Imaging beta cell function in vivo with a Zinc responsive MRI contrast agent

描述（由申请人提供）：II型糖尿病是一种慢性疾病，其特征是β细胞功能的暂时性丧失和逐渐的胰岛素缺乏。尽管对-细胞功能衰退的机制进行了多年的深入研究，但由于我们无法监测-细胞在疾病进展或治疗恢复过程中的命运，对糖尿病发病机制的了解一直受到阻碍。尽管各种分子成像方法已经在体外得到证实，但体内细胞质量和功能的非侵入性成像仍然难以捉摸。虽然一些针对细胞的抗体和小分子显示出通过正电子发射断层扫描（PET）监测细胞质量的希望，但检测生物功能的首选成像方式仍然是磁共振成像（MRI），因为它在临床上更广泛使用，并且提供更高的图像分辨率。然而，对-细胞功能有反应的新型MRI试剂很少，只有少数已经在体内应用。我们最近在对照小鼠、stz治疗小鼠和饲喂高脂肪饮食16周的小鼠中证明，低分子量Zn2+传感器分子GdDOTA-diBPEN在大量注射葡萄糖启动葡萄糖刺激胰岛素分泌（GSIS）后增强了胰腺的功能。在提供的低浓度情况下，胰腺周围的其他组织不会被药物增强。胰腺在没有葡萄糖丸的情况下也没有增强，在缺乏细胞的动物（stz处理的动物）中也没有增强。这些观察结果与该药物仅在葡萄糖刺激胰岛素分泌（GSIS）过程中感知胰腺细胞释放Zn2+的假设一致。在长时间的高脂肪（60%）喂养中收集的小鼠图像显示整个腹部的对比度增强，与II型糖尿病进展过程中胰腺细胞团块的扩张一致。在本项目中，我们将优化I型和II型大鼠模型中葡萄糖和成像细胞功能剂的递送方案，胰岛素分泌快、慢期的图像Zn2+释放，图像细胞功能

DESCRIPTION (provided by applicant): Type II diabetes is chronic disease characterized by temporal loss of beta-cell function and gradual insulin deficiency. Despite years of intensive research into the mechanisms of -cell functional decline, progress in understanding the pathogenesis of diabetes has been hampered by our inability to monitor the fate of -cells during progression of the disease or during therapeutic recovery. Although various molecular imaging approaches have been demonstrated in vitro, non-invasive imaging of -cell mass and function in vivo remains elusive. Although a few antibodies and small molecules that target the -cell are showing promise for monitoring -cell mass by positron emission tomography (PET), the preferred imaging modality for detecting biological function continues to be magnetic resonance imaging (MRI) because it is more widely available clinically and offers the much greater image resolution. However, novel MRI agents that respond to -cell function are sparse and only a few have been applied in vivo. We recently demonstrated in control mice, in STZ-treated mice, and in mice fed a high fat diet over a period of sixteen weeks that the low molecular weight Zn2+ sensor molecule, GdDOTA-diBPEN, enhances the pancreas after a bolus injection of glucose to initiate glucose stimulated insulin secretion (GSIS). Other tissues surrounding the pancreas are not enhanced by the agent at the low concentration provided. The pancreas is also not enhanced in the absence of the glucose bolus nor is it enhanced in animals lacking -cells (STZ-treated animals). These observations are consistent with the hypothesis that this agent senses release of Zn2+ from pancreatic -cells only during glucose stimulated insulin secretion (GSIS). Images of mice collected over a prolonged period of high-fat (60%) feeding show dramatic contrast enhancement throughout the abdomen, consistent with expansion of pancreatic -cell mass during progression of type II diabetes. In this project, we will optimize the protocol for delivery of glucose and the agent for imaging -cell function, image Zn2+ release during both the fast and slow phases of insulin secretion, image -cell function in rat models of type I and type II diabetes, and image -cell function in Ossabaw mini-pigs using a clinical 3T scanner. Our goal is to determine the general utility of this novel MRI agent for imaging -cell function in anticipationof translating this technology to clinical imaging.