IMAGING AGENTS FOR BETA CELL MASS OF PANCREAS

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。胰岛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(BCM)的下降是糖尿病治疗的主要目标之一。通过活体成像测量胰腺中的BCM将为了解糖尿病的病理生理机制提供迫切需要的信息，并有助于新药治疗的开发。本研究的目的是开发18F标记的(+)-二氢四苯并嗪([18F](+)-DTBZ)衍生物，用正电子发射断层扫描(PET)成像技术研究囊泡单胺转运体2(VMAT2)在β细胞上的结合部位。最近的报道表明，[11C]DTBZ，一种用于帕金森病诊断的VMAT2选择性试剂，也有望通过活体PET成像来定位人胰腺的BCM。然而，11C较短的半衰期(20分钟)限制了它的广泛应用；因此，我们建议开发具有更长半衰期(110分钟)和更好的胰腺靶向性的18F衍生物，适合于广泛的临床应用。另外，还将合成并标记含有体内代谢基团(环氧化物)的新型DTBZ衍生物，以加快肝脏和肾脏的排泄速度。在体内的生物分布将证明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衍生物显示了良好的胰腺靶向性和低背景噪声。正常大鼠静脉注射VMAT2后30分钟胰腺摄取为5%剂量/克，并被VMAT2受体激活剂阻断摄取(80%)，提示与相同的VMAT2结合部位存在竞争性结合。对正常大鼠的PET成像研究显示，胰腺的图像非常好，与周围组织或器官形成了鲜明的对比。基于令人兴奋的初步结果，所提出的18F标记的DTBZ衍生物可能为寻找最佳的β细胞团(BCM)显像剂提供了一个很好的平台。所提出的β细胞靶向PET显像剂用于测量胰腺中的BCM具有重要的科学意义，它们可能对糖尿病患者的诊断和治疗有用。 公共卫生相关性： 糖尿病是一种主要的代谢性疾病，在美国的重要性越来越大。胰岛细胞是负责分泌胰岛素的细胞，在糖尿病中起着重要作用。通过活体成像测量胰腺中的β细胞质量(BCM)将为糖尿病患者的诊断和治疗提供重要的有用信息。

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.