PET imaging of human beta cell mass

描述(由申请人提供)： 我们假设，在1型糖尿病(T1 DM)患者的前瞻性研究中，使用PET放射性配体[11C]DTBZ对2型囊泡单胺转运体进行无创性的PET定量将提供对β细胞质量(BCM)的临床有意义的估计。这一假设是基于对糖尿病啮齿动物模型的临床前研究，在这些研究中，我们已经证明，基于PET的胰腺感兴趣区(PROI)中[11C]DTBZ活性的定量是β细胞质量的有效替代标记物。在这一应用中，提出了以下一系列研究，以确定在临床研究和实践中使用[11C]DTBZ和PET来量化β细胞质量的可行性。具体目标1将检验假设，即正常人和长期存在的1型糖尿病(T1 DM)患者胰腺内的[11C]DTBZ放射性配基摄取存在显著差异。我们提出了一项横断面研究，以确定正常血糖健康对照组和生化证明不能分泌C-肽的T1糖尿病患者之间是否存在可测量的BCM差异，如使用[11C]DTBZ的PET扫描所定义的。在具体目标2中，我们将确定使用[11C]DTBZ进行PET扫描的临床操作特点。在这些研究中，我们将在健康志愿者中进行重测实验，以更好地了解PET测定β细胞质量的方法间和方法内的可变性。我们预计，目前的PET成像技术和定量将足够精确，以检测伴随疾病进展的BCM预期差异。在具体目标3中，我们建议在新发的T1 DM患者中用正电子发射计算机断层扫描(PET)连续测量BCM。我们假设，对PROI中[11C]DTBZ活性的纵向测量将揭示1)BCM下降，以及2)BCM的丧失将与T1 DM进展的标准实验室测量相关。研究人群将在诊断为T1 DM的100天内，每年在两个额外的时间点进行[11C]DTBZ的PET成像，总共为期3年。放射性配基摄取在PROI中的定量将通过包括隔室建模在内的标准技术来执行。如果成功，这些研究将为进一步开发一种新工具奠定基础，用于1)研究糖尿病(1型和2型)的自然病史，2)评估糖尿病的药物和细胞治疗，以及3)进行与早期疾病有关的临床诊断。

DESCRIPTION (provided by applicant): We hypothesize that non-invasive PET quantitation of vesicular monoamine transporters type 2 using the PET radioligand [11C] DTBZ will provide clinically meaningful estimates of beta cell mass (BCM) in prospective studies of individuals with type 1 diabetes mellitus (T1DM). This hypothesis is based on preclinical studies in rodent models of diabetes where we have demonstrated that PET based quantitation of [11C] DTBZ activity in the pancreas region of interest (pROI) is a valid surrogate marker of beta cell mass. In this application the following series of studies are proposed to determine the feasibility of using [11 C] DTBZ and PET to quantify beta cell mass in clinical research and practice. Specific Aim 1 will test the hypothesis that there is significant difference in [11C] DTBZ radioligand uptake within the pancreata of normal individuals and patients with long standing type 1 diabetes mellitus (T1DM). We propose a cross-sectional study to determine whether there are measurable differences in BCM, as defined by PET scan using [11C] DTBZ, between euglycemic healthy controls and T1DM patients with biochemically documented inability to secrete c-peptide. In Specific Aim 2, we will determine the clinical operating characteristics of PET scans with [11C] DTBZ. In these studies we will perform test-retest experiments in healthy volunteers to better understand the inter- and intra- assay variability of beta cell mass determinations by PET. We expect that the current PET imaging techniques and quantitation will be sufficiently precise to allow detection of the anticipated differences in BCM that accompany disease progression. In Specific Aim 3, we propose to serially measure BCM by PET in individuals with new onset T1DM. We hypothesize that longitudinal measurement of [11C] DTBZ activity in the pROI will reveal 1) declining BCM, and 2) that the loss of BCM will correlate with standard laboratory measures of T1DM progression. The study population will be imaged by PET with [11C] DTBZ within 100 days of T1DM diagnosis and at two additional time points yearly for a total of 3 years.. Quantitation of radioligand uptake in the pROI will be performed by standard techniques including compartmental modeling. If successful, these studies will provide a foundation for further development of a new tool for 1) studying the natural history of diabetes (both type 1 and type 2), 2) evaluating pharmaceutical and cell-based treatments of diabetes, and 3) making clinical diagnoses related to incipient disease.