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

使用 Ga-68 标记的胰高血糖素样肽 1 ana 进行非侵入性 β 细胞成像

• 批准号: 7224577
• 负责人: Martin Gotthardt
• 金额: $ 15万
• 依托单位: RADBOUD UNIVERSITY NIJMEGEN MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7224577
• 关键词: bioimaging /biomedical imaging; biological models; clinical research; computed axial tomography; disease /disorder model; gallium; human subject; insulin dependent diabetes mellitus; laboratory mouse; laboratory rabbit; molecular /cellular imaging; noninsulin dependent diabetes mellitus; pancreatic islet transplantation; pancreatic islets; patient oriented research; pharmacokinetics; positron emission tomography; radiation dosage; radionuclides; radiotracer; technology /technique development; tissue /cell culture

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.

描述（由申请人提供）： 胰腺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 细胞量的几个方面仍有待阐明，例如：（1）2 型糖尿病发病时的总 β 细胞量是否减少，（2）2 型糖尿病发病期间 β 细胞量如何发展？疾病的病程，(3) 哪些因素影响 β 细胞量，以及 (4) β 细胞量与治疗反应有何关系。此外，测量胰岛移植后的β细胞质量也将非常有意义。由于没有可靠的方法来评估和量化体内人类 β 细胞质量，这一事实阻碍了研究。如果可以通过非侵入性方法测定β细胞质量，这将是推进这一研究领域的巨大财富。 我们开发了一种放射性标记试剂 (DOTA-Lys40-Exendin 4)，可实现特定 β 细胞成像。在小鼠中，示踪剂显示每克胰腺组织吸收了大约 9% 的注射活性。因此，这种特定的示踪剂是人类体内 β 细胞成像的一种很有前途的工具。根据这项拨款提案，我们将开发一种 Ga-68 标记的 DOTA-Exendin 化合物，用于通过正电子发射断层扫描 (PET) 对体内 β 细胞进行成像。与传统核医学成像相比，使用 Ga-68 等正电子发射器将具有许多优势：1. 高空间分辨率，2. 精确定量，3. 通过使用集成的 PET/CT 扫描仪（CT=计算机断层扫描），即使在 β 细胞丢失后胰腺示踪剂的摄取减少。与磁共振成像 (MRI) 相比，该方法非常灵敏，不需要直接标记 β 细胞进行成像。直接标记（例如用铁）只能在 β 细胞移植中（胰岛移植之前）进行，但不适用于胰腺 β 细胞的体内成像。 在本项目中，我们将研究不同糖尿病动物模型中 Ga-68 标记的 DOTA-Exendin 摄取与 β 细胞质量的相关性。示踪剂临床前开发成功后，将在人体中进行试点研究。除了在健康志愿者以及 I 型和 II 型糖尿病患者中进行原理验证研究外，还将建立一种剂量测定方法，通过 PET 成像简单可靠地量化 β 细胞质量。