GLP-1 receptor antagonist as a potential probe for pancreatic β-cell imaging

Mukai, Eri; Toyoda, Kentaro; Kimura, Hiroyuki; Kawashima, Hidekazu; Fujimoto, Hiroyuki; Ueda, Masashi; Temma, Takashi; Hirao, Konomu; Nagakawa, K.; Saji, Hideo; Inagaki, Nobuya

doi:10.1016/j.bbrc.2009.09.014

Cited by 64 publications

(73 citation statements)

References 16 publications

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“…At the same time, however, GLP-1 is able to inhibit the effects of glucagon [287]. Interestingly and very important for the present study Ex9-39 does not physically bind to the liver [288]. In contrast, our results show a strong influence of Ex9-39 on organotypic liver slices and in vivo.…”

Section: Per2 Induction Both In Vitro and In Vivosupporting

confidence: 40%

Metabolic Synchronization of the Liver Circadian Clock

Landgraf¹

2011

The Endocrine Society's 93rd Annual Meeting &Amp; Expo, June 4–7, 2011 - Boston

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Section: Per2 Induction Both In Vitro and In Vivosupporting

confidence: 40%

Metabolic Synchronization of the Liver Circadian Clock

Landgraf¹

2011

The Endocrine Society's 93rd Annual Meeting &Amp; Expo, June 4–7, 2011 - Boston

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“…Exendin(9-39)-amide isolated from Heloderma suspectum venom has been reported to be a GLP-1 receptor-specific antagonist (20), and the 125 I-Bolton-Hunter-conjugated Ex(9-39)NH 2 was shown to target rat pancreatic islets in vivo (21). In addition, Brom et al showed that the antagonist [Lys 40 In)NH 2 ] Ex(9-39) was an inferior imaging agent (6).…”

mentioning

confidence: 99%

Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers

Rylova

Waser

Pozzo³

et al. 2016

J Nucl Med

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The glucagon-like peptide-1 (GLP-1) receptors are important biomarkers for imaging pancreatic β-cell mass and detection of benign insulinomas. Using GLP-1 receptor antagonists, we aimed to eliminate the insulin-related side effects reported for all GLP-1 receptor agonists. Additionally, using a nonresidualizing tracer, 125 I-BoltonHunter-Exendin(9-39)NH 2 ( 125 I-BH-Ex(9-39)NH 2 ), we aimed to reduce the high kidney uptake, enabling a better detection of insulinomas in the tail and head of the pancreas. Methods: The affinity and biodistribution of Ex (9- ) uptake in Ins-1E tumor, 12.5 ± 2.2 %IA/g in the pancreas, and 235.8 ± 17.0 %IA/g in the kidney, with tumor-to-blood and tumor-to-kidney ratios of 100.52 and 0.17, respectively. Biodistribution of [Lys 40 (NODAGA-68 Ga)NH 2 ]Ex(9-39) showed only 2.2 ± 0.2 %IA/g uptake in Ins-1E tumor, 1.0 ± 0.1 %IA/g in the pancreas, and 78.4 ± 8.5 %IA/g in the kidney at 1 h after injection, with tumor-to-blood and tumor-to-kidney ratios of 7.33 and 0.03, respectively. In contrast, 125 I-BH-Ex(9-39)NH 2 showed tumor uptake (42.5 ± 8.1 %IA/g) comparable to the agonist and 28.8 ± 5.1 %IA/g in the pancreas at 1 h after injection. As we hypothesized, the kidney uptake of 125 I-BH-Ex(9-39)NH 2 was low, only 12.1 ± 1.4 %IA/g at 1 h after injection. The tumor-to-kidney ratio of 125 I-BH-Ex(9-39)NH 2 was improved 20-fold. Conclusion: Our results suggest that iodinated Ex(9-39)NH 2 may be a promising tracer for imaging GLP-1 receptor expression in vivo. Because of the 20-fold improved tumorto-kidney ratio 125 I-BH-Ex(9-39)NH 2 may offer higher sensitivity in the detection of insulinomas and imaging of β-cell mass in diabetic patients. Further studies with 124 I-BH-Ex(9-39)NH 2 are warranted.Key Words: GLP-1 receptor; insulinoma; β-cell mass; antagonist The glucagon-like peptide (GLP-1) receptors are important targets because they are overexpressed on more than 90% of benign insulinomas, some malignant insulinomas, most gastrinomas, and most phaeochromocytomas (1). Physiologically they are also expressed in the endocrine pancreas. Preoperative imaging of insulinomas is critical, because it helps to precisely localize these often very small lesions in the pancreas. Therefore, imaging probes for optical (2), bimodal (3), SPECT (4-7), and PET (8-13) imaging as well as MRI (14) were developed to localize GLP-1 receptors preoperatively and in addition to determine b-cell mass in diabetic animal models and potentially in patients. In particular, SPECT (4,5,7) and PET (8,13,15) agents were successfully translated into the clinic, and several promising clinical studies were reported. Still, there are a few shortcomings with the available tracers. The tracers accumulate highly in the kidneys when residualizing radiometals are used for labeling, possibly leading to not only unnecessary high radiation doses but also problems in localizing tumors in the tail and head of the pancreas (5,8,13). The usually low specific activity of the imaging tracers, exclusively agonists, and the concomitant relative...

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“…We designed and synthesized various derivatives of Exendin-4 and Exendin(9-39), which bind to the GLP-1 receptor selectively expressed at a high level in pancreatic β cells, as molecular imaging probes targeting pancreatic β cells. [67][68][69] That is, compounds in which 18 F-fluorobenzoyl group and 123 I-iodobenzoyl group were introduced into the lysine residue at position 12 of Exendin-4 and Exendin(9-39) through polyethylene glycol, were successfully developed as molecular probes for PET and SPECT of pancreatic β cells, respectively. In addition, since an increase in the number of pancreatic β cells in insulinoma has been reported, imaging of insulinoma using these probes is also being investigated.…”

Section: Molecular Imaging Of Pancreatic β-Cellsmentioning

confidence: 99%

<i>In Vivo</i> Molecular Imaging

Saji

2017

Biological & Pharmaceutical Bulletin

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In vivo molecular imaging is the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems. Among the methodologies used in in vivo molecular imaging, two methodologies are of great interest from the view of high sensitivity. One is nuclear medical imaging, and distribution and kinetics of a radiolabeled molecular probe are measured using positron emission tomography (PET) and single-photon emission computed tomography (SPECT). The other is optical molecular imaging, and distribution and kinetics of a fluorescent probe are measured using a fluorescent imaging instrument. In this review, the development of imaging probes for these two methodologies is briefly discussed. In nuclear medical molecular imaging, based on structure-activity-biodistribution relationship studies for small molecule and the concept of "functional unit-binding multifunctional molecular probe" containing 3 functional units (target recognition unit, signal-releasing unit, linker unit) for peptides and proteins, we developed radiolabeled probes with high and specific accumulation to the target for neuroreceptors, β-amyloid plaques, and tau aggregates in the brain, tumors, atherosclerotic plaques, pancreatic β-cell, myocardial sympathetic nerves, and so on. We also discuss the progression of molecular imaging toward therapy (radiotheranotics). In in vivo optical molecular imaging, taking into account the characteristics of optical imaging, we designed tumor-specific optical imaging probes with characteristic imaging mechanism, including near-infrared (NIR) fluorescent probes and activatable probes. Furthermore, we developed a photoacoustic imaging probe, which enables highly sensitive and high-resolution imaging in deep tissues.

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GLP-1 receptor antagonist as a potential probe for pancreatic β-cell imaging

Cited by 64 publications

References 16 publications

Metabolic Synchronization of the Liver Circadian Clock

Metabolic Synchronization of the Liver Circadian Clock

Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers

<i>In Vivo</i> Molecular Imaging

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