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）： 糖尿病是一种重要的代谢性疾病，其重要性日益增加。美国至少有2000万糖尿病患者。胰岛β细胞是负责分泌胰岛素的细胞，在糖尿病中起着重要作用。维持或逆转β细胞质量（β cell mass，简称β cell mass）的下降是糖尿病治疗的主要目标之一。通过体内成像测量胰腺中的胰岛素将提供迫切需要的信息，以了解糖尿病的病理生理学，并协助开发新的药物治疗。本研究的目的是开发18 F标记的（+）-二氢丁苯那嗪（[18 F]（+）-DTBZ）衍生物，通过正电子发射断层扫描（PET）成像研究β细胞上的囊泡单胺转运体2（VMAT 2）结合位点。最近的报道表明，[11 C]DTBZ，一种用于诊断帕金森病的VMAT 2选择性试剂，也显示出通过体内PET成像绘制人类胰腺组织的前景。然而，11 C的短半衰期（20 min）限制了其广泛应用;因此，我们建议开发具有更长半衰期（110 min）和改善的胰腺靶向能力的18 F衍生物，适合广泛的临床应用。将合成和放射性标记含有体内代谢基团（环氧化物）的其他新型DTBZ衍生物，以加快肝脏和肾脏排泄。体内生物分布将证明VMAT 2在正常和链脲霉素处理的大鼠（糖尿病模型）中的结合。我们实验室最近开发的18 F标记DTBZ衍生物之一显示出优越的上级胰腺靶向和低背景噪声。正常大鼠胰腺中的摄取在静脉注射后30分钟为> 5%dose/g，并且通过预先给予挑战剂量的VMAT 2配体来阻断（>80%）该摄取，表明与相同的VMAT 2结合位点竞争性结合。正常大鼠的PET成像研究显示胰腺的良好图像，与周围组织或器官具有突出的对比度。基于令人兴奋的初步结果，建议的18F标记DTBZ衍生物可能提供一个很好的平台，以寻找最佳的显像剂的β细胞团（β细胞团）。所提出的用于测量胰腺中β细胞的靶向PET成像剂具有科学重要性，并且它们可能用于糖尿病患者的诊断和管理。 公共卫生关系： 糖尿病是一种主要的代谢性疾病，在美国日益重要。胰岛β细胞是负责分泌胰岛素的细胞，在糖尿病中起着重要作用。通过体内成像测量胰腺中的β细胞质量（beta cell mass，β细胞质量）将为糖尿病患者的诊断和管理提供非常有用的信息。