Project 2: TARGETED RESPONSIVE MR AND PET AGENTS FOR B-CELL IMAGING

项目 2：用于 B 细胞成像的靶向响应 MR 和 PET 试剂

• 批准号: 7556982
• 负责人: Dean Sherry
• 金额: $ 40.65万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7556982
• 关键词: Acetates; Acetyl Coenzyme A; Animal Experiments; Animal Model; Animals; Arts; B-Lymphocytes; Binding; Biological; Blood Glucose; Calcium Channel; Carbon; Cell Line; Cell physiology; Cell surface; Cells; Citrate (si)-Synthase; Citric Acid Cycle; Collaborations; Complex; Detection; Dose; Electron Transport; Environment; Enzymes; Exocytosis; Funding; Glucose; Glucose Transporter; Glucose-6-Phosphate; Glycolysis; Goals; Human; Image; Imidazole; Insulin; Islet Cell; Islets of Langerhans; Label; Ligands; Lipids; Magnetic Resonance Imaging; Measures; Melanocytic nevus; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modality; Mole the mammal; Molecular Weight; NADH; Organ; Oxaloacetates; Oxidation-Reduction; Oxidative Phosphorylation; Pan Genus; Pancreas; Peptide T; Peptides; Perfusion; Phage Display; Potassium Channel; Principal Investigator; Propionates; Protein Kinase; Proteins; Pyruvate; Pyruvates; RIPK2 gene; Rattus; Regulation; Relative (related person); Reporting; Resolution; Secretory Vesicles; Signal Transduction; Specificity; Surface; System; Techniques; Technology; Testing; Translating; Water; Work; base; carboxylation; cellular imaging; concept; copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); cyclen; design; glucose metabolism; glucose sensor; in vivo; indexing; insulin secretion; insulinoma; islet; molecular imaging; novel; oxaloacetate; oxidation; programs; research clinical testing; research study; response; tool; uptake; voltage

The goal of Project 2 is to merge the metabolic strategies of Project 1 and islet targeting core (Core B) and with state-of-the-art imaging agent technologies to create novel PET and MR agents for molecular imaging of the b-cell in vivo. Our goal 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. Before moving to animal experiments, we will initially develop a platform for both high resolution MR and PET imaging of cultured rat b-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 b-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, PARACESTbased Zn2+ and glucose sensors) and PET agents (both 18F and 64Cu) to measure a) b-cell mass and b) bcell 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 b-cell mass but also provide an imaging index of b-cell function.

项目2的目标是合并项目1和胰岛靶向核心（核心B）的代谢策略， 与最先进的成像剂技术，以创造新的PET和MR剂的分子成像， 体内的B细胞。我们的目标是开发显像剂，不仅在体内靶向胰腺b细胞， 也通过功能性激活响应B细胞代谢。在进行动物实验之前，我们将 初步开发了一个平台，用于培养大鼠b细胞和分离的 大鼠胰岛，并使用该技术筛选氧化还原敏感性PET试剂（64 Cu-ATSM）的包埋， 氧化还原敏感的PARACEST试剂（Eu 3+或Tm 3+的基于环戊二烯的四酰胺络合物）。证明 关于特异性靶向B细胞的药剂的概念研究将使用多聚体肽进行 通过噬菌体展示淘选胰岛素瘤INS 832/1细胞和分离的大鼠胰岛鉴定。鉴于这些 肽或核心B中鉴定的其他肽，我们将开发一种有效的标记方法， 所有靶向肽的基于环戊二烯的配体，以产生MR（pH敏感的基于Gd 3+的试剂，基于PARACEST的试剂， Zn 2+和葡萄糖传感器）和PET试剂（18 F和64 Cu）测量a）b细胞质量和B）b细胞 功能最后一个目标是将目标1和目标2的技术联合收割机结合起来，以创建有针对性和响应性的MR 以及PET试剂，其不仅报告B细胞质量，而且提供B细胞功能的成像指数。