IMAGING AGENTS FOR BETA CELL MASS OF PANCREAS

胰腺 β 细胞团显像剂

• 批准号: 7781545
• 负责人: Hank F Kung
• 金额: $ 41.26万
• 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/7781545
• 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; 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）： 糖尿病是一种主要的代谢疾病，其显着性越来越高。美国至少有2000万糖尿病患者。 β小岛细胞是负责分泌胰岛素的细胞，在糖尿病中起重要作用。保存或逆转β细胞质量（BCM）的下降是治疗糖尿病的主要目标之一。通过体内成像测量胰腺中的BCM将提供急需的信息，以了解糖尿病的病理生理学并帮助开发新药物治疗。该提案的目的是开发18F标记（+） - 二氢苯甲嗪（[[18f]（+） - dtbz）衍生物，以研究beta细胞对beta细胞的囊泡单胺转运蛋白转运蛋白转运蛋白转运蛋白转运蛋白转运蛋白转运蛋白转运蛋白。最近的报道表明，用于诊断帕金森氏病的VMAT2选择剂[11C] DTBZ也显示了通过体内宠物成像映射人胰腺BCM的有望。但是，11C的半衰期（20分钟）限制了其广泛的应用；因此，我们建议以更长的半衰期（110分钟）和改进的胰腺靶向能力来开发其18F衍生物，适合广泛的临床应用。将合成和放射标记的其他新型DTBZ衍生物，该衍生物含有含有体内代谢组（环氧），以进行更快的肝脏和肾脏排泄。体内生物分布将证明在正常和链蛋白酶治疗的大鼠（糖尿病模型）中VMAT2的结合。最近在我们的实验室中开发的18F标记的DTBZ衍生物之一显示，胰腺靶向和背景噪声低。静脉注射后30分钟，正常大鼠胰腺的摄取量> 5％剂量/g，并且通过预处理有挑战性的VMAT2配体的预处理来阻断（> 80％）的摄取（> 80％），这表明与同一VMAT2结合位点具有竞争性结合。对正常大鼠的PET成像研究表明，胰腺的出色图像与周围的组织或器官形成鲜明对比。在令人兴奋的初步结果的基础上，拟议的18F标记为DTBZ衍生物可能为寻找β细胞质量（BCM）的最佳成像剂提供了绝佳的平台。提出的用于测量胰腺中BCM的PET成像剂的β细胞在科学上很重要，并且可能对诊断和管理糖尿病患者有用。 公共卫生相关性： 糖尿病是一种主要的代谢疾病，在美国的显着性越来越高。 β小岛细胞是负责分泌胰岛素的细胞，在糖尿病中起重要作用。通过体内成像测量胰腺中的β细胞量（BCM）将为诊断和管理糖尿病患者提供至关重要的信息。