THE PET RADIOTRACER TRANSLATION AND RESOURCE CENTER (PET-RTRC)

总体摘要 这一提议的推动力是对先进的人类分子成像工具的日益增长的需求 人类健康。造成这种未得到满足的需求的驱动因素是各种人类致病机制的演变 限制临床前应用的疾病(如动脉粥样硬化、各种癌症和阿尔茨海默病) 疾病模型，人类对非侵入性读数的渴望，以促进药物的发现和开发 为了成功实施正在进行的努力，使精准医疗成为现实。虽然是PET 放射性示踪剂在这方面特别有吸引力，成功地将 新的PET放射性示踪剂从替补席到诊所。例子很多，从低水平的商业投资 主要的发展瓶颈，包括需要简化的综合计划以促进传播， 放射性示踪剂评估所需的各种临床前疾病模型在单一地点的有限可获得性， 对新放射性示踪剂进行第一手评估的能力仅限于全国范围内的几个中心 新兴成像项目缺乏可用的培训机会，特别是那些专业知识较少的项目 在合成和放射化学方面。 我们建议通过以下方式建立PET放射性示踪剂翻译和资源中心(PET-RTRC 利用华盛顿大学(Wu)和Mallinckrodt Radiology Institute(MIR)在PET方面的专业知识 与全国各地的研究小组一起设计、开发、培训和使用放射性示踪剂 研究感兴趣的分子和细胞过程以促进小说的发展和传播 宠物放射性示踪剂。我们的愿景是将吴和和平号的PET放射性示踪剂计划扩展到全国范围。 为了实现这一愿景，我们将实现以下具体目标： 目标1：技术研究与开发项目将开发一系列PET放射性示踪剂 用于人类成像以检测调节无处不在的疾病的重要分子和细胞事件 炎症(鞘氨醇-1-磷酸受体1和各种趋化因子)和氧化应激的过程 (诱导型一氧化氮合酶和总活性氧/氮物种)。 目标2：创建用于临床前评估的分布式模型，以缩短放射性示踪剂开发时间 并重要地扩大新型PET放射性示踪剂的翻译潜力，通过以下方式加强全国范围内的研究 与WU内外的合作项目(CP)合作，评估由 R&D。提出了许多优化中心和合作伙伴之间“推-拉”互动的策略。 目标3：通过提供基础设施(例如，GMP能力)和专业知识(例如， 毒性和剂量学评估；化学、制造和控制程序；以及EIND提交和 维护)对初始人类评估和随后的传播是必要的。 目标4：建立一个培训和传播核心，该核心将：a)为个人培训提供资源 在PET放射性示踪剂的合成和使用这项技术的科学家以及在采取的详细步骤中 完成关于人类使用该中心生产的放射性示踪剂的法规要求；B)提供 一种资源，以提高对PET-RTRC开发的放射性示踪剂的使用和认识，例如 确定将使用研究与开发部门开发的最有前景的放射性示踪剂的服务项目；以及 开发和维护一个描述PET-RTRC活动的网站。 行政核心将在执行委员会的指导下监督PET-RTRC的运作 并建立关键功能，如追踪器审查委员会和定量成像/信息学 资源，以及外部咨询委员会，以确保这一BRTC的有效运作，以满足其 科学、培训和传播目标。

Overall Summary The impetus for this proposal is the increasing need for sophisticated human molecular imaging tools to advance human health. Drivers that are creating this unmet need are the evolution in the pathogenesis of various human diseases (e.g., atherosclerosis, various cancers and Alzheimer's Disease) that limit the applicability of pre-clinical disease models, the desire for noninvasive readouts in humans to facilitate drug discovery and development and for the successful implementation of the ongoing efforts to make precision medicine a reality. Although PET radiotracers are particularly attractive in this regard, there are several obstacles to the successful translation of new PET radiotracers from the bench to the clinic. Examples range from the low level of commercial investment to major development bottle-necks including the need for simplified synthetic schemes to facilitate dissemination, limited availability at a single-site of diverse pre-clinical models of disease necessary for radiotracer evaluation, the capability to perform first-in-man evaluation of new radiotracers is limited to a few centers nationwide and the lack of available training opportunities at emerging imaging programs, particularly those with less expertise in synthetic and radiochemistry. We are proposing establishing the PET Radiotracer Translation and Resource Center (PET-RTRC) by leveraging the expertise at Washington University (WU) and the Mallinckrodt Institute of Radiology (MIR) in PET radiotracer design, development, training and use with that of research groups throughout the country who are studying molecular and cellular processes of interest to facilitate the development and dissemination of novel PET radiotracers. Our vision is to expand the PET radiotracer program here at WU and MIR to a national scale. To realize this vision we will address the following Specific Aims: Aim 1: The Technological Research & Development (TR&D) Projects will develop a portfolio of PET radiotracers for human imaging to detect important molecular and cellular events that modulate the ubiquitous disease processes of inflammation (sphingosine-1-phosphate receptor 1 and various chemokines) and oxidative stress (inducible form of nitric oxide synthase and total reactive oxygen/nitrogen species). Aim 2: Create a distributed model for pre-clinical evaluation to both shorten the radiotracer development timeline and importantly expand the translational potential of novel PET radiotracers to enhance research nationwide by engaging Collaborative Projects (CPs) from both within and outside WU to evaluate radiotracers developed by TR&Ds. Numerous strategies to optimize the “push-pull” interaction between the Center and CPs are proposed. Aim 3: Facilitate first-in-man studies by providing the infrastructure (e.g., GMP capabilities) and expertise (e.g, toxicity and dosimetry evaluation; Chemistry, Manufacturing and Control procedures; and eIND submission and maintenance) necessary for initial human evaluation and subsequent dissemination. Aim 4: Establishing a Training and Dissemination Core that will: A) Provide a resource for training of individuals in PET radiotracer synthesis and scientists who use this technology as well as in the detailed steps taken to complete the regulatory requirements for human use of the radiotracers produced by the Center and; B) Provide a resource to increase the use and awareness of the radiotracers developed by the PET-RTRC such as identification of Service Projects that will utilize the most promising radiotracers developed by the TR&Ds, and development and maintenance of a website describing PET-RTRC activities. The Administrative Core will oversee PET-RTRC operations under the guidance of the Executive Committee and establish key functionalities, such as the Tracer Review Committee and Quantitative Imaging/Informatics Resource, and the External Advisory Committee to ensure efficient operation of this BRTC so that it meets its scientific, training and dissemination objectives.