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：
9556612
负责人：
Martin Schnermann
金额：
$ 44.33万
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/9556612
关键词：
Alkaloids Animals Antibodies Area Biological Biology Chemicals Clinical Development Evaluation Exhibits Eye Fluorescence Goals Image Libraries Light Malignant Neoplasms Medicine Methods Microscopy Modernization Molecular Molecular Target Natural Products New Agents Optics Organic Synthesis Penetration Pharmaceutical Chemistry Property Reaction Role Techniques Tissues Umbelliferones Variant absorption bioimaging cancer diagnosis cancer therapy chemical stability cyanine design experimental study fluorescence-guided surgery fluorophore functional group imaging agent imaging modality improved in vivo in vivo optical imaging interest molecular imaging novel scaffold screening small molecule tumor

Alkaloids Animals Antibodies Area Biological Biology Chemicals Clinical Development Evaluation Exhibits Eye Fluorescence Goals Image Libraries Light Malignant Neoplasms Medicine Methods Microscopy Modernization Molecular Molecular Target Natural Products New Agents Optics Organic Synthesis Penetration Pharmaceutical Chemistry Property Reaction Role Techniques Tissues Umbelliferones Variant absorption bioimaging cancer diagnosis cancer therapy chemical stability cyanine design experimental study fluorescence-guided surgery fluorophore functional group imaging agent imaging modality improved in vivo in vivo optical imaging interest molecular imaging novel scaffold screening small molecule tumor

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项目摘要

The clinical 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. 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 modern organic synthesis), we seek to develop new agents with improved utility for cancer-related imaging and microscopy. 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, with extensive recent progress in the context of 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 antibodies and resulting conjugates display exhibit excellent fluorescence properties in microscopy experiments and in vivo animal studies. We have also shown that small changes in the polar functional groups appended to these fluorophores can have a dramatic impact on biodistrubution and tumor accumulation. We are currently pursuing approaches to improve other aspects of the optical properties of these molecules, especially their brightness and absorption profile. 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. We completed the total synthesis of the eudistidine alkaloids, and are currently examining the biological and optical properties of these molecules. We are also developing and implementing screening strategies to probe natural product libraries for novel fluorescent scaffolds.

近年来，分子靶向成像方式的临床实施已经取得了长足的发展。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。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（例如药物化学和现代有机合成），我们试图开发具有改善癌症相关成像和显微镜效用的新代理。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，在荧光引导手术的背景下，最近的进展广泛。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体偶联，结果结合物显示在显微镜实验和体内动物研究中具有出色的荧光特性。我们还表明，附加到这些荧光团的极性官能团的微小变化可能会对生物分裂和肿瘤积累产生巨大影响。我们目前正在采用改善这些分子光学特性的其他方面的方法，尤其是它们的亮度和吸收曲线。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。我们还正在制定并实施筛选策略，以探测新型荧光支架的天然产品库。