Noninvasive Assessment of Pancreatic Beta-Cell Mass

描述(申请人提供)：目前还没有一种非侵入性的方法来量化人类的β细胞质量。这种差距的持续存在是一个重要的问题，因为它潜在地限制了糖尿病患者和胰腺移植患者的医疗保健，并留下了对成像工具的未得到满足的需求，不仅用于评估这种疾病发病机制的机械性研究，而且还作为新的药物干预的结果工具。长期目标是开发基于新型探针的成像方法，用于非侵入性评估β细胞质量(BCM)和功能。在胰腺内，胰高血糖素样多肽-1受体(GLP-1R)在胰岛中唯一表达。本应用的目的是开发和测试一类基于GLP-1类似物的新型放射性示踪剂，用于β细胞团的正电子发射断层扫描(PET)成像。中心假设是，基于GLP-1的PET探针可用于监测BCM的变化，具有临床可接受的特异性、准确性和重复性。这一假说是基于成功开发出用于小鼠β细胞特异性成像的双环GLP-1类似物的初步数据而提出的。这项拟议研究的基本原理是，这些探头和相关成像方法的开发有可能转化为糖尿病患者(目前占美国人口的8%)、胰腺或胰岛细胞移植患者和胰岛素瘤患者的更好医疗保健。在强大的初步数据的指导下，将通过追求三个具体目标来验证这一假说：目标1：合成、表征和评估NOTA-(EM2198)n。EM2198多聚体在一类新型的双功能螯合支架上与PET同位素68Ga一起将提高成像的敏感性和特异性。支架前体和EM2198偶联物将用现有的方法合成。将使用细胞系、新分离的大鼠/猪胰岛和小鼠模型来评估其生物学行为；目标2：在临床相关模型(即Ossabaw小型猪)中确定BCM的PET-CT成像的准确性和重复性。迷你猪在基因、解剖和生理上与人类有相似之处。Ossabaw小型猪在食用致动脉粥样硬化的食物时会患上2型糖尿病。~(68)Ga-NOTA-EM2198摄取的PET测量结果将与猪胰腺病理检测的金标准相关联。目的：纵向监测二维超声心动图(T2D Ossabaw)猪血流动力学改变，评价纵向成像的潜在毒性效应。在T2D发病前和进展过程中，将对消瘦和糖尿病的Ossabaw猪进行连续的PET-CT成像。成像和临床结果将是相关的。这种纵向成像技术和辐射剂量学的潜在风险将被确定。在这个项目成功完成后，我们希望有一种安全的成像技术可用于进一步的临床评估。 公共卫生相关性：这项拟议的研究与公共健康相关，因为开发新的成像探针来非侵入性地监测胰岛β细胞团(BCM)最终有望影响糖尿病患者的医疗保健，糖尿病是一种全球流行病。因此，拟议的研究与NIH使命的一部分有关，该使命涉及寻求将减轻疾病负担的基础知识。

DESCRIPTION (provided by applicant): There is currently no non-invasive method to quantify beta-cell mass in humans. Continued existence of this gap represents an important problem because it potentially limits health care of patients with diabetes, with pancreas transplants, and leaves in place an unmet need for an imaging tool not only for mechanistic studies which evaluate the pathogenesis of this disease, but also as an outcome tool for new pharmacologic interventions. The long-term goal is to develop imaging methods, based on novel probes, for non-invasive assessment of beta cell mass (BCM) and function. Within the pancreas the glucagon-like peptide-1 receptor (GLP-1R) is uniquely expressed in the islets. The objective in this application is to develop and test a novel class of radiotracers for positron emission tomography (PET) imaging of beta cell mass based on analogues of GLP-1. The central hypothesis is GLP-1 based PET probes can be used to monitor BCM change with clinically acceptable specificity, accuracy, and reproducibility. This hypothesis has been formulated on the basis of preliminary data derived from successful development of a bicyclic GLP-1 analog for beta cell specific imaging in mice. The rationale for the proposed research is that development of these probes and the attendant imaging method has the potential to translate into better health care of patients with diabetes, currently 8% of the US population, and patients with pancreas or islet cell transplants, and insulinomas. Guided by strong preliminary data, the hypothesis will be tested by pursuing three specific aims: Aim 1: To synthesize, characterize, and evaluate NOTA-(EM2198)n. Multimers of EM2198 on a novel class of bifunctional chelator scaffolds together with the PET isotope, 68Ga will enhance the sensitivity and specificity of imaging. The scaffold precursors and EM2198 conjugates will be synthesized by existing methods. The biological behavior will be evaluated using cell lines, freshly isolated rat/pig islets, and mouse models; Aim 2: To determine the accuracy and reproducibility of PET-CT imaging of BCM in a clinically relevant model, namely Ossabaw minipigs. Mini-pigs have genetic, anatomical, and physiological similarities to humans. The Ossabaw miniature pigs develop type 2 diabetes when placed on an atherogenic diet. PET measures of 68Ga-NOTA-EM2198 uptake will be correlated with the gold standard of pathology assay of porcine pancreas. Aim 3: To longitudinally monitor the dynamic BCM change in T2D Ossabaw swine and assess the potential toxic effect of the longitudinal imaging procedure. Serial PET-CT imaging will be performed on lean and diabetic Ossabaw swine before the onset and during the progression of T2D. Imaging and clinical outcomes will be correlated. The potential risk of this longitudinal imaging technique and radiation dosimetry will be determined. Upon the successful completion of this project, we expect to have a safe imaging technique available for further clinical evaluation. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the development of novel imaging probes to noninvasively monitor pancreatic beta cell mass (BCM) is ultimately expected to impact health care of patients with diabetes, a global epidemic. Thus, the proposed research is relevant to the part of NIH's mission that pertains to seeking fundamental knowledge that will reduce the burdens of illness.