Demonstrating miniaturized production of a KOR PET tracer as a proof-of-concept for low-cost distribution of nascent PET neurotracers

展示 KOR PET 示踪剂的小型化生产，作为新兴 PET 神经示踪剂低成本分销的概念验证

• 批准号: 10822523
• 负责人: Jason Jones
• 金额: $ 28.63万
• 依托单位: DROPLETPHARM INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10822523
• 关键词: Academia; Address; Adolescent; Adult; Alcohol consumption; Anxiety; Area; Biological; Capital; Cells; Cessation of life; Clinical; Clinical Research; Clinical Trials; Coffee; Communities; Consumption; Cost Measures; Cyclic GMP; Cyclotrons; DSM-V; Data; Depressive disorder; Development; Devices; Diagnostic; Disease; Dose; Drug usage; Dynorphins; Equipment; Feedback; Fluorides; Formulation; Future; Half-Life; Health; Human; Image; Impairment; Infrastructure; Institution; Isotopes; Label; Ligands; Link; Major Depressive Disorder; Manuals; Measurement; Mental Depression; Methods; Mole the mammal; Monitor; Multi-Institutional Clinical Trial; N-Methylaspartate; Neurologic; Pathway interactions; Performance; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Play; Positron-Emission Tomography; Process; Production; Protocols documentation; Public Health; Radiochemistry; Reaction; Reagent; Research; Research Personnel; Resources; Role; Sensory Receptors; Site; Societies; Source; Substance Use Disorder; Substance abuse problem; System; Technology; Testing; Time; Tracer; Translating; Treatment Protocols; Validation; chronic pain; commercialization; cost; cost comparison; flexibility; hypocretin; imaging properties; in vivo; in vivo evaluation; interest; kappa opioid receptors; manufacture; manufacturing technology; miniaturize; neuropathology; neuropsychiatric disorder; neuropsychiatry; novel; operation; pharmacologic; radiotracer; receptor; receptor density; scale up; single episode major depressive disorder; substance abuse treatment; success; targeted biomarker; therapy design; treatment response

PROJECT SUMMARY / ABSTRACT Positron-emission tomography (PET) studies play a critical role in many areas of neurological health by enabling quantitative in vivo measurements of specific neuroreceptor systems (e.g. receptor density, drug occupancy, endogenous ligand occupancy) to (i) evaluate fundamental hypotheses about disease or (ii) aid in the development of novel treatments targeting those receptors. As biological understanding evolves, novel PET radiotracers targeting relevant receptors are continually being developed, but access to these novel PET ligands is extremely limited. Short half-lives limit tracer distribution beyond the initial institution where it was developed, and it can be very difficult for other investigators in the field to perform additional studies to evaluate, validate, or make use of the novel ligand. Due to the relatively infrequent usage in early stages, and the absence of foreseeable widespread diagnostic use for many neurotracers, commercial radiopharmacies are not interested in manufacturing them. Instead, researchers can only benefit from these novel tracers by producing the tracers themselves, an endeavor that incurs an enormous resource cost to set up suitable space and equipment, and then develop and optimize an in-house synthesis protocol for routine production. New microscale technologies for radiotracer production have the potential to overcome these challenges by reducing consumption of expensive reagents (~100x), increasing yields, and shortening synthesis times, and their compact size allows self-shielded operation and avoids the need for the infrastructure (hot cells) of a conventional radiochemistry lab. DropletPharm, Inc. is commercializing a droplet-based reaction technology in which radiotracers are prepared in high-yield and molar activity in a device the size of a coffee cup. By reducing costs of all aspects of tracer production (isotope, reagents, operator time, space, capital), and relying on commercial [18F]fluoride sources, this technology will enable a highly economical pathway to build out a “network” of low-cost radiopharmacies for supplying a variety of investigational PET tracers for researchers in academia and pharmaceutical companies. As a proof-of-concept, DropletPharm plans to adapt the radiosynthesis of an early-stage kappa opioid receptor (KOR) ligand, [18F]LY2459989, to the droplet radiosynthesizer, establish a cGMP compatible radiosynthesis process, and compare the costs (between conventional and droplet-based approaches) of the synthesis development effort as well as routine batch production. This particular ligand shows considerable promise for imaging the KOR / dynorphin systems in humans, and supplying it to researchers will benefit studies of a wide range of neuropsychiatric disorders in which KOR/dynorphin is implicated, including chronic pain, anxiety, depressive disorders, substance abuse and other conditions with far-reaching negative impacts on society. Success of the project will also show that this process can be replicated quickly and economically to increase accessibility of additional novel PET ligands for other receptors (e.g. µOR, SV2A, NMDA, orexin) in the future.

项目摘要 /摘要 正电子发射断层扫描（PET）研究在神经健康的许多领域起着至关重要的作用 启用特定神经感受器系统的体内测量（例如受体密度，药物） 占用，内源性配体占用）至（i）评估有关疾病或（ii）帮助的基本假设 针对这些受体的新型治疗方法的发展。随着生物学理解的发展，新颖 靶向相关接收器的宠物放射性示例正在不断开发，但可以访问这些新型宠物 配体非常有限。短半衰期限制示踪剂分布以外的初始机构 开发的，该领域的其他研究人员可能很难进行其他研究 评估，验证或利用新型配体。由于在早期阶段的相对不经常使用，并且 缺乏许多神经训练剂，商业放射性药物的森林宽度诊断用途 对制造它们不感兴趣。相反，研究人员只能通过这些新颖的示踪剂受益 生产示踪剂本身，这项工作会产生巨大的资源成本来建立合适的空间 和设备，然后开发并优化用于常规生产的内部合成协议。 新的用于放射性示意剂生产的微观微观技术有可能克服这些挑战 减少昂贵试剂的消耗（〜100倍），增加产量和缩短合成时间，以及 它们的紧凑尺寸允许自屏蔽的操作，并避免了对A的基础设施（热单元） 常规放射化学实验室。 DropletPharm，Inc。正在商业化基于液滴的反应技术 哪些放射性示例是在咖啡杯大小的设备中以高产物和摩尔活性制备的。经过 降低示踪剂生产方面的各个方面（同位素，试剂，操作员时间，空间，资本），并依靠 在商业[18F]氟化物来源，这项技术将使一条高度经济的途径能够建立一个 低成本放射性药物的“网络”，用于为研究人员提供各种研究宠物示踪剂 学术界和制药公司。 作为概念验证，液滴计划适应早期Kappa阿片类药物接收器的放射性合成 （kor）配体，[18F] LY2459989，到达液滴放射合成器，建立CGMP兼容的放射性合成 过程，并比较合成的成本（传统和基于液滴的方法） 开发工作以及常规批处理生产。这种特殊的配体对 对人类的Kor / Dynorphin系统进行成像，并将其提供给研究人员，将有益于广泛的研究 隐含Kor/dynorphin的神经精神疾病范围，包括慢性疼痛，焦虑， 抑郁症，滥用药物和其他对社会的负面影响。 该项目的成功还将表明，该过程可以快速，经济地复制以增加 未来其他受体（例如µOR，SV2A，NMDA，OREXIN）的其他新型PET配体可访问性。