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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：
8829003
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/8829003
关键词：
Advisory Committees Affinity Agonist Alder plant Amino Acids Animal Cancer Model Animal Model Biological Models Biology Bombesin Receptor Buffers Calibration Chemicals Chemistry Chromatography Clinic Clinical Clinical Research Cyclooctenes Data Development Diagnosis Disease Drug Kinetics Evaluation Excision Generations Goals Health 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 animal imaging aqueous base bioimaging career cycloaddition design experience fluorescence imaging functional group glucagon-like peptide high throughput screening imaging agent imaging modality imaging probe in vitro testing in vivo meetings member molecular imaging new technology novel novel strategies peptidomimetics pre-clinical 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)：这项提案的广泛目标是开发新的方法，以实现用PET示踪剂进行多肽和多肽仿制的位置选择性标记。新的策略将基于通过固相肽合成方案加入生物正交标记的非天然氨基酸。所产生的放射性标记多肽将被平行评估，并在动物成像实验中进一步测试命中候选者。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。他以前从事过生物正交策略的研究。他将把他的技能应用于这种翻译方法，我在有机合成、生物学和生物医学成像的界面上使用这种方法。能够选择性地将生物正交标记物结合到多肽中的技术和方案的成功开发，以及相应的放射性标记版本的并行化评估将代表着生物医学成像研究的重要一步，极大地促进了诊断放射性标记探针的设计、评估和最终的临床翻译。候选人的长期目标是开发新的和更有效的方法，允许PET标记的显像剂与目标生物分子偶联。这项工作将在纪念斯隆-凯特琳癌症中心放射科进行，由杰森·刘易斯博士指导。赫德维格·赫里卡克博士和沃尔夫冈·韦伯博士都是临床前和临床影像研究方面的专家，他们将担任共同导师。咨询委员会成员完全致力于对候选人的指导性研究培训，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。这项建议的具体目标是首先合成四嗪和反式环辛烯氨基酸，然后将它们合并到生长抑素类似物中，生成一个生物正交标记多肽库。然后，利用平行生物正交组装和纯化技术，将这些多肽转化为相应的18F、89Zr和64Cu标记版本。高亲和力和选择性的多肽随后将在癌症动物模型中进行测试。在这里，四嗪和反式环辛烯氨基酸不仅可以快速和选择性地合成，而且还可以快速、免色谱地纯化放射性标记多肽，促进放射性标记多肽文库的多路并行合成。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的靶向探针。如果成功，这些新技术将允许对目标多肽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。通过四氮杂环辛烯设计放射性标记的多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。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

PARPi-FL--a fluorescent PARP1 inhibitor for glioblastoma imaging.

DOI：
10.1016/j.neo.2014.05.005
发表时间：
2014-05
期刊：
NEOPLASIA
影响因子：
4.8
作者：
Irwin, Christopher P.;Portorreal, Yasiri;Brand, Christian;Zhang, Yachao;Desai, Pooja;Salinas, Beatriz;Weber, Wolfgang A.;Reiner, Thomas
通讯作者：
Reiner, Thomas

Optical Imaging of PARP1 in Response to Radiation in Oral Squamous Cell Carcinoma.