In Vivo Imaging of β-Cell Mass in Rats Using <sup>18</sup>F-FP-(+)-DTBZ: A Potential PET Ligand for Studying Diabetes Mellitus

Kung, Mei Ping; Hou, Catherine; Lieberman, Brian P.; Oya, Shunichi; Ponde, Datta E.; Blankemeyer, Eric; Skovronsky, Daniel; Kilbourn, Michael R.; Kung, Hank F.

doi:10.2967/jnumed.108.051680

Cited by 87 publications

(75 citation statements)

References 35 publications

(70 reference statements)

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“…Ideally, two basic criteria should be met for adequate beta cell imaging [6]: (1) beta cells should retain the tracer 100-to 1,000-fold more than the exocrine cells; and (2) agents that label beta cell surface proteins should do this at high enough concentrations to overcome imaging signals arising from unbound tracer retained in the extracellular and vascular spaces, and from tracer bound to the other tissues surrounding the pancreas. Agents being tested currently for BCM imaging include glibenclamide [6], glucagon-like peptide 1 receptor [7,8], sulfonylurea receptor [6], vesicular monoamine transporter 2 (VMAT2) [9][10][11][12][13] and gangliosides [14]. Unfortunately, the uptake/binding of these agents to beta cells, compared with exocrine pancreas and non-beta cells, is insufficient to allow reliable imaging of the BCM [6,15].…”

Section: Introductionmentioning

confidence: 99%

“…Promising preliminary data were obtained with 11 C-labelled dihydrotetrabenazine (the PET ligand binding specifically to VMAT2) in streptozotocin (STZ)-induced diabetic Lewis rats [11] and in the BB-DP rat [12], but the data obtained in baboons [15] and in patients with longstanding type 1 diabetes [16] are not conclusive. A recent study using an 18 F-labelled epoxide derivative of tetrabenazine showed good pancreas specificity and significantly reduced uptake in rat liver [9], but it remains unclear whether substituting isotopes will produce better biodistribution results in larger mammals. As a whole, these observations emphasise the need for the identification of new beta cell biomarkers.…”

Section: Introductionmentioning

confidence: 99%

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A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2)γa as a pancreatic beta cell-specific biomarker

et al. 2010

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Aims/hypothesis Non-invasive imaging of the pancreatic beta cell mass (BCM) requires the identification of novel and specific beta cell biomarkers. We have developed a systems biology approach to the identification of promising beta cell markers. Methods We followed a functional genomics strategy based on massive parallel signal sequencing (MPSS) and microarray data obtained in human islets, purified primary rat beta cells, non-beta cells and INS-1E cells to identify promising beta cell markers. Candidate biomarkers were validated and screened using established human and macaque (Macacus cynomolgus) tissue microarrays.Results After a series of filtering steps, 12 beta cell-specific membrane proteins were identified. For four of the proteins we selected or produced antibodies targeting specifically the human proteins and their splice variants; all four candidates were confirmed as islet-specific in human D. Flamez and I. Roland contributed equally to this study. Electronic supplementary materialThe online version of this article

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2)γa as a pancreatic beta cell-specific biomarker

et al. 2010

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“…Recent years have seen exponential progress in applying various imaging modalities (MRI, positron emission tomography, optical) for noninvasive detection and monitoring of pancreatic ␤ -cell mass (2)(3)(4)(5)(6). A crucial prerequisite for clinical application of these techniques is the availability of a contrast agent with high affi nity and high specifi city toward ␤ -cell surface markers.…”

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confidence: 99%

Unique sphingomyelin patches are targets of a beta-cell-specific antibody

Kavishwar

Medarova

Moore

2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org this restoration noninvasively ( 1 ). Recent years have seen exponential progress in applying various imaging modalities (MRI, positron emission tomography, optical) for noninvasive detection and monitoring of pancreatic ␤ -cell mass ( 2-6 ). A crucial prerequisite for clinical application of these techniques is the availability of a contrast agent with high affi nity and high specifi city toward ␤ -cell surface markers.Antibodies or their fragments, owing to their high specifi city, biocompatibility and ability to carry payload to the target site, could serve as an ideal molecule for imaging applications. A number of different antibodies have been suggested for noninvasive determination of ␤ -cell mass ( 7-9 ). However, most of them suffer from lack of specifi city for islet ␤ cells. Part of this problem emanates from the fact that ␤ cells share the same lineage as other cells in the pancreas, making it diffi cult to elucidate unique targets on the ␤ -cell surface. In addition, there is a challenging requirement for imaging agents to be retained by ␤ cells at least 1,000-fold more strongly than by exocrine cells ( 10 ). No antibodies/antibody fragments have yet been described that fulfi ll all the requirements, necessitating a further search for ␤ -cell biomarkers. The single-chain antibody SCA B5 has shown promise in the past ( 11 ). However, its target and its utility for ␤ -cell imaging are unknown.In a previous study, we showed that the 125 I-labeled ␤ -cell-specifi c IC2 antibody accumulates in the pancreas of streptozotocin-induced mice in direct proportion to ␤ -cell mass ( 2 ). However, further progress toward the development of an antibody-based in vivo imaging probe was impeded due to lack of information about the nature and identity of the ␤ -cell surface antigen. IC2 is a rat monoclonal antibody of the IgM isotype, obtained by fusing lymphocytes from diabetes-prone BB rats with a rat myeloma partner and selected by screening hybridoma supernatants against Rin5F insulinoma cells ( 12 ). In this study, we present Abstract To devise successful imaging and therapeutic strategies, the identifi cation of ␤ -cell surface markers is one of the challenges in diabetes research that has to be resolved. We previously showed that IC2, a rat monoclonal IgM antibody, can be used for ex vivo determination of Increased blood glucose levels mostly accompanied by a decrease in functional ␤ -cell mass are a key characteristic of human diabetes. While type 1 diabetes results from autoimmune destruction of insulin-producing ␤ cells, type 2 diabetes is characterized by insulin resistance and relative insulin defi ciency. In both cases, pancreatic ␤ -cell mass is affected by the disease. Patients suffering from these conditions would benefi t from clinical interventions aimed at restoring functional ␤ -cell mass and methods to monitor Award JDRF 37-2009-30 (A.M.). This work was supported in part by Juvenile Diabetes Research Foundation

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“…The DTBZ analog [ 18 F]FP-DTBZ ( 18 F-AV-133) was prepared with fluorine-18 using precursors supplied by Avid Radiopharmaceuticals (39). Detailed radiochemical synthesis is provided in SI Methods.…”

Section: Methodsmentioning

confidence: 99%

Multimodal image coregistration and inducible selective cell ablation to evaluate imaging ligands

Virostko

Henske

Vinet

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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 {[ 18 F]fluoropropyl-(+)-dihydrotetrabenazine ([ 18 F]FP-DTBZ), [ 18 F](+)-2-oxiranyl-3-isobutyl-9-(3-fluoropropoxy)-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline ( 18 F-AV-266), and (2S,3R, 11bR)-9-(3-fluoropropoxy)-2-(hydroxymethyl)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol ( 18 F-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.diabetes | insulin | molecular imaging | pancreatic islet | bioluminescence tomography

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In Vivo Imaging of β-Cell Mass in Rats Using ¹⁸F-FP-(+)-DTBZ: A Potential PET Ligand for Studying Diabetes Mellitus

Cited by 87 publications

References 35 publications

A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2)γa as a pancreatic beta cell-specific biomarker

A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2)γa as a pancreatic beta cell-specific biomarker

Unique sphingomyelin patches are targets of a beta-cell-specific antibody

Multimodal image coregistration and inducible selective cell ablation to evaluate imaging ligands

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In Vivo Imaging of β-Cell Mass in Rats Using 18F-FP-(+)-DTBZ: A Potential PET Ligand for Studying Diabetes Mellitus

Cited by 87 publications

References 35 publications

A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2)γa as a pancreatic beta cell-specific biomarker

A genomic-based approach identifies FXYD domain containing ion transport regulator 2 (FXYD2)γa as a pancreatic beta cell-specific biomarker

Unique sphingomyelin patches are targets of a beta-cell-specific antibody

Multimodal image coregistration and inducible selective cell ablation to evaluate imaging ligands

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In Vivo Imaging of β-Cell Mass in Rats Using ¹⁸F-FP-(+)-DTBZ: A Potential PET Ligand for Studying Diabetes Mellitus