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

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发挥着关键作用 能够对特定神经受体系统(例如，受体密度、药物)进行体内定量测量 占有率、内源性配体占有率)以(I)评估关于疾病的基本假设或(Ii)帮助 针对这些受体的新型治疗方法的开发。随着生物学理解的演变，新奇 针对相关受体的PET放射性示踪剂正在不断开发，但获得这些新型PET 配基是极其有限的。短暂的半衰期限制了示踪剂在初始机构之外的分布 开发出来的，该领域的其他研究人员可能很难进行额外的研究 评估、验证或利用该新型配体。由于早期使用相对较少，以及 许多神经示踪剂、商业放射性药物缺乏可预见的广泛诊断用途 对制造它们不感兴趣。相反，研究人员只能通过以下方式从这些新型示踪剂中受益 生产示踪剂本身，这一努力会产生巨大的资源成本来建立合适的空间 和设备，然后开发和优化常规生产的内部合成方案。 用于生产放射性示踪剂的新的微型技术有可能通过以下方式克服这些挑战 减少昂贵试剂的消耗(~100倍)，提高产率，缩短合成时间，以及 其紧凑的尺寸允许自我屏蔽操作，避免了对基础设施(热室)的需要 常规放射化学实验室。卓普莱特制药公司正在将一种基于液滴的反应技术商业化 这些放射性示踪剂是在咖啡杯大小的设备中以高产率和摩尔活度制备的。通过 降低示踪剂生产各方面的成本(同位素、试剂、操作员时间、空间、资金)，并依赖于 在商业[18F]氟化物来源上，这项技术将使一种非常经济的途径建立一个 为研究人员提供各种研究用PET示踪剂的低成本放射性药物网络 学术界和制药公司。 作为一项概念验证，DropletPharm计划调整早期kappa阿片受体的放射合成 (Kor)配体[18F]LY2459989与液滴放射合成器结合，建立与cGMP相容的放射合成 过程，并比较合成的成本(传统方法和液滴方法之间) 开发工作以及常规批量生产。这种特殊的配体显示出相当大的前景 对人类的KOR/强啡肽系统进行成像，并将其提供给研究人员，将有助于广泛的研究 与KOR/强啡肽有关的一系列神经精神障碍，包括慢性疼痛、焦虑、 抑郁障碍、药物滥用等对社会产生深远负面影响的疾病。 该项目的成功还将表明，这一过程可以快速和经济地复制以增加 未来可与其他受体(例如，µOR、SV2A、NMDA、Oresin)结合的其他新型PET配体的可获得性。

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.