Zinc(II) Sensitive MRI Contrast Agents as Diagnostic Sensors for Tracking Insulin Secretion

摘要 意义：1型糖尿病（T1D），特别是2型糖尿病（T2D，> 90%的病例）正在成为糖尿病的一个重要因素。 随着全世界患者数量的大幅增加，社会经济资源的负担不断增加。 胰岛素依赖性治疗方案，如定期胰岛素注射，已为T1D和T2D患者充分建立。 T2D，但与各种长期的患者生活质量的负面影响有关， 长期并发症。除了代表T1D标准治疗方案的胰岛素给药外， T2D更典型的治疗选择包括口服降糖药物，例如二甲双胍 或阿卡波糖。目前和未来的研究领域集中在寻找胰岛素非依赖性治疗方案。 40多年来，人们一直在追求这一重要但又难以捉摸的科学目标，并取得了可喜的成果 特别是在胰岛移植领域。在这里，移植整个尸体胰腺或 在保护性胶囊中包含产生胰岛素的β细胞的胶囊化胰岛已经成为主要焦点 研究。然而，胰腺组织或胰岛移植成功的一个主要缺点是， 监测过程以量化移植后移植物的胰岛素分泌。的成像技术 可以适用于获得胰岛素分泌的定量信息，理想情况下， 时尚，可能是非常宝贵的未来成功的胰岛/胰腺移植。此外，这样的 技术也可以用于定量胰岛素分泌和确定TD 1或TD 2的开始， 从而提供关于糖尿病的进展和病因的诊断信息。假设：我们 假设使用锌（II）敏感的MRI造影剂提供了解决这些治疗问题的能力， 诊断问题。特别地，我们已经表明，这种传感器类型表现出高效率、高灵敏度和高可靠性。 当用于小动物或甚至灵长类动物（例如恒河猴）时，具有选择性和低毒性。初步 数据：我们已经证明，这种分子传感器类型代表了锌（II）敏感MRI的先锋 具有使用不同动物物种在体内对胰岛素分泌进行灵敏成像的能力的造影剂， 包括小鼠、大鼠和灵长类动物。所取得的初步成果将对进一步发展 该技术用于筛选移植的胰岛或整个胰腺组织。目标：关键 第一阶段的目标是合成、纯化和表征大量的CP 027， 其他结构相似的类似物（I期-目标1和2）。所有化合物将用于第二阶段， 对稳定性、物理性质和生物分布的深入研究。最有效的传感器种类将是 用于毒性研究，准备提交IND以获得首次人体临床试验的批准 试验（第二阶段-目标1）。此外，最有效的化合物将用于定量胰岛素分泌， 在裸鼠中通过移植胰腺组织体内提取胰岛（阶段II-Aim 2）。最后，健康的老鼠 以及使用Sprague-Dawley大鼠的T1D和T2D大鼠模型将用于胰腺成像。 数周至数月的疗程。常见的抗高血糖药物（例如Liratuglide）将在 使用我们的传感器评估药物疗效的T2D模型（第II阶段-目标3）。整体影响：采取一致行动， VitalQuan开发的技术将提供给临床实验室和开发新的 提高胰岛移植成功率的方法和技术。我们的代理商还将提供直接的措施， 振荡相1与相2胰岛素分泌，因此将为那些 公司目前正在开发促进或增强胰岛素分泌的先进药物。 此外，使用我们的药物还将有助于建立前所未有的体内研究， 胰岛素追踪这些应用将加速这种MRI造影剂的商业化 用于糖尿病研究和治疗的临床使用的试剂。

ABSTRACT Significance: Diabetes mellitus type 1 (T1D) and particularly type 2 (T2D, >90% of cases) are becoming an increasing burden on socioeconomic resources with vastly increasing patient numbers all over the world. Insulin-dependent treatment regimen such as regular insulin injections are well established for both T1D and T2D but have been associated with a negative impact on the quality of life of patients with a variety of long- term complications. Apart from insulin administration that represents the standard treatment regimen for T1D, more typical treatment options for T2D involve administration of oral antihyperglycemic drugs, e.g. metformin or acarbose. Current and future research fields focus on the search for insulin-independent treatment options. This important, albeit elusive, scientific goal has been pursued for over 40 years, with promising results particularly in the field of pancreatic islet transplantation. Here, grafting of either entire cadaveric pancreases or encapsulated islets comprised of insulin producing beta cells in a protective capsule has been the main focus of research. However, one major drawback in the grafting success of pancreatic tissue or islets is the monitoring process to quantify insulin secretion of the graft upon transplantation. An imaging technique that could be adapted to gain quantitative information on the insulin secretion, ideally in a minimally invasive fashion, may be invaluable for the future success of islet/pancreas transplantation. Furthermore, such a technique could also be used in order to quantify insulin secretion and to determine the onset of TD1 or TD2, therefore providing diagnostic information on the progression and etiology of diabetes. Hypothesis: We hypothesize that the use of zinc(II) sensitive MRI contrast agents offers the ability to solve these therapeutic and diagnostic problems. In particular, we have already shown that this sensor type exhibits high efficacy, high selectivity and low toxicity when used in small animals or even in primates (e.g. rhesus macaque). Preliminary Data: We have demonstrated that this molecular sensor type represents the vanguard of zinc(II) sensitive MRI contrast agents with the ability to sensitively image insulin secretion in vivo using different animal species, including mice, rats and primates. The preliminary results obtained will be crucial for the further development of this technology in the screening of transplanted islets or whole pancreatic tissue. Specific Aims: The key objectives in Phase I entail the synthesis, purification and characterization of a large amount of CP027 and other structurally similar analogues (Phase I – Aims 1 and 2). All compounds will be used in Phase II for advanced studies on stability, physical properties and biodistribution. The most efficient sensor species will be used for toxicity studies in preparation for submission of an IND to receive approval for a first-in-human clinical trial (Phase II – Aim 1). Furthermore, the most effective compound will be used to quantify insulin secretion in extracted islets in vivo via transplanted pancreatic tissue in nude mice (Phase II – Aim 2). Finally, healthy rats as well as a T1D and T2D rat model using Sprague-Dawley rats will be used for pancreatic imaging over the course of weeks to months. Common anti-hyperglycemic drugs (e.g. Liratuglideâ) will be administered in the T2D model to assess drug efficacy using our sensors (Phase II – Aim 3). Overall Impact: Taken in concert, the technologies developed by VitalQuan will be made available to clinical labs and companies developing new methods and technologies to improve islet graft success. Our agents will also provide direct measures of oscillating phase 1 versus phase 2 insulin secretion and will therefore offer an invaluable tool for those companies currently developing advanced pharmaceuticals that promote or enhance insulin secretion. Furthermore, the use of our agents will also help to establish unprecedented studies designed for in vivo insulin tracking. Taken in concert, these applications will accelerate the commercialization of such MRI contrast agents for clinical use in diabetes research and treatment.