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

这个小型企业创新研究（SBIR）二期项目建议开发新型的“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。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。人们公认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。在本项目下开发的优化螯合基团将稳定地配位目前用于放射性同位素诊断和治疗的金属阳离子，显示容易的络合动力学，并为附着在靶向部分提供方便的合成手柄。通过这种方法，新型螯合剂将提高现有放射性药物的效用，并允许使用目前在临床中不发达的放射性核素。如果该项目成功，其更广泛的影响/商业潜力将是芳香烃大环双功能螯合剂（ambfc）的开发，这将有可能改变癌症检测和治疗方式的格局。由于AMBFCs可用于癌症成像，医生可以从治疗进展、缓解和预后的有效反馈循环中获益，从而进一步缩短治疗时间。伴随放射诊断中的AMBFCs还可以降低无效药物的成本，这是FDA的战略目标。此外，通过在AMBFCs中使用新的放射性核素来杀死肿瘤及其转移，可以大大减少治疗的时间和成本。所有这些特征都可以促进更好的临床结果，并通过早期干预挽救生命，降低医疗保健的总体成本。通过这门独特的科学改善临床结果，ambfc将促进国家健康、繁荣和他人的福利。

This Small Business Innovation Research (SBIR) Phase II project proposes to develop novel "caged" macrocyclic chelating groups that display faster and more stable binding as compared to acyclic and mono-macrocyclic chelators currently used. 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 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 must also stably bind the cation so that none is released in vivo, at least prior to its decay. The optimized chelating groups to be developed under this project 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. By means of this approach, the novel chelators will both improve the utility of existing radiopharmaceuticals and permit the use of radionuclides that are at present underdeveloped in the clinic.The broader impact/commercial potential of this project, if successful, will be that aromatic macrocyclic bifunctional chelators (AMBFCs) will be developed that will potentially change the landscape in the way cancer is detected and treated. Because the AMBFCs can be used in cancer imaging, the physician benefits from an effective feedback loop on therapeutic progress, remission, and prognosis that could further shorten the time of treatment. AMBFCs in companion radiodiagnostics also could reduce the cost of ineffectual medication, which is a strategic goal of the FDA. Plus, by employing novel radionuclides in the AMBFCs to kill tumors and their metastases, the benefit could materially cut down the time and cost of therapy. All of these features could promote better clinical outcomes and reduce the overall cost of healthcare by saving lives with earlier intervention. Through improved clinical outcomes from this unique science, AMBFCs will advance the national health, prosperity and welfare of others.