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：
8487906
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/8487906
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）：该提案的总体目标是开发新的方法来实现使用 PET 示踪剂对肽和肽模拟物进行位点选择性标记。新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。由此产生的放射性标记肽将被并行评估，并在动物成像实验中进一步测试候选化合物。候选人托马斯·赖纳 (Thomas Reiner) 在定量科学，特别是合成有机金属和有机化学方面拥有丰富的经验。他之前曾研究过生物正交策略。他将把他的技能应用于这种有机合成、生物学和生物医学成像交叉领域的转化方法。允许将生物正交标记选择性地掺入肽中的技术和方案的成功开发，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，极大地促进设计、评估和最终的临床转化诊断放射性标记探针。该候选人的长期目标是开发新颖且更有效的方法，使 PET 标记的显像剂与目标生物分子结合。这项工作将在纪念斯隆-凯特琳癌症中心放射科在 Jason Lewis 博士的指导下进行。临床前和临床影像研究专家 Hedvig Hricak 博士和 Wolfgang Weber 博士将担任联合导师。咨询委员会的成员完全致力于对候选人进行指导性的研究培训，使他能够作为一名独立的生物医学研究员发展出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，然后将它们掺入生长抑素类似物中，生成生物正交标记的肽库。然后，利用平行生物正交组装和纯化技术，将这些肽转化为相应的 18F、89Zr 和 64Cu 标记版本。随后将在癌症动物模型中测试高亲和力和选择性的肽。在这里，四嗪和反式环辛烯氨基酸不仅可以快速、选择性合成，而且可以快速无色谱纯化放射性标记肽，促进放射性标记肽库的多重平行合成。热门候选人将对其表现进行评估作为癌症动物模型中的靶向探针。如果成功，这些新技术将能够对靶向肽 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。