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

SBIR 第一阶段：用于靶向放射性同位素诊断和伴随诊断/治疗应用的新型大环螯合基团

• 批准号: 1215462
• 负责人: Darren Magda
• 金额: $ 14.95万
• 依托单位: Lumiphore, Inc.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1215462&HistoricalAwards=false
• 关键词: SBIR; Phase; Novel; macrocyclic; chelating

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.

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。 靶向放射性同位素在单光子发射计算机断层扫描和正电子发射断层扫描的背景下被部署为成像剂。 这样的诊断剂还用作靶向放射性同位素疗法中的伴侣，其中发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的生物分布和药代动力学性质的辅助分子而类似地定位在特定的生物学位点内。 金属放射性同位素提供了多功能的成像和治疗特性，但金属放射性同位素从其位点导向分子中的损失可能导致有害的副作用或降低的对比度和功效。 因此，对于用于放射性药物的改进的螯合基团存在公认的迫切需要。 这种螯合基团必须快速结合放射性同位素，以便它们与临床实验室制备的实用性相容。它们还必须稳定地结合阳离子，使得至少在其衰变之前，在体内不释放阳离子。我们提出的优化的螯合基团将稳定地协调目前用于基于放射性同位素的诊断和治疗的金属阳离子，显示出容易的络合动力学，并提供了一个方便的合成手柄连接到靶向部分。该项目更广泛的影响/商业潜力将是开发新型“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，其显示出更快和更稳定的结合。 这些离子不仅与In+3配位，还与更奇特的阳离子配位，如Zr+4，其同位素迄今尚未开发，但具有有趣的放射化学特性，例如，锆-89，正电子发射半衰期78小时。通过这种方法，目的是提高现有放射性药物的效用，并将这种技术的范围扩大到目前临床上尚不发达的放射性核素。