放射性药物开发中的临床前分子成像：机遇与挑战

Contributing Author:

Syed Nuruddin - Associate Professor II at Department of Pharmacy, University of Oslo & Preclinical Research Manager at Oslo Imaging and Therapy laboratory (OITL), Norsk medisinsk syklotronsenter AS

Syed Nuruddin-奥斯陆大学药学系副教授II，奥斯陆成像和治疗实验室（OITL）临床前研究经理，Norsk medisinsk syklotronsenter AS

The development of radiopharmaceuticals represents a critical intersection of medicine, chemistry, nuclear physics, and pharmaceutical sciences, with preclinical imaging techniques playing an indispensable role in this process. Preclinical imaging facilitates the visualization and quantification of radiopharmaceutical distribution within biological systems, providing invaluable insights into their pharmacokinetics and biodistribution. Imaging modalities, such as Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET), together with CT/MRI, enable researchers to visualize radiopharmaceuticals’ distribution and anatomical localization within biological systems in real-time. The importance of preclinical imaging extends beyond mere visualization; it is fundamental for evaluating radiopharmaceuticals’ therapeutic potential and safety profiles. By assessing pharmacokinetics—how a drug is absorbed, distributed, metabolized, and excreted—these imaging modalities provide a comprehensive understanding of how effectively a radiopharmaceutical targets its intended tissues (Sgouros, 2023). This knowledge is crucial for optimizing dosage regimens that enhance therapeutic effects while minimizing potential toxicity (Sgouros, 2023).

Figure 1: Tumor uptake and Biodistribution of an 89Zr labeled antibody in liver tumor xenograft over the different period

图1：在不同时期内，89Zr标记的抗体在肝肿瘤异种移植物中的肿瘤摄取和生物分布

However, the application of preclinical imaging is not without its challenges. Issues such as the scarcity of specific radionuclides for targeted alpha therapy and limitations in current imaging technologies necessitate ongoing research to refine these methodologies. Integrating advanced preclinical models also poses logistical challenges that must be addressed to ensure accurate translation from bench to bedside.

然而，临床前成像的应用并非没有挑战。诸如用于有针对性的α治疗的特定放射性核素的稀缺和当前成像技术的局限性等问题需要进行不断的研究以完善这些方法。集成先进的临床前模型也带来了后勤挑战，必须解决这些挑战，以确保从实验室到床边的准确翻译。

One primary issue is the scarcity of specific radionuclides, particularly those used in targeted alpha therapy (TAT). The limited availability of alpha-emitting radionuclides, such as Actinium-225 and Lead-212, poses substantial obstacles for researchers aiming to develop effective imaging modalities for these agents (Machaba, 2024). This scarcity complicates the ability to conduct thorough preclinical evaluations and may delay the progression of promising therapies into clinical trials.

一个主要问题是缺乏特定的放射性核素，特别是那些用于靶向α治疗（达特）。α发射放射性核素（如锕-225和铅-212）的可用性有限，这对旨在为这些试剂开发有效成像模式的研究人员构成了重大障碍（Machaba，2024）。这种稀缺性使进行彻底的临床前评估的能力变得复杂，并可能延迟有希望的疗法进入临床试验的进展。

It is also noteworthy that the investigation of alpha particle-emitting radionuclides presents significant challenges, particularly regarding the mismatch between their energy profiles and ethically justifiable scanning periods for animal subjects. The available options for evaluating alpha emitters’ tissue distribution include specialized imaging techniques (alpha camera systems or SPECT). Furthermore, theragnostic approaches can be employed if there is a uniform distribution between diagnostic and therapeutic agents, enhancing treatment efficacy while mitigating ethical concerns. On this note, some studies deserve to be highlighted. For example, to realize imaging of Actinium-225, the presence of daughter decay can be utilized to produce SPECT by way of capturing 11% of 218 keV emissions produced by Francium-221 and the 26% of 440 keV produced by Bismuth-213 (Yong Du 2022).

还值得注意的是，对发射α粒子的放射性核素的研究提出了重大挑战，特别是关于其能量分布与动物受试者的伦理上合理的扫描周期之间的不匹配。用于评估α发射体的组织分布的可用选项包括专门的成像技术（α相机系统或SPECT）。此外，如果在诊断剂和治疗剂之间存在均匀分布，则可以采用治疗诊断方法，从而提高治疗功效，同时减轻伦理问题。在这方面，一些研究值得强调。例如，为了实现Actinium-225的成像，可以利用子体衰变的存在来产生SPECT，方法是捕获Francium-221产生的218 keV发射的11%和Bisperium-213产生的440 keV发射的26%（Yong Du 2022）。

Figure 2: Representative nuclear imaging of a rabbit bearing VX2 hepatic tumor xenograft. The micro-SPECT/CT images were acquired and reconstructed using the Francium-221 energy window (left) and Bismuth-213 energy window (right), respectively (Yong Du et al., 2022)

图2：携带VX 2肝肿瘤异种移植物的兔的代表性核成像。分别使用Francium-221能量窗（左）和Biscium-213能量窗（右）采集和重建micro-SPECT/CT图像（Yong Du等人，2022年）

Furthermore, existing imaging technologies often have limitations regarding sensitivity and resolution. While techniques like SPECT and PET are invaluable for visualizing radiopharmaceutical distribution, they may not be sufficiently advanced to detect low levels of radioactivity or differentiate between closely located tissues effectively. This inadequacy can result in inaccurate assessments of biodistribution and pharmacokinetics, ultimately affecting the interpretation of therapeutic efficacy (Sgouros, 2023). As a result, researchers must continuously seek innovative strategies to enhance imaging capabilities while ensuring that these advancements align with regulatory standards.

此外，现有的成像技术通常具有关于灵敏度和分辨率的限制。虽然像SPECT和PET这样的技术对于可视化放射性药物分布是非常宝贵的，但它们可能不足以检测低水平的放射性或有效地区分紧密定位的组织。这种不足可能导致生物分布和药代动力学评估不准确，最终影响疗效的解释（Sgouros，2023）。因此，研究人员必须不断寻求创新策略来增强成像能力，同时确保这些进步符合监管标准。

Additionally, there is often a lack of standardized protocols concerning preclinical imaging practices across different research institutions. This inconsistency complicates data comparison and interpretation between studies, making it challenging to establish universal benchmarks for assessing radiopharmaceuticals (Olkowski, 2023). The absence of harmonized methodologies may lead to variability in results that could obscure genuine therapeutic effects or safety concerns.

此外，在不同的研究机构中，通常缺乏关于临床前成像实践的标准化协议。这种不一致性使研究之间的数据比较和解释复杂化，使得建立评估放射性药物的通用基准具有挑战性（Olkowski，2023）。缺乏统一的方法可能导致结果的变异性，从而可能掩盖真正的治疗效果或安全性问题。

Finally, ethical considerations surrounding animal welfare also present a challenge in preclinical imaging applications. Researchers must balance the need for extensive biodistribution studies with the ethical imperative to minimize animal use and suffering (Hobbs, 2023). Using improved (higher resolution and sensitive) non-invasive imaging techniques that require fewer animals while still yielding robust data is essential, but it remains an ongoing area of research.

最后，围绕动物福利的伦理考虑也对临床前成像应用提出了挑战。研究人员必须平衡广泛的生物分布研究的需要与伦理要求，以尽量减少动物的使用和痛苦（霍布斯，2023）。使用改进的（更高分辨率和灵敏度）非侵入性成像技术，需要更少的动物，同时仍然产生强大的数据是必不可少的，但它仍然是一个正在进行的研究领域。

Another challenge lies in integrating advanced preclinical models into research protocols. Complex animal models—such as patient-derived xenografts (PDX) or genetically engineered mice—can yield more relevant data regarding human responses; however, these models also introduce logistical difficulties. Variability among individual animals can affect the reproducibility of results, making it challenging to draw definitive conclusions about a radiopharmaceutical’s performance across different biological contexts (Hobbs, 2023). Moreover, ethical considerations surrounding animal welfare necessitate careful planning and compliance with established guidelines.

另一个挑战在于将先进的临床前模型整合到研究方案中。复杂的动物模型，如患者来源的异种移植物（PDX）或基因工程小鼠，可以产生更多有关人类反应的数据;然而，这些模型也引入了后勤困难。个体动物之间的变异性可能会影响结果的重现性，因此难以得出关于放射性药物在不同生物学背景下性能的明确结论（Hobbs，2023）。此外，围绕动物福利的伦理考虑需要仔细规划和遵守既定的指导方针。

In conclusion, the continuous evolution of imaging technologies bolsters our capacity to visualize intricate biological processes. It paves the way for innovative therapeutic strategies that improve patient outcomes in nuclear medicine. As we advance into an era of precision medicine and personalized healthcare solutions, the synergistic relationship between preclinical imaging modalities and radiopharmaceutical developments will remain pivotal in effectively addressing emerging health challenges.

总之，成像技术的不断发展增强了我们可视化复杂生物过程的能力。它为改善核医学患者结局的创新治疗策略铺平了道路。随着我们进入精准医疗和个性化医疗解决方案的时代，临床前成像模式和放射性药物开发之间的协同关系将仍然是有效应对新兴健康挑战的关键。

References引用

Olkowski, C., (2023). Preclinical Development in Radiopharmaceutical Therapy for prostate cancer.Olkowski，C.，（2023年）。前列腺癌放射性药物治疗的临床前发展。https://www.sciencedirect.com/science/article/abs/pii/S0001299823000533

Machaba, M., (2024). Do current preclinical strategies for radiopharmaceutical development meet the needs of targeted alpha therapy?Machaba，M.，（2024年）。当前放射性药物开发的临床前策略是否满足靶向α治疗的需求？https://link.springer.com/article/10.1007/s00259-024-06719-5

Sgouros, G., (2023). Guidance for Preclinical Studies with Radiopharmaceuticals | IAEA.斯古罗斯湾，（2023年）。放射性药物临床前研究指南|原子能机构。https://www.iaea.org/publications/14818/guidance-for-preclinical-studies-with-radiopharmaceuticals

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Du Y., (2022). Preliminary evaluation of alpha-emitting radioembolization in animal models of hepatocellular carcinoma. PLoS ONE. https://doi.org/10.1371/journal.pone.0261982

杜云，（2022年）。α放射性栓塞治疗肝癌动物模型的初步评价。PLoS ONE. https://doi.org/10.1371/journal.pone.0261982