TARGETED RESPONSIVE MR AND PET AGENTS FOR BETA-CELL IMAGING

用于 β 细胞成像的靶向响应 MR 和 PET 试剂

• 批准号: 7600863
• 负责人: XIAOFENG SUN
• 金额: $ 1.51万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7600863
• 关键词: Acetates; Animal Experiments; Animals; Arts; Attention; Beta Cell; Carbon Dioxide; Cell physiology; Cells; Chelating Agents; Chemistry; Citrate (si)-Synthase; Citric Acid Cycle; Clinical Research; Collaborations; Complement component C1s; Complex; Computer Retrieval of Information on Scientific Projects Database; Count; Cyclotrons; Detection; Development; Disease; Evaluation; Facility Construction Funding Category; Faculty; Floor; Funding; Generations; Glucose; Goals; Grant; Head; Heart; Housing; Hybrids; Hypoxia; Image; Imaging Techniques; Institution; Invasive; Label; Laboratories; Libraries; Ligands; Measures; Medical center; Metabolic; Metabolism; Metastatic Neoplasm to the Bone; Modality; Modeling; Molecular; Monitor; N-terminal; Nuclear; Oxidation-Reduction; Palliative Care; Pan Genus; Pancreas; Pattern; Peptides; Phage Display; Positioning Attribute; Positron-Emission Tomography; Production; Pyruvate; Pyruvates; Radiation therapy; Radiochemistry; Rattus; Reporting; Research; Research Personnel; Resolution; Resources; Role; Route; Science; Sensitivity and Specificity; Series; Source; Support of Research; Techniques; Technology; Testing; Tracer; Translating; United States National Institutes of Health; Universities; Work; base; bisphosphonate; concept; cyclen; design; glucose sensor; imaging probe; in vivo; indexing; innovation; insulinoma; interest; islet; mathematical model; molecular imaging; novel; radiotracer; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is Project #2 in a pending PPG grant renewal led by Chris Newgard of Duke University. The goal is to merge the beta-cell metabolic strategies described in Project #1 and islet targeting core (headed by Kathlynn Brown) with state-of-the-art imaging agent technologies to create novel PET and MR agents for molecular imaging of the ¿-cell in vivo. Our goal is to develop imaging agents that not only target the pancreatic ¿-cell in vivo but also respond to ¿-cell metabolism by functional activation. Before moving to animal experiments, we will initially develop a platform for both high resolution MR and PET imaging of cultured rat ¿-cells and isolated rat islets and use this technology to screen for entrapment of redox sensitive PET agents (64Cu-ATSM) and redox sensitive PARACEST agents (cyclen-based tetraamide complexes of Eu3+ or Tm3+) in ¿-cells. Proof of concept studies on agents that specifically target b-cells will be performed using multimeric peptides identified by phage display panning of insulinoma INS 832/1 cells and isolated rat islets. Given these peptides or others identified in Core B, we will develop an efficient labeling approach to attach either 18F or cyclen-based ligands to all targeting peptides to create MR (pH sensitive Gd3+-based agents, PARACEST-based Zn2+ and glucose sensors) and PET agents (both 18F and 64Cu) to measure a) ¿-cell mass and b) ¿-cell function. A final aim is to combine the technologies of aims 1 & 2 to create targeted & responsive MR and PET agents that not only report ¿-cell mass but also provide an imaging index of ¿-cell function. With the recent technical innovations of imaging modalities, molecular imaging is gaining more and more attention in the fields of basic biomedical sciences and clinical research and practice. Indeed, non-invasive imaging techniques are revolutionizing the understanding of diseases at the cellular and molecular levels. Among the current available imaging modalities, tomographic nuclear imaging approaches, especially positron emission tomography (PET), have demonstrated their significant importance and promising potential in applications of molecular imaging probes due to the superior sensitivity and specificity in diverse subjects, and the ability to quantitatively analyze the regions of interest. In collaboration with Dr. Dean Sherry, Dr. Suns radiochemistry laboratory is interested in the design and in vivo evaluation of a series of hybrid agents featuring both radiometal bifunctional chelators and bisphosphonates (commonly used in the treatment of bone metastasis) for multi-modality (BLI/ MRI/SPECT/PET) detection of bone metastasis and the monitoring of radiotherapeutic/palliative treatment. Additionally, we are developing collaborations with the Advanced Imaging center to study intermediary metabolism by PET. One such project is to develop imaging agents that not only target the pancreatic b-cell in vivo but also respond to b-cell metabolism by functional activation. In this project, Drs. Sherry and Sun will create novel PET and MR agents for molecular imaging of the b-cell in vivo with state-of-the-art imaging agent technologies. Prior to animal experiments, a platform will be developed for both high resolution MR and PET imaging of isolated rat islets and this technology will be used to screen for entrapped hypoxia sensitive PET agents (64Cu-ATSM) and redox sensitive PARACEST agents (cyclen-based tetraamide complexes of Eu3+ or Tm3+) in b-cells. Proof of concept studies on agents that specifically target b-cells will be performed on isolated rat islets using a peptide (MSKSPEEGRATVQPSTQPHY) isolated from panning of glucose low-responding insulinoma INS 832/1 cells. With this, or similar peptides, either an 18F-labeled group or cyclen-based ligands will be added to the N-terminal amino position of all targeting peptides to create a library of targeted MR agents (both Gd3+ and PARACEST based) and targeted PET agents (both 18F and 64Cu) for measuring b-cell mass. In a related project, Dr. Suns laboratory will synthesize [b-18F]-fluoropropionate as a tracer of pyruvate cycling for to test the hypothesis that [b-18F]-fluoropropionate will accumulate at significantly higher levels in ¿-cells than a-cells. If the technique works in isolated islet experiments, it will then be quickly translated to in vivo studies in small animals. This is a relatively easy hypothesis to test and, if proven correct, could provide a powerful, convenient way to image b-cell function by PET. The ultimate aim is to create targeted and responsive MR and PET agents that not only report b-cell mass but also provide an imaging index of b-cell function. It is noteworthy that the UT Southwestern Medical Center has planned to purchase a cyclotron to facilitate PET imaging studies and radiotracer developments. Construction is nearly complete on the Advanced Imaging Research Center (AIRC), which will house a 2,000 sq ft space on the first floor designated for a comprehensive PET chemistry laboratory. Once complete, Dr. Suns laboratory will occupy this new space and begin to work closely with the faculty of the AIRC on in vivo metabolism. A novel project of potentially high impact is to administer [1-11C]acetate and [2-11C]acetate simultaneously in an attempt to tease out in vivo fluxes intersecting in the TCA cycle. Preliminary modeling by Dr. Jeffrey indicate that by placing the label in both the C1 and C2 positions of acetate, the temporal pattern of 11CO2 generation will be sufficiently sophisticated for mathematical modeling to reveal metabolic fluxes such as citrate synthase. Preliminary experiment will be performed in rat hearts perfused with [1-11C]acetate and [2-11C]acetate, and the perfusate will be analyzed via the gamma counts for hot CO2 production. Unfortunately a synthetic route for [2-11C]acetate has not been reported, therefore Dr. Sun will develop a synthetic route for [2-11C]acetate production prior to experimentation (one does exist for [1-11C]acetate). Obviously, Dr. Sun will extend his research with 18F and 11C to other metabolic substrates once the cyclotron is in place, giving PET chemistry an active role in the collaborative projects supported by this Research Resource grant.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 这是由杜克大学克里斯·纽格德（Chris Newgard）领导的待处理的PPG赠款续签的项目＃2。目的是合并项目＃1中描述的β细胞代谢策略，并将目标核心（由凯瑟琳·布朗（Kathlynn Brown）领导）与最先进的成像剂技术合并，以创建新颖的PET和MR代理，以用于体内的分子成像 - 细胞。我们的目标是开发成像剂，不仅针对体内胰腺»细胞，而且还通过功能激活对细胞代谢做出反应。在进行动物实验之前，我们最初将开发一个平台，用于对培养的老鼠和孤立的大鼠胰岛进行高分辨率的MR和PET成像，并使用该技术来筛选氧化氧化还原敏感的宠物剂（64cu -atsm）（64cu -atsm）和氧化还原敏感的paracest剂和基于Cyclen的Tetraamide Agemess（Cyclen基于Cyclen的Tetraamide copplectes of Eu3+或TM3+）。对代理的概念验证研究将使用特定针对B细胞的药物进行使用，以通过噬菌体显示器插入胰岛素瘤INS 832/1细胞和分离的大鼠胰岛来鉴定的多聚辣椒进行。 Given these pepperides or others identified in Core B, we will develop an efficient labeling approach to attach either 18F or cyclen-based ligands to all targeting pepperides to create MR (pH sensitive Gd3+-based agents, PARACEST-based Zn2+ and glucose sensors) and PET agents (both 18F and 64Cu) to measure a) ¿ -cell mass and b) ¿ -cell function.最终的目的是结合目标1和2的技术，以创建有针对性的MR和宠物代理，不仅报告了``细胞质量''，而且还提供了–细胞功能的成像索引。随着成像方式的最新技术创新，分子成像在基本的生物医学科学以及临床研究和实践领域中越来越关注。实际上，非侵入性成像技术正在彻底改变细胞和分子水平上疾病的理解。在当前可用的成像方式中，层析成像成像方法，尤其是正电子发射断层扫描（PET），已经证明了由于潜水员受试者的较高敏感性和特异性，它们在分子成像问题的应用中的重要性和有望潜力，并且具有定量分析利益区域的能力。与Dean Sherry博士合作，Sun S放射化学实验室对一系列具有放射性双功能螯合剂和双膦酸盐和双膦酸盐（通常用于骨转移治疗）的设计和体内评估感兴趣，以进行多模式（BLI/MRI/MRI/MIRS/PET/PET/PET）监控和骨化的射频/PRI radie and radie radie and radie radie radie。此外，我们正在与高级成像中心开发合作，以研究PET中间代谢。这样的项目是开发成像剂，不仅针对体内胰腺B细胞，而且还通过功能激活对B细胞代谢做出反应。在这个项目中，博士。 Sherry和Sun将使用最先进的成像剂技术创建新型PET和MR代理，用于B细胞体内B细胞的分子成像。在进行动物实验之前，将开发一个平台，用于隔离大鼠胰岛的高分辨率MR和PET成像，该技术将用于筛选出B-Cells中B-Cells中的敏感性敏感性PET剂（64CU-ATSM）（64CU-ATSM）和氧化还原敏感的Paracest Agent（Cyclen基于Cyclen的基于Cyclen的基于Cyclen的基于EU3+或TM3+）的复合物。针对特定靶向B细胞的概念研究证明将使用肽（MSKSPEEGRATVQPSTQPHY）对分离的大鼠胰岛进行，从葡萄糖低反应胰岛素瘤INS 832/1细胞中分离出来。借助此或类似的肽，将将18F标记的组或基于Cyclen的配体添加到所有靶向肽的N末端氨基位置，以创建目标MR代理的库（GD3+和Paracest最高的基于GD3+和Paracest），并靶向宠物剂（18F和64CU），以测量B-Cell质量。在相关的项目中，Sun S博士实验室将合成[B-18F]氟丙酸作为丙酮酸循环的示踪剂，以检验[B-18F] - 氟丙酸的假设，即比A细胞中的水平明显更高。如果该技术在孤立的胰岛实验中起作用，则将快速转化为小动物的体内研究。这是一个相对容易的测试假设，如果证明是正确的话，可以为通过PET提供强大，方便的方式来映射B细胞功能。最终的目的是创建有针对性且响应的MR和PET代理，不仅报告B细胞质量，还提供B细胞功能的成像索引。值得注意的是，UT西南医学中心计划购买一款回旋子来促进宠物成像研究和放射性示踪剂的发展。高级成像研究中心（AIRC）几乎完成了建筑，该研究中心将在指定的综合宠物化学实验室的一楼容纳2,000平方英尺的空间。一旦完成，Sun S博士的实验室将占据这个新的空间，并开始与AIRC的体内代谢紧密合作。潜在的高影响力的一个新型项目是管理[1-11c]乙酸盐和[2-11c]乙酸盐，只是试图在TCA循环中教导体内通量。 Jeffrey博士的初步建模表明，通过将标签置于乙酸的C1和C2位置，11CO2生成的临时模式将足够复杂，以使数学建模以揭示诸如柠檬酸盐合酶等代谢通量。初步实验将在[1-11c]乙酸盐和[2-11c]乙酸盐灌注的大鼠心脏中进行，灌注酸盐将通过伽马计数分析热CO2的产生。不幸的是，尚未报道[2-11c]乙酸盐的合成途径，因此，Sun博士将在实验之前为[2-11c]乙酸[2-11c]乙酸盐产生合成途径（[1-11c]乙酸盐确实存在一种）。显然，一旦建立了回旋器，Sun博士将将其研究的研究扩展到其他代谢底物，从而将其研究到其他代谢基质，从而使PET化学在该研究资源资助支持的协作项目中发挥了积极作用。