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Bioorthogonal Strategies for Targeted PET Imaging Probe Development

靶向 PET 成像探针开发的生物正交策略

基本信息

批准号：
8643230
负责人：
Thomas Reiner
金额：
$ 17.49万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8643230
关键词：
Advisory Committees Affinity Agonist Alder plant Amino Acids Animal Cancer Model Animal Model Animals Biological Models Biology Bombesin Receptor Buffers Calibration Chemicals Chemistry Chromatography Clinic Clinical Clinical Research Commit Cyclooctenes Data Development Diagnosis Disease Drug Kinetics Evaluation Excision Generations Goals Image In Vitro Inhibitory Concentration 50 Isotopes Label Laboratories Lead Libraries Literature Malignant Neoplasms Memorial Sloan-Kettering Cancer Center Mentors Mentorship Methodology Organic Chemistry Organic Synthesis Organometallic Chemistry Outcome Peptide Library Peptide Synthesis Peptides Performance Pharmacodynamics Phase Physiological Plant Resins Positron-Emission Tomography Protocols documentation Radiation therapy Radiochemistry Radiolabeled Radiology Specialty Radiopharmaceuticals Reaction Research Research Personnel Research Training Route Science Screening procedure Series Site Solid Solvents Somatostatin Specificity Techniques Technology Temperature Testing Time Tissues Tracer Translating Translations Work aqueous base bioimaging career cycloaddition design experience fluorescence imaging functional group glucagon-like peptide high throughput screening imaging modality imaging probe in vitro testing in vivo meetings member molecular imaging new technology novel novel strategies peptidomimetics pre-clinical public health relevance radiochemical radiotracer receptor research study screening small molecule somatostatin analog somatostatin receptor 2 technique development tool translational approach vector

项目摘要

DESCRIPTION (provided by applicant): The broad goal of this proposal is to develop novel methodologies to achieve site-selective labeling of peptides and peptidomimetics with PET tracers. The novel strategies will be based on the incorporation of bioorthogonally labeled unnatural amino acids via solid phase peptide synthesis protocols. The resulting radiolabeled peptides will be evaluated in parallel, and hit candidates further tested in animal imaging experiments. The candidate, Thomas Reiner, has extensive experience in the quantitative sciences, specifically synthetic organometallic and organic chemistry. He has worked on bioorthogonal strategies before. He will apply his skillset to this translational approach, which i at the interface of organic synthesis, biology and biomedical imaging. The successful development of techniques and protocols which allow site-selective incorporation of bioorthogonal labels into peptides, as well as the parallelized evaluation of their corresponding radiolabeled versions will represent a major step in biomedical imaging research, greatly facilitating design, evaluation, and ultimately clinical translation of diagnosic radiolabeled probes. The long term goal of the candidate is to develop novel and more efficient methodologies which allow conjugation of PET labeled imaging agents to targeted biomolecules. This work will be performed at the Department of Radiology of Memorial Sloan-Kettering Cancer Center under the mentorship of Dr. Jason Lewis. Both Dr. Hedvig Hricak and Dr. Wolfgang Weber, who are experts in preclinical and clinical imaging research, will serve as co-mentors. The members of the advisory committee are fully committed to the mentored research training of the candidate, allowing him to develop a strong and successful career as an independent biomedical researcher. The specific aims of this proposal are to first synthesize tetrazine and trans-cyclooctene amino acids, followed by their incorporation into somatostatin-analogs, generating a library of bioorthogonally labeled peptides. Then, these peptides will be converted into their corresponding 18F, 89Zr and 64Cu labeled versions by utilizing parallel bioorthogonal assembly and purification techniques. High affinity and selectivity peptides will subsequently be tested in animal models of cancer. Here, tetrazine and trans-cyclooctene amino acids will not only allow the fast and selective synthesis, but also the rapid chromatography free purification of radiolabeled peptides, facilitating multiplexed parallel synthesis of radiolabeled peptide libraries. Hit candidates will be evaluated for their performance as targeted probes in animal models of cancer. If successful, these new technologies will allow the rational and high-throughput evaluation of targeted peptidic PET probes, streamlining their development and increasing the chances of successful outcomes. The design of radiolabeled targeted peptides via tetrazines/trans-cyclooctenes could become a standard technique for preclinical biomedical imaging and ultimately clinical research.

描述（由申请人提供）：本提案的广泛目标是开发新方法，以实现用PET示踪剂对肽和肽模拟物进行位点选择性标记。新的策略将基于通过固相肽合成方案掺入生物正交标记的非天然氨基酸。将平行评价所得放射性标记的肽，并在动物成像实验中进一步测试命中候选物。候选人托马斯赖纳在定量科学方面拥有丰富的经验，特别是合成有机金属和有机化学。他以前曾研究过生物正交策略。他将把他的技能应用到这种转化方法中，这种方法是有机合成，生物学和生物医学成像的接口。成功开发的技术和协议，允许位点选择性掺入的生物正交标签到肽，以及平行评价其相应的放射性标记的版本将代表一个重要的步骤，在生物医学成像研究，大大促进设计，评价，并最终临床翻译诊断放射性标记的探针。候选人的长期目标是开发新的和更有效的方法，使PET标记的成像剂的共轭靶向生物分子。这项工作将在纪念斯隆-凯特琳癌症中心放射科进行，由Jason刘易斯博士指导。Hedvig Hricak博士和Wolfgang Weber博士都是临床前和临床成像研究方面的专家，他们将担任共同导师。咨询委员会的成员完全致力于指导候选人的研究培训，使他能够作为一名独立的生物医学研究人员发展强大而成功的职业生涯。该提案的具体目标是首先合成四嗪和反式环辛烯氨基酸，然后将其掺入生长抑素类似物中，产生生物正交标记肽的文库。然后，通过利用平行生物正交组装和纯化技术将这些肽转化为其相应的18F、89 Zr和64 Cu标记形式。随后将在癌症动物模型中测试高亲和力和选择性肽。这里，四嗪和反式环辛烯氨基酸不仅允许快速和选择性合成，而且允许放射性标记的肽的快速无色谱纯化，促进放射性标记的肽文库的多重平行合成。热门候选人将根据他们的表现进行评估作为癌症动物模型中的靶向探针。如果成功，这些新技术将允许对靶向肽PET探针进行合理和高通量的评估，简化其开发并增加成功结果的机会。通过四嗪/反式环辛烯设计放射性标记的靶向肽可能成为临床前生物医学成像和最终临床研究的标准技术。