 01提案的具体目标是设计、合成和开发具有优化动力学的氟化FAAH抑制剂，用18F放射性标记最有前途的先导化合物，并在非人灵长类动物中评价这些化合物。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相关的内源性大麻素调节成瘾的机制。相关性：该提案有可能通过使用18F标记的FAAH示踪剂推进PET神经成像来改善公共健康并帮助患有成瘾的患者。

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.