Fast in vivo CLICK chemistries for PET imaging

用于 PET 成像的快速体内 CLICK 化学物质

基本信息

批准号：
8464101
负责人：
Neal Krishna Devaraj
金额：
$ 16.7万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8464101
关键词：
Advisory Committees Affinity Affinity Labels Alkynes Azides Biomedical Research Cells Chemistry Clinical Colon Carcinoma Coupling Cyclooctenes Data Detection Development Development Plans Diagnosis Disease Doctor of Philosophy Dose Drug Kinetics Effectiveness Exposure to Fluorescent Probes Fluorine GPA33 gene Generic Drugs Glycoprotein A33 Goals Home environment Hour Human Image Immersion Investigative Technique Immunoglobulin Fragments Journals Label Lead Life Ligands Membrane Glycoproteins Mentors Mentorship Metabolic Methodology Methods Monitor Monoclonal Antibodies Mus Physiological Positron-Emission Tomography Procedures Proteins Protocols documentation Radioisotopes Radiolabeled Reaction Reading Reagent Reporter Research Research Proposals Science Scientist Site Surface Systems Biology Technology Testing Time Toxic effect Training Translational Research Work Xenograft procedure affinity labeling bioimaging career development catalyst colon cancer cell line cycloaddition functional group humanized monoclonal antibodies imaging probe improved in vivo in vivo Model information gathering interest molecular imaging nanomaterials novel public health relevance radiotracer reaction rate research study skills small molecule symposium tool

项目摘要

DESCRIPTION (provided by applicant): The broad goal of this proposal is to use fast in vivo click chemistries to enable biomedical imaging with affinity ligands such as monoclonal antibodies. The candidate, Neal Devaraj, has received extensive training in the field of chemistry and now wishes to transition to biomedical research. His immediate goal is to further develop skill sets through immersion in translational research and to make significant contributions to the field of in vivo imaging. Long term, the candidate wishes to make a full transition from chemist to independent biomedical research scientist. The candidate proposes to carry out the proposal at the Harvard/MGH Center for Systems Biology under the mentorship of Dr. Ralph Weissleder MD PhD. In addition to the research proposal, his career development plan includes supplemental coursework, mentored readings, journal clubs, attendance and presentation at several seminars and conferences, practical exposure to the imaging sciences, and close formal interaction with both his mentor and an advisory committee consisting of Prof. Robert Langer, Prof. Moungi Bawendi, and Prof. Marcelo Di Carli. The research plan aims to develop platform chemistries to allow site specific in vivo targeting of affinity ligands once they have homed to their target (i.e. decoupled administration of affinity ligand and imaging reporter). Though a large number of targeting ligands have been developed to date, target-reporter constructs have inherent pharmacokinetics which are undesirable for in vivo imaging. To achieve site specific coupling, the candidate proposes to work with the recently introduced tetrazine/strained dienophile cycloaddition. This extremely rapid reaction is highly selective, irreversible, and can be performed in physiological conditions. The proposal aims to build on this cutting-edge technology and to develop generic in vivo click reactions for molecular imaging with positron emission tomography (PET). The specific aims are to 1) develop and characterize a panel of fast "click" reactions for radioisotope labeling and 2) pursue in vivo click labeling for biomedical imaging. To test this method, the candidate will create dienophile affinity ligands against A33 glycoprotein, a surface persistent marker that is highly expressed in human colon cancers. Mice bearing primary and metastatic colon cancer will be injected with dienophile affinity ligands. After several days of clearance, a small, readily cleared tetrazine imaging probe will be administered. Imaging with PET will be used to quantify probe localization and the method will be optimized and compared to other methods such as direct labeling of affinity ligands and the metabolic reporter 18fluorodeoxglucose. If successful, the development of in vivo "click" chemistry for biomedical imaging will provide a nearly universal methodology for in vivo imaging of virtually any targeting affinity ligand.

描述（由申请人提供）：该提案的总体目标是使用快速体内点击化学来实现利用亲和配体（例如单克隆抗体）进行生物医学成像。候选人 Neal Devaraj 在化学领域接受了广泛的培训，现在希望转向生物医学研究。他的近期目标是通过沉浸在转化研究中进一步发展技能，并为体内成像领域做出重大贡献。从长远来看，候选人希望从化学家全面转变为独立的生物医学研究科学家。候选人提议在哈佛/麻省总医院系统生物学中心在医学博士 Ralph Weissleder 博士的指导下实施该提案。除了研究计划外，他的职业发展计划还包括补充课程、指导阅读、期刊俱乐部、出席多个研讨会和会议并进行演讲，实际接触成像科学，并与他的导师和由 Robert Langer 教授、Moungi Bawendi 教授和 Marcelo Di Carli 教授组成的咨询委员会进行密切的正式互动。该研究计划旨在开发化学平台，一旦亲和配体定位到目标（即亲和配体和成像报告分子的解耦管理），就可以在体内对亲和配体进行位点特异性靶向。尽管迄今为止已开发出大量靶向配体，但靶标报告基因构建体具有固有的药代动力学，这对于体内成像来说是不理想的。为了实现位点特异性偶联，候选人建议使用最近引入的四嗪/应变亲二烯体环加成反应。这种极快的反应具有高度选择性、不可逆，并且可以在生理条件下进行。该提案旨在以这项尖端技术为基础，开发用于正电子发射断层扫描（PET）分子成像的通用体内点击反应。具体目标是 1) 开发和表征一组用于放射性同位素标记的快速“点击”反应，2) 追求用于生物医学成像的体内点击标记。为了测试这种方法，候选人将创建针对 A33 糖蛋白的亲双烯亲和配体，A33 糖蛋白是一种在人类结肠癌中高度表达的表面持久标记物。患有原发性和转移性结肠癌的小鼠将被注射亲双烯亲和配体。经过几天的清除后，将使用一个小的、易于清除的四嗪成像探针。 PET 成像将用于量化探针定位，并且该方法将被优化并与其他方法（例如亲和配体的直接标记和代谢报告物 18 氟脱氧葡萄糖）进行比较。如果成功的话，开发用于生物医学成像的体内“点击”化学将为几乎任何靶向亲和配体的体内成像提供几乎通用的方法。