SBIR Phase I: Novel macrocyclic chelating groups for use in targeted radioisotope diagnostic and companion diagnostic/therapeutic applications

这个小企业创新研究（SBIR）第一阶段项目描述了用于靶向放射性同位素应用的新型大环螯合基团的合成和评估。在单光子发射计算机断层扫描和正电子发射断层扫描中，靶向放射性同位素被部署为显像剂。这种诊断试剂也被用作靶向放射性同位素治疗中的伴侣，其中放射治疗上有用的电离辐射的放射性核素通过附着于赋予适当生物分布和药代动力学特性的辅助分子类似地定位在特定的生物位点内。金属放射性同位素具有多种成像和治疗特性，但其定位分子中金属放射性同位素的丢失可能导致有害的副作用或降低对比度和疗效。因此，人们迫切需要改进用于放射性药物的螯合基团。这种螯合基团必须迅速结合放射性同位素，使其与临床实验室制备的实用性相兼容。它们还必须稳定地结合阳离子，这样在体内就不会释放阳离子，至少在其衰变之前是这样。我们提出的优化的螯合基团将稳定地配位目前用于基于放射性同位素的诊断和治疗的金属阳离子，显示容易的络合动力学，并提供一个方便的合成手柄附着到靶向部分。该项目更广泛的影响/商业潜力将是开发新的“笼状”大环螯合基团，与目前使用的无环和单大环螯合剂相比，它们的结合速度更快、更稳定。它们不仅可以配位In+3，还可以配位更多的奇异阳离子，如Zr+4，这些阳离子的同位素迄今为止尚未开发，但具有有趣的放射化学特征，例如，锆-89，正电子发射半衰期为78小时。通过这种方法，目的是提高现有放射性药物的效用，并将这项技术的范围扩大到目前在临床中不发达的放射性核素。

This Small Business Innovative Research (SBIR) Phase I project describes the synthesis and evaluation of novel macrocyclic chelating groups intended for use in targeted radioisotope applications. Targeted radioisotopes are deployed as imaging agents in the context of single-photon emission computed tomography and positron emission tomography. Such diagnostic agents also are used as a companion in targeted radioisotope therapy wherein a radionuclide that emits therapeutically useful ionizing radiation is similarly localized within specific biological sites by attachment to an accessory molecule that imparts appropriate biodistribution and pharmacokinetic properties. Metallic radioisotopes offer versatile imaging and therapeutic properties, but loss of metallic radioisotopes from their site-directing molecules can lead to deleterious side-effects or reduced contrast and efficacy. There is, therefore, a recognized, compelling need for improved chelating groups for use in radiopharmaceuticals. Such chelating groups must rapidly bind radioisotopes, so that they are compatible with the practicalities of clinical laboratory preparation. They also must stably bind the cation so that none is released in vivo, at least prior to its decay. The optimized chelating groups we propose will stably coordinate metal cations currently used for radioisotope-based diagnosis and therapy, display facile complexation kinetics, and provide a convenient synthetic handle for attachment to targeting moieties. The broader impact/commercial potential of this project will be the development of novel "caged" macrocyclic chelating groups that display faster and more stable binding as compared to acyclic and mono-macrocyclic chelators currently used. These will coordinate not only In+3, but also more exotic cations such as Zr+4 whose isotopes have hitherto remained undeveloped but possess intriguing radiochemical characteristics, e.g., zirconium-89, positron emission half-life 78 hr. By means of this approach, the aim is both to improve the utility of existing radiopharmaceuticals, and to expand the scope of this technology to radionuclides that are, at present, underdeveloped in the clinic.