Imaging pancreatic beta-cells with PET neuroimaging agents

描述(由申请人提供)：一种临床上可行的测量胰腺β细胞质量(BCM)的方法对于评估恢复胰岛素分泌能力缺陷的治疗方法的生理学基础至关重要。通过利用已成功用于神经成像的受体特异性成像探针，在成像BCM方面取得了重大进展。神经元和β细胞在功能上相似，都能通过分泌细胞内小泡的内容来响应细胞特异性的细胞外刺激。因此，正电子发射断层扫描(PET)成像配体最初是为了与神经元特异性结合而开发的，可能被证明对BCM成像有用。耶鲁大学PET中心一直处于脑受体和BCM成像的前沿，并建议评估其广泛的人类神经成像剂库，作为体内探针来定量确定BCM。为了最大限度地发挥这些研究的价值，我们将对健康人和1型和2型糖尿病患者的胰腺进行验证研究，同时进行人体胰腺成像。显示合适的体内胰腺特异性摄取和人体合适的成像特性，并能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T1 DM患者胰腺中的放射性示踪剂结合是否有可测量的减少。在具体目标1中，我们将评估耶鲁大学PET中心目前用于人类神经成像的经批准的放射性示踪剂是否可以用于健康个体的BCM成像。我们计划利用正在进行的成像研究来评估目前用于神经成像的至少10种放射性配基在胰腺成像中的适用性。在特定目标2中，我们将验证从糖尿病患者胰腺器官捐赠者网络获得的健康人、T1 DM和T2 DM人胰腺组织以及人胰岛组织中放射性配体的β细胞特异性。与T1 DM或T2 DM患者的胰腺相比，那些可能用于测量胰岛素分泌β细胞的放射性配体与健康人的胰岛和健康捐赠者的胰腺具有更高的特异性结合。在特定的目标3中，我们将在健康和T1 DM志愿者中对符合以下标准的药物进行临床评估：1)目标1中确定的有希望的胰腺成像特征；2)目标2中确定的良好的β细胞特异性。有必要进行有限的临床评估，以确定放射性配基是否能够定量测量与糖尿病进展相关的生理上的骨髓基质细胞的变化。

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.