Rapid low-cost production of contrast agents for metabolic imaging

项目总结 含氟脱氧葡萄糖(FDG)的正电子发射断层扫描(PET)使分子成像和 极大地改善了对癌症等许多致命疾病的诊断和监测反应。 然而，FDG-PET技术存在检查时间长、预扫描时间长等局限性 禁食时间，并使用电离辐射。核自旋的超极化增加了它们与 核磁共振扫描仪的场强提高了4-6个数量级，导致了核磁共振信号的相应增益。作为一名 结果可以在体内检测到低浓度的代谢物。此外，光谱磁共振成像 能够实时检测注射的外源性超极化造影剂的代谢，因为它 可以映射注射的新陈代谢探针及其产物。整个超极化MRI扫描是在 大约1分钟。主要的超极化造影剂是[1-13C]丙酮酸，它探测 细胞水平能量代谢异常的生化途径。这项下一代技术具有 未来给分子成像带来革命性变化的潜力。目前正在近30项临床试验中对其进行评估。 [1-13C]丙酮酸的超极化状态目前是通过溶出动力学在临床规模上产生的 核极化(d-DNP)技术是一种利用低温、强磁场和强磁场来实现的新型极化技术。 功率微波辐射。这项技术非常慢：大约需要1个小时才能生产出一个临床 剂量。次要的担忧是超过200万美元的高成本，以及运营所需的昂贵冷冻机。 需要更快和更负担得起的方法来使超极化[1-13C]丙酮酸可用于 广泛的临床应用。2015年，我们共同发明了一种替代技术，用于低成本生产 被称为可逆交换信号放大的代谢探针使对齐转移到 异核(剑鞘)。在2019-2022年，我们和其他人已经证明了超极化[1- 13C]丙酮酸可以使用这一新技术产生，这依赖于同时交换 对氢气(核自旋超极化的来源)和[1-13C]丙酮酸在金属络合物上的作用。 与d-DNP不同的是，军刀鞘具有高度的可扩展性，速度快(1分钟)，潜在地允许生产超过10剂 每小时。此外，我们的合作证明了将SABRE催化剂从 超极化溶液制备超极化化合物的无催化剂溶液。这项提案将重点放在 关于解决军刀鞘的关键剩余方面以制备生物相容的制剂 超极化[1-13C]丙酮酸造影剂。具体地说，调查人员将制定和优化 将集成(1)临床规模(~1克剂量)的仪器(基于已商业化的原型) 生产；(2)军刀催化剂提取；(3)在生物相容缓冲液中重建，随后是可行性 在细胞中的研究。我们预计我们这两年奖项的最终产品，即开发的仪器 (也就是超偏振器)将进入临床试验，并将商业化。

PROJECT SUMMARY Positron Emission Tomography (PET) with fluorodeoxyglucose (FDG) has revolutionized molecular imaging and substantially improved diagnosis and monitoring response to treatment of many deadly diseases such as cancer. However, FDG-PET technology has a number of limitations including long examination time, long pre-scan fasting time, and the use ionizing radiation. Hyperpolarization of nuclear spins increases their alignment with the field of an MRI scanner by 4-6 orders of magnitude, resulting in corresponding gains in the MRI signal. As a result, it becomes possible to detect low-concentration metabolites in vivo. Furthermore, spectroscopic MRI enables detection of real-time metabolism of an injected exogenous hyperpolarized contrast agent because it can map the injected metabolic probe and its products. The entire hyperpolarized MRI scan is performed in approximately 1 minute. The leading hyperpolarized contrast agent is [1-13C]pyruvate, which probes the biochemical pathways of aberrant energy metabolism at the cellular level. This next-generation technology has the potential to revolutionize molecular imaging in the future. It is now being evaluated in nearly 30 clinical trials. The hyperpolarized state of [1-13C]pyruvate is currently produced at clinical-scale via dissolution Dynamic Nuclear Polarization (d-DNP) technology, which employs cryogenic temperature, high magnetic field, and high- power microwave irradiation. This technology is very slow: it takes approximately 1 hour to produce a clinical dose. Minor concerns are the high cost of over $2M and requirement for expensive cryogens for operation. Faster and more affordable approaches are needed to make hyperpolarized [1-13C]pyruvate accessible for widespread clinical use. In 2015, we have co-invented an alternative technology for low-cost production of metabolic probes called Signal Amplification by Reversible Exchange Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH). In 2019-2022, we and others have demonstrated that hyperpolarized [1- 13C]pyruvate can be produced using this new technique, which relies on the simultaneous exchange of parahydrogen gas (the source of nuclear spin hyperpolarization) and [1-13C]pyruvate on metal complexes. Unlike d-DNP, SABRE-SHEATH is highly scalable, rapid (1 min) potentially allowing to produce over 10 doses per hour. Moreover, our collaboration has demonstrated the feasibility of removing the SABRE catalyst from hyperpolarized solutions to prepare catalyst-free solutions of hyperpolarized compounds. This proposal focuses on addressing the key remaining aspects of SABRE-SHEATH to prepare bio-compatible formulations of hyperpolarized [1-13C]pyruvate contrast agent. Specifically, the investigators will develop and optimize the instrumentation (based on an already commercialized prototype) that will integrate (1) clinical-scale (~1 g dose) production; (2) SABRE-catalyst extraction; and (3) reconstitution in a biocompatible buffer, followed by feasibility studies in cells. We anticipate that our end product of this two-year award, i.e., the developed instrumentation (a.k.a. hyperpolarizer) will enter clinical trials and will be commercialized.