New Synthetic Approaches to Small Molecules for Imaging

用于成像的小分子合成新方法

• 批准号: 9153959
• 负责人: Martin Schnermann
• 金额: $ 31.81万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9153959
• 关键词: Alkaloids; Antibodies; Area; Biological; Biological Factors; Biology; Chemicals; Clinical; Clinical Trials; Complex; DNA Sequence; Development; Epidermal Growth Factor Receptor; Evaluation; Exhibits; Eye; FDA approved; Fluorescence; Goals; Image; Indocyanine Green; Laboratories; Light; Malignant Neoplasms; Medicine; Methods; Microscopy; Molecular; New Agents; Operative Surgical Procedures; Optics; Penetration; Pharmaceutical Chemistry; Property; Reaction; Role; Staging; Techniques; Tissues; Umbelliferones; bioimaging; cancer diagnosis; cancer therapy; chemical stability; cyanine; design; fluorophore; imaging agent; imaging modality; improved; in vivo; in vivo imaging; interest; optical imaging; optical switch; panitumumab; research study; small molecule; targeted imaging; tumor

The implementation of molecularly targeted imaging modalities has progressed considerably in recent years. Fluorophores in the near-IR range are of particular interest for in vivo optical imaging due to the significant tissue penetration of light in this range. One such agent, indocyanine green, is FDA approved and currently involved in over 100 active clinical trials, including over 30 for cancer diagnosis. Moreover, fluorescence-guided surgery methods that use targeted agents to demarcate tumor margins are progressing rapidly in a clinical context. Despite a central role in modern biology and medicine, the compounds employed in near-IR fluorescence techniques have changed little in recent decades. In fact, many of these agents were developed for laboratory methods (i.e. DNA sequencing) and not clinical use. Using molecular design concepts borrowed from related fields (e.g. medicinal chemistry and complex molecule synthesis), we seek to develop new agents with improved utility for cancer-related imaging. The long-term goal is to identify develop readily synthesized, stable, and bright fluorophores with optimal properties for biomedical imaging. To date, our efforts have centered on the heptamethine cyanine class of near-IR fluorophores, which, among many other applications, are being investigated extensively for use in fluorescence-guided surgery. We have developed a new rearrangement reaction that enables the synthesis of previously inaccessible of cyanine fluorophores. Compared to existing agents, these compounds exhibited improved optical properties and, most importantly, significantly greater chemical stability to biological nucleophiles. We have shown that these new agents, when conjugated to the anti-HER1 antibody, panitumumab, exhibit useful fluorescence properties in microscopy experiments and excellent in vivo imaging properties. An additional area of interest is the synthesis and study of natural products with useful optical properties. Many natural products have evolved to, at least in part, interact with light, and derivatives of some including umbelliferone, are key fluorophores in modern biology. We completed the total synthesis of the eudistidine alkaloids, and are currently examining the biological and optical properties of these molecules. My lab is in also interested in a natural product with close structural homology to the cyanine class of fluorophores. We anticipate this compound may exhibit useful optical switching properties with utility for various microscopy applications. At this stage, we are developing a concise synthesis that will enable efficient access to this promising compound.

近年来，分子靶向成像方式的实施已经取得了长足的进步。由于该范围内的光渗透显着的组织渗透，因此近红外范围内的荧光团特别关注体内光学成像。其中一种药剂是吲哚烷绿色，已获得FDA批准，目前参与了100多次活跃的临床试验，包括30多个用于癌症诊断。此外，在临床情况下，使用靶向药物来划定肿瘤边缘的荧光引导手术方法正在迅速发展。尽管在现代生物学和医学中起着核心作用，但近几十年来，近红外荧光技术中采用的化合物几乎没有改变。实际上，这些药物中的许多是用于实验室方法（即DNA测序）而不是临床用途的。使用从相关领域借用的分子设计概念（例如药物化学和复杂分子合成），我们试图开发具有改善与癌症相关成像效用的新药物。长期目标是确定具有最佳特性的生物医学成像特性，易于合成，稳定和明亮的荧光团。迄今为止，我们的努力集中在近红外荧光团的己氨酸氰氨酸类型上，在许多其他应用中，正在对此进行广泛研究以用于荧光引导手术。我们已经开发了一种新的重排反应，该反应能够综合以前无法访问的氰荧光团。与现有药物相比，这些化合物表现出改善的光学特性，最重要的是，化学稳定性明显更大。我们已经表明，当将这些新药物与抗HER1抗体共轭时，Panitumumumab在显微镜实验中具有有用的荧光特性，并且具有出色的体内成像特性。感兴趣的另一个领域是对具有有用光学特性的天然产物的合成和研究。许多天然产品至少部分与光相互作用，其中一些天然产品包括脐酮在内的衍生物是现代生物学的关键荧光团。我们完成了Eudistidine生物碱的总合成，目前正在研究这些分子的生物学和光学特性。我的实验室也对与氰富荧光团类别具有紧密结构同源性的天然产物感兴趣。我们预计该化合物可能会在各种显微镜应用中具有实用性具有有用的光学开关性能。在此阶段，我们正在开发一种简洁的综合，该合成将有效地访问这种有希望的化合物。