New Synthetic Approaches to Small Molecules for Imaging

用于成像的小分子合成新方法

基本信息

批准号：
8938168
负责人：
Martin Schnermann
金额：
$ 56.27万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/8938168
关键词：
Animals Antibodies Area Biological Biological Factors Biology Cells Chemicals Clinical Trials Complex DNA Sequence Rearrangement Development ERBB2 gene Evaluation Exhibits FDA approved Fluorescence Goals Image Indocyanine Green Life Light Malignant Neoplasms Medicine Methods Microscopy Molecular New Agents Operative Surgical Procedures Optics Penetration Pharmaceutical Chemistry Property Reaction Role Staging Techniques Tissues Trastuzumab Umbelliferones Variant Work bioimaging cancer diagnosis cancer therapy chemical stability cyanine design fluorophore imaging modality improved in vivo interest optical imaging optical switch research study small molecule

Animals Antibodies Area Biological Biological Factors Biology Cells Chemicals Clinical Trials Complex DNA Sequence Rearrangement Development ERBB2 gene Evaluation Exhibits FDA approved Fluorescence Goals Image Indocyanine Green Life Light Malignant Neoplasms Medicine Methods Microscopy Molecular New Agents Operative Surgical Procedures Optics Penetration Pharmaceutical Chemistry Property Reaction Role Staging Techniques Tissues Trastuzumab Umbelliferones Variant Work bioimaging cancer diagnosis cancer therapy chemical stability cyanine design fluorophore imaging modality improved in vivo interest optical imaging optical switch research study small molecule

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项目摘要

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. Despite a central role in modern biology and medicine, the compounds employed in near-IR fluorescence techniques have changed little in recent decades. 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 readily synthesized, stable, and bright fluorophores with optimal properties for biomedical imaging. Our current efforts in this area are split in two aims. Aim 1 - Synthetic methods to prepare heptamethine cyanine fluorophores. The heptamethine cyanine class of near-IR fluorophores are used for many applications, including for fluorescence-guided surgery. We have developed a new rearrangement reaction that enables the synthesis of previously inaccessible variants. Compared to existing agents, the compounds we have prepared exhibited improved optical properties and, most importantly, significantly greater chemical stability to biological nucleophiles. We have shown that these new agents can be conjugated to the anti-HER2 antibody, trastuzumab, and exhibit excellent fluorescence properties in microscopy experiments. Ongoing efforts are centered on employing these readily synthesized compounds in a variety of applications, including for in vivo animal studies. Aim 2 - Synthesis and evaluation of fluorescent natural products. Many natural products have evolved to, at least in part, interact with light, and derivatives of some, such as umbelliferone, are important fluorophores. My lab is particularly interested in a natural product with structural similarity to cyanine fluorophores. We anticipate this compound may exhibit useful optical switching properties with utility for certain microscopy applications. At this stage, we are developing a concise synthesis to provide 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。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。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。长期目标是鉴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。我们目前在这一领域的努力分为两个目标。目的1-制备己氨酸氰胺荧光团的合成方法。近红外荧光团的己氨酸氰氨酸类用于许多应用，包括用于荧光引导的手术。我们已经开发了一种新的重排反应，该反应能够综合以前难以访问的变体。与现有药物相比，我们制备的化合物表现出改善的光学特性，最重要的是，化学特性显着更大的化学稳定性。我们已经表明，这些新药物可以与抗HER2抗体，曲妥珠单抗结合，并在显微镜实验中具有出色的荧光性能。持续的努力集中在使用这些容易合成的化合物中，包括用于体内动物研究在内的各种应用中。目标2-荧光天然产物的合成和评估。许多天然产物至少部分地与光相互作用，而某些天然产物（例如脐带酮）是重要的荧光团。我的实验室对与氰荧光团结构相似的天然产品特别感兴趣。我们预计该化合物可能会在某些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，以提供对这种有希望的化合物的访问。