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）： 糖尿病是一种日益重要的代谢性疾病。美国至少有2000万糖尿病患者。 β胰岛细胞是负责分泌胰岛素的细胞，在糖尿病中发挥着重要作用。保持或逆转β细胞量（BCM）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 BCM 将为了解糖尿病的病理生理学并协助开发新的药物治疗提供迫切需要的信息。该提案的目的是开发 18F 标记的 (+)-二氢丁苯那嗪 ([18F](+)-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蛋白 2 (VMAT2) 结合位点。最近的报告表明，[11C]DTBZ（一种用于诊断帕金森病的 VMAT2 选择剂）也显示出通过体内 PET 成像绘制人类胰腺 BCM 的前景。然而，11C的半衰期短（20分钟）限制了其广泛应用；因此，我们建议开发其半衰期更长（110分钟）和改善胰腺靶向能力的18F衍生物，适合广泛的临床应用。将合成并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，以加快肝脏和肾脏的排泄。体内生物分布将证明 VMAT2 在正常和链脲佐菌素治疗的大鼠（糖尿病模型）中的结合。我们实验室最近开发的一种 18F 标记的 DTBZ 衍生物显示出优异的胰腺靶向性和低背景噪音。静脉注射后 30 分钟，正常大鼠胰腺的摄取量 > 5% 剂量/克，并且通过预处理具有挑战性剂量的 VMAT2 配体，摄取被阻断 (>80%)，这表明与相同剂量的 VMAT2 配体存在竞争性结合。 VMAT2 结合位点。对正常大鼠的 PET 成像研究显示，胰腺图像良好，与周围组织或器官形成鲜明对比。基于令人兴奋的初步结果，所提出的18F标记的DTBZ衍生物可能为寻找β细胞团（BCM）的最佳成像剂提供一个极好的平台。所提出的用于测量胰腺 BCM 的 β 细胞靶向 PET 显像剂具有重要的科学意义，并且可能有助于糖尿病患者的诊断和管理。 公共卫生相关性： 糖尿病是一种主要的代谢疾病，在美国的重要性与日俱增。 β胰岛细胞是负责分泌胰岛素的细胞，在糖尿病中发挥着重要作用。通过体内成像测量胰腺中的β细胞质量（BCM）将为糖尿病患者的诊断和管理提供至关重要的信息。