Imaging pancreatic beta-cells with PET neuroimaging agents

描述（由申请方提供）：测量胰腺β细胞质量（β细胞质量）的临床可行方法对于评价恢复胰岛素分泌能力缺陷的治疗方法的生理基础至关重要。通过利用已成功用于神经成像的受体特异性成像探针，成像探针已取得重大进展。神经元和β细胞在功能上相似，能够通过分泌胞内囊泡的内容物来响应细胞特异性的细胞外刺激。因此，最初开发用于特异性结合神经元的正电子发射断层扫描（PET）成像配体可能被证明可用于成像神经元。耶鲁大学PET中心一直处于脑受体和神经元成像的最前沿，并建议评估其广泛的人类神经成像剂库作为体内探针，以定量测定神经元。为了最大限度地发挥这些研究的价值，将获得人类胰腺成像以及健康和1型和2型糖尿病胰腺的验证研究。在胰腺中显示合适的体内特异性摄取和人体中适当的成像特性，并且可以在体外区分健康和糖尿病胰腺的成像探针将在有限的临床PET成像试验中进行测试，以评估T1DM患者胰腺中放射性示踪剂结合是否存在可测量的降低。在特定目标1中，我们将评估耶鲁PET中心目前使用的获批放射性示踪剂是否可用于健康个体的脑血管成像。我们计划在正在进行的影像学研究中，评估目前用于神经影像学的至少10种放射性配体对胰腺成像的适用性。在特定目标2中，我们将在从糖尿病胰腺器官供体网络（nPOD）获得的健康、T1DM和T2DM人胰腺组织和人胰岛中验证放射性配体的体外β细胞特异性。与来自T1DM或T2DM患者的胰腺相比，可用于测量胰岛素分泌β细胞的那些放射性配体与健康人胰岛和来自健康供体的胰腺具有更高的特异性结合。在特定目标3中，我们将在健康和T1DM志愿者中对符合以下标准的药物进行临床评价：1）目标1中确定的有前景的胰腺成像特征和2）目标2中确定的有利β细胞特异性。有必要进行有限的临床评价，以确定放射性配体是否可以定量测量与糖尿病进展相关的生理学变化。

DESCRIPTION (provided by applicant): A clinically viable means to measure pancreatic beta-cell mass (BCM) is essential for evaluating the physiological basis of therapeutic approaches to restore deficient insulin secretory capacity. Major advances in imaging BCM have been made by taking advantage of receptor-specific imaging probes that have been successfully used for neuroimaging. Neurons and β-cells are functionally similar in being able to respond to cell-specific extracellular stimuli with the secretion of the contents of intracellular vesicles. Hence, Positron Emission Tomography (PET) imaging ligands that were originally developed to specifically bind to neurons may prove useful for imaging BCM. The Yale PET Center has been at the forefront of imaging both brain receptors and BCM and proposes to evaluate its extensive library of human neuroimaging agents as in vivo probes to quantitatively determine BCM. To maximize the value of these studies, pancreatic imaging in humans will be obtained together with validation studies in healthy and type 1 and 2 diabetes mellitus pancreas. Imaging probes that show suitable in vivo specific uptake in pancreas and appropriate imaging properties in humans, and can distinguish between healthy and diabetic pancreas in vitro will then be tested in a limited clinical PET-imaging trial to assess whether there is a measurable decrease in radiotracer binding in the pancreas of T1DM patients. In Specific Aim 1, we will evaluate whether the approved radiotracers currently in use at the Yale PET center for human neuroimaging can be used for imaging BCM in healthy individuals. We plan to either piggyback onto ongoing imaging studies to evaluate the suitability for pancreas imaging of at least 10 radioligands currently in use for neuroimaging. In Specific Aim 2, we will validate β-cell specificity of the radioligands in vitro in healthy, T1DM, and T2DM human pancreas tissue obtained from the network for Pancreatic Organ Donors with Diabetes (nPOD), and in human islets. Those radioligands that may be useful for measuring insulin secreting beta-cells will have higher specific binding to healthy human islets and to pancreas from healthy donors compared to pancreas from patients with T1DM or T2DM. In Specific Aim 3, we will perform a clinical evaluation in healthy and T1DM volunteers of those agents that meet the criteria of 1) promising pancreas imaging characteristics determined in Aim 1 and 2) favorable β-cell specificity as determined in Aim 2. A limited clinical evaluation is necessary to establish whether the radioligand can quantitatively measure changes in BCM that are physiologically relevant to diabetes progression.