? 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. ? ?

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZDK1-GRB-3 (O1))
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Dutta, Chhanda
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Radboud University Nijmegen Medical Center
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Joosten, Lieke; Brom, Maarten; Peeters, Hanneke et al. (2018) Enhanced Specific Activity by Multichelation of Exendin-3 Leads To Improved Image Quality and In Vivo Beta Cell Imaging. Mol Pharm 15:486-494
van der Kroon, Inge; Woliner-van der Weg, Wietske; Brom, Maarten et al. (2017) Whole organ and islet of Langerhans dosimetry for calculation of absorbed doses resulting from imaging with radiolabeled exendin. Sci Rep 7:39800
Willekens, Stefanie M A; Joosten, Lieke; Boerman, Otto C et al. (2016) Strain Differences Determine the Suitability of Animal Models for Noninvasive In Vivo Beta Cell Mass Determination with Radiolabeled Exendin. Mol Imaging Biol 18:705-14
Brom, Maarten; Joosten, Lieke; Frielink, Cathelijne et al. (2015) (111)In-exendin uptake in the pancreas correlates with the ?-cell mass and not with the ?-cell mass. Diabetes 64:1324-8
Brom, Maarten; Woliner-van der Weg, Wietske; Joosten, Lieke et al. (2014) Non-invasive quantification of the beta cell mass by SPECT with ¹¹¹In-labelled exendin. Diabetologia 57:950-9
Brom, Maarten; Joosten, Lieke; Oyen, Wim J G et al. (2012) Radiolabelled GLP-1 analogues for in vivo targeting of insulinomas. Contrast Media Mol Imaging 7:160-6
Brom, Maarten; Joosten, Lieke; Laverman, Peter et al. (2011) Preclinical evaluation of 68Ga-DOTA-minigastrin for the detection of cholecystokinin-2/gastrin receptor-positive tumors. Mol Imaging 10:144-52
Disselhorst, Jonathan A; Brom, Maarten; Laverman, Peter et al. (2010) Image-quality assessment for several positron emitters using the NEMA NU 4-2008 standards in the Siemens Inveon small-animal PET scanner. J Nucl Med 51:610-7
Brom, Maarten; Oyen, Wim J G; Joosten, Lieke et al. (2010) 68Ga-labelled exendin-3, a new agent for the detection of insulinomas with PET. Eur J Nucl Med Mol Imaging 37:1345-55
Brom, Maarten; Andra?oj?, Karolina; Oyen, Wim J G et al. (2010) Development of radiotracers for the determination of the beta-cell mass in vivo. Curr Pharm Des 16:1561-7