期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 51, 页码 20719-20724出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1109480108
关键词
diabetes; insulin; molecular imaging; pancreatic islet; bioluminescence tomography
资金
- National Institute of Diabetes and Digestive and Kidney Diseases
- Juvenile Diabetes Research Foundation [1-2003-170, 37-2009-59, 1-2006-874, 26-2008-892, 40-2011-11]
- Swiss National Science Foundation [310000-109402, 310000-122423, 1Z73ZO-127935CR32I3129987]
- European Union and Innovative Medicines Initiative for Diabetes (IMIDIA) [BETAIMAGE 222980, C2008-T7]
- Veterans Affairs Research Service
- National Institutes of Health [DK072473, DK66636, DK68764, DK68854, DK69603, DK089572, T32EB001628]
- South-Eastern Center for Small-Animal Imaging [U24CA126588]
- Vanderbilt Mouse Metabolic Phenotyping Center [DK59637]
- Vanderbilt Diabetes Research and Training Center [DK20593]
We combined multimodal imaging (bioluminescence, X-ray computed tomography, and PET), tomographic reconstruction of bioluminescent sources, and two unique, complementary models to evaluate three previously synthesized PET radiotracers thought to target pancreatic beta cells. The three radiotracers {[F-18]fluoropropyl-(+)-dihydrotetrabenazine ([F-18]FP-DTBZ), [F-18](+)-2-oxiranyl-3-isobutyl-9-(3-fluoropropoxy)-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline (F-18-AV-266), and (2S, 3R, 11bR)-9-(3-fluoropropoxy)-2-(hydroxymethyl)-3-isobutyl-10-methoxy2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a] isoquinolin-2-ol (F-18-AV-300)} bind vesicular monoamine transporter 2. Tomographic reconstruction of the bioluminescent signal in mice expressing luciferase only in pancreatic beta cells was used to delineate the pancreas and was coregistered with PET and X-ray computed tomography images. This strategy enabled unambiguous identification of the pancreas on PET images, permitting accurate quantification of the pancreatic PET signal. We show here that, after conditional, specific, and rapid mouse beta-cell ablation, beta-cell loss was detected by bioluminescence imaging but not by PET imaging, given that the pancreatic signal provided by three PET radiotracers was not altered. To determine whether these ligands bound human beta cells in vivo, we imaged mice transplanted with luciferase-expressing human islets. The human islets were imaged by bioluminescence but not with the PET ligands, indicating that these vesicular monoamine transporter 2-directed ligands did not specifically bind beta cells. These data demonstrate the utility of coregistered multimodal imaging as a platform for evaluation and validation of candidate ligands for imaging islets.
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