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）生物标志物的发现和验证以及特定的挑战主题03- dk -101：“NINDK感兴趣的疾病中疾病风险、进展或治疗反应的生物标志物的发现”。胰岛中产生胰岛素的细胞（胰腺的内分泌成分，被称为β细胞团（BCM））的减少，导致无法控制血糖水平。这导致糖尿病（DM）， 1型（TIDM）或2型（T2DM）。T1DM，以前被称为“胰岛素依赖型糖尿病”（IDDM）或“青少年糖尿病”。TIDM是一种终身疾病，由于自身免疫反应导致BCM损失，胰腺停止分泌胰岛素。T2DM，以前被称为“非胰岛素依赖型糖尿病”（NIDDM）或“成人发病型糖尿病”，是糖尿病最常见的形式。大约90%到95%的糖尿病患者患有2型糖尿病。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，糖尿病的总患病率增加了13.5%。尽管严格控制血糖，但大多数糖尿病患者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。临床T1DM发生前有一个以BCM逐渐消失为特征的长时间无症状临床前期。目前预测临床T1DM发展的方法依赖于检测多种胰岛相关蛋白自身抗体并结合HLA基因分型。糖尿病预测方法的能力和可靠性的提高将提高在临床前阶段和蜜月期进行药物干预的可能性，以减缓或阻止正在进行的对剩余细胞的破坏。它还将允许胰岛移植的监测和管理，并有助于开发免疫抑制疗法。由于胰腺不是活检的理想器官，因此监测BCM的非侵入性成像方法将能够更早、更好地诊断/管理TIDM和T2DM。几个小组已经描述了非侵入性成像方法来检测和跟踪BCM的丢失。目前正在研究胰腺摄取差异的各种放射性示踪剂方法包括6-脱氧-6- 125i -碘-D-葡萄糖、3h -单糖D-甘露庚糖、3h -格列本脲、2- 14c -四氧嘧啶、11c -醋酸盐、11c -蛋氨酸和18F-FDG。最近，研究人员利用特异性放射配体11C-DTBZ靶向了胰腺β细胞和支配胰岛和外分泌胰腺的交感神经末梢中的单胺转运蛋白-2。应用18F-FDOPA诊断婴儿先天性高胰岛素血症。诊断胰岛素相关疾病的能力是非常需要的，迄今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。多巴胺D2/D3受体的表达最近被证实在啮齿类动物和人类的¿-细胞使用分离的胰岛和β细胞系。这些受体存在于胰岛中，与产生胰岛素的颗粒共定位，可作为BCM影像学改变的替代标记物。我们使用高亲和力D2/D3 PET显像剂18F-fallypride对啮齿动物胰腺的胰岛细胞和BCM进行了研究，并取得了良好的结果。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，表明特异性结合。用链脲佐菌素治疗减少了70%的18F-fallypride结合，胰岛素免疫染色证实了-细胞损失。在静脉注射18F-fallypride后，离体pet成像显示胰腺中的18F-fallypride。为了最大限度地显示胰腺（允许清除邻近器官）并监测移植的胰岛细胞，我们在本应用中建议开发124I-epid （t1/2 124I=4.2天），与18F-fallypride （t1/2 18F=0.076天）相比，它将允许更长时间的成像。124i - epipride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，可用于监测糖尿病中的¿-细胞损失，并提供测量对新疗法的反应性和评估胰岛移植生存效率的工具。PHS 398/2590（09/04修订版）

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"