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）个体的前瞻性研究中，使用PET放射性配体[11 C] DTBZ对囊泡单胺转运体2型进行无创PET定量将提供有临床意义的β细胞质量（β细胞）估计值。该假设基于啮齿类动物糖尿病模型的临床前研究，我们已证明，胰腺感兴趣区域（pROI）中基于PET的[11 C] DTBZ活性定量是β细胞质量的有效替代标志物。在本申请中，提出了以下一系列研究，以确定在临床研究和实践中使用[11 C] DTBZ和PET定量β细胞质量的可行性。具体目标1将检验正常个体和长期1型糖尿病（T1 DM）患者胰腺内[11 C] DTBZ放射性配体摄取存在显著差异的假设。我们提出了一项横断面研究，以确定是否有可测量的差异，在正常血糖的健康对照组和T1 DM患者之间，使用[11 C] DTBZ的PET扫描定义，生化记录无法分泌C-肽。在特定目标2中，我们将确定使用[11 C] DTBZ进行PET扫描的临床操作特征。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法测定β细胞质量的试验间和试验内变异性。我们希望目前的PET成像技术和定量将足够精确，以允许检测伴随疾病进展的预期差异。在具体目标3中，我们建议在新发T1 DM患者中通过PET连续测量BMI。我们假设pROI中[11 C] DTBZ活性的纵向测量将揭示1）R2下降，和2）R2损失将与T1 DM进展的标准实验室测量相关。研究人群将在T1 DM诊断后100天内和每年另外两个时间点接受[11 C] DTBZ PET成像，共持续3年。将通过标准技术（包括房室模型）对pROI中的放射性配体摄取进行定量。如果成功，这些研究将为进一步开发新工具提供基础，用于1）研究糖尿病（1型和2型）的自然史，2）评估糖尿病的药物和细胞治疗，以及3）进行与早期疾病相关的临床诊断。

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.