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）：该提案的广泛目标是开发新的方法论，以使用宠物示踪剂实现肽和肽仪的现场选择性标记。新型策略将基于通过固相肽合成方案掺入生物封装标记的非天然氨基酸。所得的放射性标记的肽将平行评估，并在动物成像实验中进一步测试了候选者。候选人托马斯·雷纳（Thomas Reiner）在定量科学方面具有丰富的经验，特别是合成的有机化学和有机化学。他以前从事生物正交策略。他将把自己的技能应用于这种翻译方法，这是有机合成，生物学和生物医学成像的界面。技术和协议的成功开发允许将生物异位标签纳入肽的现场选择性融合以及对其相应放射性标记版本的并行评估将代表生物医学成像研究的重要一步，极大地促进了设计，评估，最终促进诊断放射辐射式放射线放射线的临床转换。候选人的长期目标是开发新颖，更有效的方法论，从而使宠物标记的成像剂与靶向生物分子结合。这项工作将在杰森·刘易斯（Jason Lewis）博士的指导下在纪念斯隆 - 凯特林癌症中心放射科进行。临床前和临床成像研究专家Hedvig Hricak博士和Wolfgang Weber博士都将担任联合会。咨询委员会的成员完全致力于对候选人进行指导的研究培训，使他能够发展出独立的生物医学研究人员的强大而成功的职业。该提案的具体目的是首先合成四嗪和反式环辛氨基酸，然后将其掺入生物元素标记的肽库中。然后，通过利用平行的生物循环装配和纯化技术，将将这些肽转换为其相应的18F，89ZR和64CU标记的版本。高亲和力和选择性肽随后将在癌症动物模型中进行测试。在这里，四嗪和反式环绕烯氨基酸不仅允许快速和选择性合成，而且还允许对放射性标记的肽的快速色谱纯化，从而促进放射性标记的肽库的多重平行合成。 HIT候选人的性能将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探针进行理性和高通量评估，简化其发展并增加成功结果的机会。通过四嗪/反式循环的靶向肽的设计可能成为临床前生物医学成像的标准技术，并最终成为临床研究。

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.