Production of radiometal-based radiopharmaceuticals at a clinical scale via droplet-scale radiochemistry

项目总结 尽管放射性药物在临床核医学中用于成像和治疗的巨大价值，以及 对于研究和药物开发，这些化合物的生产仍然非常昂贵，因为 需要复杂的资本密集型设备和基础设施(即热室、堆栈监控器、 无线电合成器和一套质量控制测试设备)。对于使用最广泛的聚酯 放射性药物，[18F]FDG，可以在同一天安排多个患者，使批量 生产成本将在多个单独剂量之间分摊。然而，对于大多数其他PET示踪剂，如 成本分担的机会很少或根本不存在，这意味着每一次生产运行实际上都致力于 单个患者，导致每个患者剂量的高成本。这些挑战阻碍了制造商 投资生产有价值但较少使用的放射性药物，这严重限制了它们的 可用性。此外，许多放射性药物的高价格阻碍了它们在研究中的使用(例如， 临床前)，并阻碍了新型放射性药物的开发和验证。除了有限的 在需求方面，一些放射性药物受到供应方问题的限制(例如，Ga-68的产量有限 这些产品本身就限制了一批生产的患者剂量。 而不是依赖于通过增加对放射性药物的需求来降低成本，以及增加 批量生产，这在很多情况下是不可能的，我们的策略是降低批量生产成本 它本身。近年来出现了制造PET示踪剂的新的微流控方法，有可能 通过大幅降低成本和复杂性，彻底改变示踪剂生产。基于液滴的方法 由加州大学洛杉矶分校的van Dam实验室开发，能够生产多种18F-放射性药物 试剂减少约100倍，合成和纯化时间缩短2-3倍，摩尔活度高，所有这些都在 一个咖啡杯大小的系统。液滴反应被测量到临床相关的量(一对多 患者剂量)通过使用上游放射性同位素浓缩器。 DropletPharm，Inc.正在商业化一种基于这项技术的台式放射性药物平台，该平台将 使一系列放射性药物能够向低成本生产转型。尽管大多数人 液滴放射化学以前的发展主要集中在18F-放射性药物上，有浓厚的兴趣 在放射性金属同位素中用于成像和治疗，具有大量的Ga-68化合物在临床前 开发、临床试验和少数获得FDA批准的常规使用。在这个第一阶段的STTR项目中，我们的目标是 将DropletPharm的液滴放射化学方法的应用扩展到F-18放射性示踪剂之外 建立了无金属液滴反应堆，建立了放射性金属标记的可行性。我们将发展 镓-68、铜-和锆-89的放射性同位素浓集方法(目标1)，发展液滴标记方法 示范放射性示踪剂(目标2)，并演示在cGMP环境中生产[68Ga]Ga-PSMA-11(目标3)。

PROJECT SUMMARY Despite the enormous value of radiopharmaceuticals for imaging and therapy in clinical nuclear medicine, and for research and drug development, the production of these compounds remains very expensive because of the need for complex, capital-intensive equipment and infrastructure (i.e., hot cells, stack monitor, radiosynthesizer, and a suite of QC testing equipment) at each site. For the most widely used PET radiopharmaceutical, [18F]FDG, multiple patients can be scheduled on the same day, enabling the batch production costs to be divided among many individual doses. However, for most other PET tracers, such cost-sharing opportunities are rare or non-existent, meaning that each production run is effectively dedicated to a single patient, resulting in a high cost per patient dose. These challenges discourage manufacturers from investing in the production of valuable but less-used radiopharmaceuticals, which severely limits their availability. Additionally, the high price of many radiopharmaceuticals discourages their use in research (e.g. pre-clinical), and hampers the development and validation of novel radiopharmaceuticals. In addition to limited demand, some radiopharmaceuticals are constrained by supply-side issues (e.g. limited output of Ga-68 generators) that inherently limits the number of patient doses that can be made in a single batch. Instead of relying on cost reductions through increased demand for radiopharmaceuticals and increase size of batches produced, which will be impossible for many cases, our strategy is to lower the batch production cost itself. New microfluidic methods of PET tracer manufacture have emerged in recent years with the potential to revolutionize tracer production via dramatic reductions in cost and complexity. The droplet-based approach developed by the van Dam laboratory at UCLA enables the production of numerous 18F-radiopharmaceuticals with ~100x reagent reduction, 2-3x reduction in synthesis and purification time, and high molar activity, all in a system the size of a coffee cup. Droplet reactions were scaled to clinically-relevant amounts (one to many patient doses) by using an upstream radioisotope concentrator. DropletPharm, Inc. is commercializing a benchtop radiopharmacy platform based on this technology that will enable a transformation to low-cost production of a broad range of radiopharmaceuticals. Though most of the prior development of droplet radiochemistry has focused on 18F-radiopharmaceuticals, there is intense interest in radiometal isotopes for imaging and therapy, with a large number of Ga-68 compounds in pre-clinical development, clinical trials and a few with FDA-approval for routine use. In this Phase I STTR project, we aim to expand the applications of DropletPharm’s droplet radiochemistry approach beyond F-18 radiotracers by building a metal-free droplet reactor and establishing the feasibility of radiometal labeling. We will develop radioisotope concentration methods for Ga-68, Cu-64, and Zr-89 (Aim 1), develop droplet labeling methods for example radiotracers (Aim 2), and demonstrate production of [68Ga]Ga-PSMA-11 in a cGMP setting (Aim 3).