Non-invasive beta-cell imaging using a Ga-68-labeled glucagone-like peptide-1 ana

描述(由申请人提供)： 胰岛β细胞的功能是糖尿病的一个关键问题，但只能间接评估。目前，有关β细胞质量的几个方面仍有待阐明，例如：(1)2型糖尿病发病时总的β细胞质量是否减少，(2)β细胞质量是如何在病程中发展的，(3)哪些因素影响β细胞质量，以及(4)β细胞质量与治疗反应有何关系。此外，测量胰岛移植后的β细胞质量将是非常有意义的。由于没有可靠的方法来评估和量化体内的人β细胞质量，这一事实阻碍了研究。如果可以用一种非侵入性的方法来确定β细胞质量，这将是推进这一研究领域的巨大财富。 我们已经开发了一种放射性标记试剂(DOTA-Lys40-Exendin 4)，可以进行特定的β细胞成像。在小鼠身上，示踪剂显示每克胰腺组织摄取了大约9%的注射活性。因此，这种特定的示踪剂是一种很有前途的活体β细胞成像工具。在这项拨款计划下，我们将开发一种Ga-68标记的DOTA-Exendin化合物，用于活体β细胞的正电子发射断层扫描(PET)成像。使用正电子发射器，如Ga-68，将提供许多优于传统核医学成像的优点：1.高空间分辨率，2.准确的定量，3.使用集成的PET/CT扫描仪(CT=计算机断层扫描)精确定位胰腺/β细胞区域，即使在β细胞丢失后胰腺示踪剂摄取减少。与核磁共振成像(MRI)相比，该方法非常敏感，不需要为成像目的直接标记β细胞。直接标记(例如，铁标记)只能在胰岛移植之前的胰岛细胞移植中进行，但不适用于体内胰腺β细胞的成像。 在这个项目中，我们将研究在不同的糖尿病动物模型中，GA-68标记的DOTA-Exendin的摄取与β细胞质量的相关性。一旦该示踪剂在临床前成功开发，将在人体上进行试点研究。除了在健康志愿者和I型和II型糖尿病患者中进行的原则验证研究外，还将建立一种剂量学方法，通过PET成像简单而可靠地定量β细胞质量。

DESCRIPTION (provided by applicant): The function of pancreatic beta-cell cells is a key issue in diabetes mellitus, but can only be assessed indirectly. Currently, several aspects regarding beta-cell mass remain to be elucidated, for example: (1) Is the total beta-cell mass at the onset of type 2 diabetes diminished or not, (2) how does the beta-cell mass develop during the course of the disease, (3) which factors affect beta-cell mass, and (4) how does beta-cell mass relate to the response to therapy. Futhermore, it would be of great interest to measure beta-cell mass after islet-transplantation. Research is hampered by the fact that no reliable methods exist to assess and quantify human beta-cell mass in vivo. If beta-cell mass could be determined by a non-invasive method, this would be of a tremendous asset in advancing this field of research. We have developed a radiolabeled agent (DOTA-Lys40-Exendin 4) that allows specific beta-cell imaging. In mice the tracer shows uptake of approximately 9% of the injected activity per gram of pancreas tissue. This specific tracer is therefore a promising tool for in vivo beta-cell imaging in humans.Under this grant proposal, we will develop a Ga-68 labeled DOTA-Exendin compound for imaging of beta-cells in vivo with positron emission tomography (PET). The use of a positron emitter such as Ga-68 will offer a number of advantages over conventional nuclear medicine imaging: 1. high spatial resolution, 2. accurate quantification, 3. exact localization of the pancreas / the beta-cell areas by use of an integrated PET/CT scanner (CT=computed tomography), even if pancreatic tracer uptake is decreased after beta-cell loss. In comparison to Magnetic Resonance Imaging (MRI), the approach is very sensitive and will not require direct labeling of beta-cells for imaging purposes. Direct labeling (for example with iron) can only be done in beta-cell transplantation (prior to islet transplantation) but is not suitable for imaging of pancreatic beta-cells in vivo. In this project, we will investigate the correlation of uptake of the Ga-68-labeled DOTA-Exendin and beta-cell mass in different animal models of diabetes. Upon succesful pre-clinical development of the tracer, pilot studies in humans will be conducted. Apart from proof-of-principle studies in healthy volunteers and diabetes type I and II patients, a dosimetric method will be established to simply and reliably quantify beta-cell mass by PET imaging.