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: 7479608
• 负责人: Martin Gotthardt
• 金额: $ 14.27万
• 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/7479608
• 关键词: Affect; Affinity; Age; Animal Model; Antibodies; Applications Grants; Area; B-Lymphocytes; Beta Cell; Binding; Biodistribution; Blood; Body Weight; Cell Transplantation; Cells; Central obesity; Control Groups; Cultured Cells; Defect; Development; Diabetes Mellitus; Discipline of Nuclear Medicine; Disease; Elderly; Enrollment; Functional disorder; GLP-I receptor; Gender; Human; Human body; Image; Insulin; Insulin-Dependent Diabetes Mellitus; Invasive; Iron; Islets of Langerhans Transplantation; Kinetics; Label; Magnetic Resonance Imaging; Measures; Methods; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Oryctolagus cuniculus; Pancreas; Pathologic; Patients; Penetration; Peptides; Pilot Projects; Positron; Positron-Emission Tomography; Procedures; Purpose; Radioisotopes; Radiolabeled; Research; Research Personnel; Resolution; Rodent; Standards of Weights and Measures; Structure of beta Cell of islet; Techniques; Testing; Tissues; Tomography, Computed, Scanners; Tracer; X-Ray Computed Tomography; age group; analog; base; cellular imaging; diabetic; exenatide; glucagon-like peptide 1; healthy volunteer; helospectin I; in vivo; incretin hormone; interest; man; non-diabetic; pre-clinical; programs; radiotracer; receptor; research study; response; tool; uptake

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。

项目成果

Strain Differences Determine the Suitability of Animal Models for Noninvasive In Vivo Beta Cell Mass Determination with Radiolabeled Exendin.

• DOI: 10.1007/s11307-016-0936-y
• 发表时间: 2016-10
• 期刊: Molecular imaging and biology
• 影响因子: 3.1
• 作者: Willekens SM;Joosten L;Boerman OC;Balhuizen A;Eizirik DL;Gotthardt M;Brom M
• 通讯作者: Brom M

68Ga-labelled exendin-3, a new agent for the detection of insulinomas with PET.

• DOI: 10.1007/s00259-009-1363-y
• 发表时间: 2010-07
• 期刊: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
• 影响因子: 9.1
• 作者: Brom, Maarten;Oyen, Wim J. G.;Joosten, Lieke;Gotthardt, Martin;Boerman, Otto C.
• 通讯作者: Boerman, Otto C.

Enhanced Specific Activity by Multichelation of Exendin-3 Leads To Improved Image Quality and In Vivo Beta Cell Imaging.

Exendin-3 多螯合增强的比活性可改善图像质量和体内 Beta 细胞成像。

• DOI: 10.1021/acs.molpharmaceut.7b00853
• 发表时间: 2018
• 期刊: Molecular pharmaceutics
• 影响因子: 4.9
• 作者: Joosten,Lieke;Brom,Maarten;Peeters,Hanneke;Heskamp,Sandra;Béhé,Martin;Boerman,Otto;Gotthardt,Martin
• 通讯作者: Gotthardt,Martin

Whole organ and islet of Langerhans dosimetry for calculation of absorbed doses resulting from imaging with radiolabeled exendin.

朗格汉斯剂量测定的整个器官和胰岛，用于计算放射性标记的毒蜥外泌肽成像产生的吸收剂量。

• DOI: 10.1038/srep39800
• 发表时间: 2017
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: vanderKroon,Inge;Woliner-vanderWeg,Wietske;Brom,Maarten;Joosten,Lieke;Frielink,Cathelijne;Konijnenberg,MarkW;Visser,EricP;Gotthardt,Martin
• 通讯作者: Gotthardt,Martin