IMAGING AGENTS FOR BETA CELL MASS OF PANCREAS

胰腺 β 细胞团显像剂

• 批准号: 8052716
• 负责人: Hank F Kung
• 金额: $ 31.73万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052716
• 关键词: Affinity; Beta Cell; Binding; Binding Sites; Biodistribution; Biological; Biological Assay; Biological Markers; Cells; Clinic; Competitive Binding; Corpus striatum structure; Data; Development; Diabetes Mellitus; Diagnosis; Discipline of Nuclear Medicine; Dissection; Dose; Endocrine; Epoxy Compounds; Evaluation; Excretory function; Functional disorder; Goals; Half-Life; Human; Image; Injection of therapeutic agent; Insulin; Islet Cell; Kidney; Kinetics; Label; Laboratories; Ligands; Liver; Maps; Measures; Membrane; Metabolic Diseases; Metabolism; Michigan; Monitor; Noise; Organ; Pancreas; Parkinson Disease; Pharmaceutical Preparations; Pharmacology; Play; Positron-Emission Tomography; Preparation; Property; Radiolabeled; Rattus; Relative (related person); Reporting; Role; Signal Transduction; Site; Specificity; Streptozocin; Structure of beta Cell of islet; Study models; Testing; Tissues; Tracer; United States; Universities; base; clinical application; complement C2a; design; diabetic patient; diabetic rat; dihydrotetrabenazine; improved; in vivo; insulin secretion; nonhuman primate; novel; pancreas imaging; public health relevance; radiotracer; uptake; vesicular monoamine transporter 2

DESCRIPTION (provided by applicant): Diabetes mellitus is a major metabolic disease with increasing significance. There are at least 20 million diabetic patients in the United States. Beta islet cells, which are the cells responsible for secreting insulin, play an important role in diabetes. Preserving or reversing the decline of beta cell mass (BCM) is one of the major goals for the treatment of diabetes. Measuring BCM in the pancreas by in vivo imaging will provide urgently needed information to understand the pathophysiology of diabetes and assist the development of new drug treatments. The objective of this proposal is to develop 18F labeled (+)-dihydrotetrabenazine ([18F](+)-DTBZ) derivatives to study vesicular monoamine transporter 2 (VMAT2) binding sites on the beta cells by positron emission tomography (PET) imaging. Recent reports suggested that [11C]DTBZ, a VMAT2 selective agent used in the diagnosis of Parkinson's disease, also showed promise for mapping the BCM of human pancreas by in vivo PET imaging. However, the short half-life (20 min) of 11C limits its widespread application; therefore, we propose to develop its 18F derivatives with a longer half-life (110 min) and an improved pancreas targeting ability suitable for a widespread clinical application. Additional novel DTBZ derivatives containing an in vivo metabolizing group (epoxide) for faster liver and kidney excretion will be synthesized and radiolabeled. In vivo biodistribution will demonstrate the binding of VMAT2 in normal and streptozotocin-treated rats (model for diabetes). One of the 18F labeled DTBZ derivatives recently developed in our laboratory showed superior pancreas targeting and low background noise. The uptake in the pancreas of normal rats was > 5 %dose/g at 30 min after an iv injection and the uptake was blocked (>80%) by a pretreatment of a challenging dose of VMAT2 ligand, suggesting a competitive binding to the same VMAT2 binding sites. PET imaging studies of normal rats showed excellent images of the pancreas with outstanding contrast to the surrounding tissues or organs. On the basis of the exciting preliminary results, the proposed 18F labeled DTBZ derivatives may provide an excellent platform to search for optimal imaging agents for beta cell mass (BCM). The proposed beta cell targeting PET imaging agents for measuring BCM in the pancreas are scientifically important and they may be useful for diagnosis and management of diabetic patients. PUBLIC HEALTH RELEVANCE: Diabetes mellitus is a major metabolic disease with increasing significance in the United States. Beta islet cells, which are the cells responsible for secreting insulin, play an important role in diabetes. Measuring beta cell mass (BCM) in the pancreas by in vivo imaging will provide critically useful information for diagnosis and management of diabetic patients.

描述（由申请人提供）：