PET Imaging Agent for Diabetes Mellitus

描述(由申请人提供)：本申请涉及广泛的挑战领域(03)生物标记物的发现和验证，以及具体的挑战主题03-DK-101：“发现NINDK感兴趣的疾病的疾病风险、进展或治疗反应的生物标记物”。胰岛是胰腺的内分泌成分，称为β细胞团(BCM)，胰岛中产生胰岛素的细胞丧失，导致无法控制血糖水平。这会导致糖尿病(DM)、1型(TIDM)或2型(T2 DM)。T1糖尿病，以前被称为“胰岛素依赖型糖尿病”(IDDM)或“青少年糖尿病”。TIDM是一种终生疾病，在这种情况下，胰腺由于自身免疫反应中失去BCM而停止分泌胰岛素。T2 DM以前被称为非胰岛素依赖型糖尿病(NIDDM)或成人型糖尿病，是最常见的糖尿病形式。大约90%到95%的糖尿病患者患有T2 DM。美国有2360万人患有糖尿病，占总人口的8%。根据美国糖尿病协会的数据，从2005年到2007年，糖尿病的总患病率上升了13.5%。尽管严格控制血糖，大多数糖尿病患者仍会出现严重的晚期并发症，包括视网膜病变、肾病、神经病变、微血管病变和中风。在临床T1 DM之前，以逐渐的BCM丢失为特征的较长的无症状潜伏期。方法目前临床预测T1 DM的方法依赖于多种胰岛相关蛋白自身抗体的检测，并结合人类白细胞抗原基因分型。预测糖尿病的方法的能力和可靠性的提高将增加在临床前阶段和蜜月期进行药物干预的可能性，以减缓或阻止剩余细胞的持续破坏。它还将允许监测和管理胰岛移植，并帮助开发免疫抑制疗法。由于胰腺不是理想的活体组织器官，因此无创监测BCM的成像方法将使TIDM和T2 DM的早期和更好的诊断/治疗成为可能。几个小组已经描述了检测和跟踪BCM丢失的非侵入性成像方法。目前正在用各种放射性示踪方法研究胰腺的不同摄取，包括6-脱氧-6-125I-D-葡萄糖、~3H-单糖D-甘露七糖、~3H-格列本脲、2-14C-四氧嘧啶、11C-乙酸酯、11C-蛋氨酸和18F-FDG。最近，胰岛β细胞和支配胰岛和胰腺外分泌的交感神经末梢上的囊泡单胺转运体2被特异性的放射性配基11C-DTBZ靶向。应用18F-FDOPA诊断婴幼儿先天性高胰岛素血症。人们迫切需要诊断胰岛素相关疾病的能力，到目前为止报道的各种方法在检测BCM变化的能力方面存在局限性。最近，利用分离的胰岛和β细胞系，证实了多巴胺D2/D3受体在啮齿动物和人类细胞上的表达。这些受体存在于胰岛中，在那里它们与胰岛素产生颗粒共同定位，并可作为BCM成像改变的替代标记。我们用高亲和力的D2/D3PET显像剂18F-FolyPride对啮齿动物胰腺的胰岛细胞和BCM进行了研究，取得了令人满意的结果。18F-FallyPride与胰腺切片和分离的胰岛细胞结合，并被D2/D3抑制剂氟哌啶醇竞争，表明具有特异性结合。用链脲佐菌素处理耗尽细胞，可使18F-FolyPride结合减少70%，胰岛素免疫染色证实细胞丢失。静脉注射18F-FolyPride后，体外微型PET成像显示胰腺中有18F-FolyPride。为了最大限度地显示胰腺(允许从相邻器官清除)和监测移植的胰岛细胞，我们在本申请中建议开发124I-epidePride(124I-EPID)(T1/2 124I=4.2d)，与18F-foryPride(T1/218F=0.076天)相比，它将允许更长时间的成像。~(124)I-EpidePride是一种新的放射性示踪剂，适用于多巴胺D2/D3受体的扩展成像，可用于监测DM的细胞丢失，并提供工具来测量对新疗法的反应性和评估胰岛移植物存活的效率。PHS 398/2590(09/04版) 公共卫生相关性：这是开发一种用于糖尿病研究的非侵入性PET显像剂的挑战要求。糖尿病是目前影响美国的一个主要健康问题。建议的方法将有助于对这一患者群体的管理。本申请涉及广泛的挑战领域(03)生物标记物的发现和验证以及特定的挑战主题03-DK-101：“发现NINDK感兴趣的疾病的疾病风险、进展或治疗反应的生物标记物”

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic 03-DK-101: "Discovery of biomarkers for disease risk, progression or response to therapy in diseases of interest to NINDK". Loss of insulin producing cells in the pancreatic islets, the endocrine component of pancreas, referred as beta cell mass (BCM), leads to an inability to manage blood sugar levels. This results in diabetes mellitus (DM), type 1 (TIDM) or type 2 (T2DM). T1DM, has previously been known as "insulin-dependent diabetes mellitus," (IDDM) or "juvenile diabetes." TIDM is a life-long condition in which the pancreas stops making insulin due to loss of BCM from an autoimmune response. T2DM, previously known as "noninsulin-dependent diabetes mellitus" (NIDDM) or "adult-onset diabetes", is the most common form of diabetes. About 90 to 95 percent of people who have diabetes have T2DM. There are 23.6 million people in the United States, or 8% of the population, who have diabetes. The total prevalence of diabetes increased 13.5% from 2005-2007 according to the American Diabetes Association. Despite rigorous control of blood sugar, the majority of diabetic patients develop serious late-stage complications including retinopathy, nephropathy, neuropathy, microangiopathy and strokes. A long asymptomatic preclinical period characterized by gradual BCM loss precedes clinical T1DM. Methods to predict the development of clinical T1DM currently rely on the detection of multiple autoantibodies to islet- associated proteins combined with HLA genotyping. Improvement of the power and reliability of methods to predict diabetes would raise the possibility for pharmacological intervention during the preclinical phase and the honeymoon period to either slow down or arrest the ongoing destruction of the remaining ¿-cells. It will also allow the monitoring and management of islet transplantation and help the development of immunosuppressive therapies. A non-invasive imaging approach to monitor BCM would enable earlier and better diagnosis/management of both TIDM and T2DM since pancreas is not an ideal organ for biopsy. Several groups have described non- invasive imaging approaches to detect and follow loss of BCM. Various radiotracer methods are currently underway to study differential pancreatic uptake include 6-deoxy-6-125I-iodo-D-glucose, 3H-monosaccharide D- mannoheptulose, 3H-glibenclamide, 2-14C-alloxan, 11C-acetate, 11C-methionine and 18F-FDG. Recently vesicular monoamine transporter-2 in pancreatic beta cells and in sympathetic nerve terminals that innervate islets and exocrine pancreas, was targeted using the specific radioligand 11C-DTBZ. 18F-FDOPA was used to diagnose infants with congenital hyperinsulinism. The ability to diagnose insulin-related disorders is in great need and the various approaches reported thus far have limitations in their ability to detect changes in BCM. Dopamine D2/D3 receptor expression have recently been demonstrated on rodent and human ¿-cells using isolated islets and beta cell lines. These receptors are present in pancreatic islets where they co-localize with insulin producing granules and may serve as a surrogate marker for imaging alterations in BCM. We have used 18F-fallypride, a high affinity D2/D3 PET imaging agent for the study of islet cells and BCM in rodent pancreas with promising results. 18F-Fallypride binds to pancreas sections and isolated islet cells and is competed off by haloperidol, a D2/D3 inhibitor, indicating specific binding. Depleting ¿-cells by treatment with streptozotocin reduced 18F-fallypride binding by 70% and immunostain for insulin confirmed ¿-cell loss. Following IV 18F- fallypride administration, ex-vivo microPET imaging reveals 18F-fallypride in the pancreas. In order to maximize visualization of the pancreas (allowing clearance from adjacent organs) and monitor transplanted islet cells we propose in this application to develop 124I-epidepride (124I-EPID) (t1/2 124I=4.2 days) which will allow imaging over extended periods compared to 18F-fallypride (t1/2 18F=0.076 days). 124I-Epidepride is a new radiotracer suitable for extended imaging of dopamine D2/D3 receptors and may have applications in monitoring of ¿-cell-loss in DM and provide tools to measure responsiveness to new therapies and evaluate efficiency of islet graft survival. PHS 398/2590 (Rev. 09/04) PUBLIC HEALTH RELEVANCE: This is a challenge request for developing a noninvasive PET imaging agent for the study of diabetes. Diabetes Mellitus is a major health problem currently affecting the US. The proposed approach will help in the management of this patient population. This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic 03-DK-101: "Discovery of biomarkers for disease risk, progression or response to therapy in diseases of interest to NINDK"