Synthesis and biological evaluation of an 111In-labeled exendin-4 derivative as a single-photon emission computed tomography probe for imaging pancreatic β-cells

Kimura, Hiroyuki; Fujita, Naotaka; Kanbe, Kaori; Matsuda, Hideaki; Watanabe, Hiroyuki; Arimitsu, Kenji; Fujimoto, Hiroyuki; Hamamatsu, Keita; Yagi, Yusuke; Ono, Masahiro; Inagaki, Nobuya; Saji, Hideo

doi:10.1016/j.bmc.2017.09.005

Cited by 20 publications

(27 citation statements)

References 16 publications

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“…Ex vivo pancreas analysis using the 111 In-exendin-4 probe The 111 In-exendin-4 probe, (Lys12[In-BnDTPA-Ahx])exendin-4 ( 111 In-Ex4) was synthesized, as previously reported 9 . Although the utility of 111 In-Ex4 for in vivo SPECT/computed tomography (CT) imaging was established in the previous report 14,17,18 , the pancreatic visualization of 10-week-old male RCS-10 mice was reconfirmed before the investigation in dulaglutide-treated mice.…”

Section: Oral Glucose Tolerance Test and Mice Glycohemoglobin Measurementioning

confidence: 99%

“…GLP-1R has been a promising target for a b-cell-specific probe. For the purpose of visualization and quantification of b-cells, GLP-1R-targeted imaging methods, such as single-photon emission computed tomography (SPECT) and positron emission tomography have recently emerged [8][9][10][11] . These methods were developed for the detection of insulinoma and transplanted islets, and the evaluation of b-cell mass [12][13][14] , and they have not been used for clinical prediction of drug efficacy in diabetes treatment.…”

Section: Introductionmentioning

confidence: 99%

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Association of glucagon‐like peptide‐1 receptor‐targeted imaging probe with in vivo glucagon‐like peptide‐1 receptor agonist glucose‐lowering effects

Murakami

Fujimoto

Fujita

et al. 2020

J of Diabetes Invest

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Aims/Introduction Glucagon‐like peptide‐1 receptor agonists (GLP‐1RA) are used for treatment of type 2 diabetes mellitus worldwide. However, some patients do not respond well to the therapy, and caution must be taken for certain patients, including those with reduced insulin secretory capacity. Thus, it is clinically important to predict the efficacy of GLP‐1RA therapy. GLP‐1R‐targeted imaging has recently emerged to visualize and quantify β‐cells. We investigated whether GLP‐1R‐targeted imaging can predict the efficacy of GLP‐1RA treatment. Materials and Methods We developed 111 Indium‐labeled exendin‐4 derivative ( 111 In‐Ex4) as a GLP‐1R‐targeting probe. Diabetic mice were selected from NONcNZO10/LtJ male mice that were fed for different durations with 11% fat chow. After 3‐week administration of dulaglutide as GLP‐1RA therapy, mice with non‐fasting blood glucose levels <300 mg/dL and >300 mg/dL were defined as responders and non‐responders, respectively. In addition, ex vivo 111 In‐Ex4 pancreatic accumulations ( 111 In‐Ex4 pancreatic values) were examined. Results The non‐fasting blood glucose levels after treatment were 172.5 ± 42.4 mg/dL in responders ( n = 4) and 330.8 ± 20.7 mg/dL in non‐responders ( n = 5), respectively. Ex vivo 111 In‐Ex4 pancreatic values showed significant correlations with post‐treatment glycohemoglobin and glucose area under curve during an oral glucose tolerance test ( R 2 = 0.76 and 0.80; P < 0.01 and <0.01, respectively). The receiver operating characteristic area under curve for identifying responders by ex vivo 111 In‐Ex4 pancreatic values was 1.00 ( P < 0.01). Conclusion Ex vivo 111 In‐Ex4 pancreatic values reflected dulaglutide efficacy, suggesting clinical possibilities for expanding GLP‐1R‐targeted imaging applications.

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Section: Oral Glucose Tolerance Test and Mice Glycohemoglobin Measurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association of glucagon‐like peptide‐1 receptor‐targeted imaging probe with in vivo glucagon‐like peptide‐1 receptor agonist glucose‐lowering effects

Murakami

Fujimoto

Fujita

et al. 2020

J of Diabetes Invest

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“…111 InCl 3 was purchased from Nihon Medi-Physics (Tokyo, Japan). Radiolabeling of [Lys 12 (BnDTPA-Ahx)]exendin-4 with 111 In was performed as we previously reported 8 . In brief, a 0.01 μM [Lys 12 (BnDTPA-Ahx)]exendin-4 precursor solution was prepared in a 0.01 M MES buffer (pH 5.5) containing 0.1% Tween-80 as a solubilizer.…”

Section: Methodsmentioning

confidence: 99%

“…We have been developing imaging methods using radiolabeled exendin derivatives targeting the glucagon-like peptide-1 (GLP-1) receptor, with the aim of quantifying BCM by measuring probe accumulation in the pancreas 5–7 . We developed [Lys 12 ( 111 In-BnDTPA-Ahx)]exendin-4 ([ 111 In]Ex4), and reported specific binding of this probe to the GLP-1 receptor 8 . We also established an analytical method for single photon emission computed tomography (SPECT) imaging of living mice to quantify pancreatic uptake of [ 111 In]Ex4 9 , and reported that pancreatic uptake is correlated with BCM as calculated by the product of the pancreatic weight and the area ratio of tissue immunostained with anti-insulin antibody to whole pancreas 10 .…”

Section: Introductionmentioning

confidence: 99%

Investigation of the preservation effect of canagliflozin on pancreatic beta cell mass using SPECT/CT imaging with 111In-labeled exendin-4

Hamamatsu

Fujimoto

Fujita

et al. 2019

Sci Rep

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Radiolabeled exendin derivatives are promising for non-invasive quantification of pancreatic beta cell mass (BCM); longitudinal observation of BCM for evaluation of therapeutic effects has not been achieved. The aim of this study is to demonstrate the usefulness of our developing method using [Lys12(111In-BnDTPA-Ahx)]exendin-4 to detect longitudinal changes in BCM. We performed a longitudinal study with obese type 2 diabetes model (db/db) mice administered canagliflozin, which is reported to preserve BCM. Six-week-old mice were assigned to a canagliflozin-administered group or a control group. Blood glucose levels of the canagliflozin group were significantly lower than those of the control group. Plasma insulin levels, insulin secretion during OGTT and insulin content in the pancreas were preserved in the canagliflozin group in comparison with those in the control group. According to SPECT/CT imaging analysis using [Lys12(111In-BnDTPA-Ahx)]exendin-4, pancreatic uptake was significantly decreased in the control group, whereas there was no significant change in the canagliflozin group. After nine weeks, both pancreatic uptake and BCM of the canagliflozin group were significantly higher than those of the control group, and a correlation between them was observed. In conclusion, our imaging method confirmed the BCM-preservation effect of canagliflozin, and demonstrated its potential for longitudinal evaluation of BCM.

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“…125 I-BHexendin (9-39) showed the highest concentration in the lungs and the second highest concentration in the pancreas, and pre-dosing of an excess amount of unlabeled exendin (9-39) significantly reduced the pancreatic uptake, indicating that radiolabeled exendin (9-39) could be another useful probe for β-cell imaging [111]. The same team then developed another probe, [Lys 12 ( 111 In-BnDTPA-Ahx)]exendin-4, and reported that SPECT imaging with this probe enabled noninvasive visualization of β-cells and measurement of BCM [112]. More recently, SPECT imaging after in vivo injection of 111 In-labeled exendin-3 showed specific targeting of the radiotracer to β-cells, facilitating noninvasive visualization and quantification of BCM in the pancreas of rodents, as well as in healthy and diabetic patients [103,113].…”

Section: Exendin-based Pet/spect Probesmentioning

confidence: 99%

Molecular imaging of β-cells: diabetes and beyond

Wei

Lan

Luo

et al. 2019

Advanced Drug Delivery Reviews

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Since diabetes is becoming a global epidemic, there is a great need to develop early β-cell specific diagnostic techniques for this disorder. There are two types of diabetes (i.e., type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM)). In T1DM, the destruction of pancreatic βcells leads to reduced insulin production or even absolute insulin deficiency, which consequently results in hyperglycemia. Actually, a central issue in the pathophysiology of all types of diabetes is the relative reduction of β-cell mass (BCM) and/or impairment of the function of individual βcells. In the past two decades, scientists have been trying to develop imaging techniques for noninvasive measurement of the viability and mass of pancreatic β-cells. Despite intense scientific efforts, only two tracers for positron emission tomography (PET) and one contrast agent for magnetic resonance (MR) imaging are currently under clinical evaluation. β-cell specific imaging probes may also allow us to precisely and specifically visualize transplanted β-cells and to improve transplantation outcomes, as transplantation of pancreatic islets has shown promise in treating T1DM. In addition, some of these probes can be applied to the preoperative detection of hidden insulinomas as well. In the present review, we primarily summarize potential tracers under development for imaging β-cells with a focus on tracers for PET, SPECT, MRI, and optical imaging. We will discuss the advantages and limitations of the various imaging probes and extend an outlook on future developments in the field. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on "Imaging and Therapy of Diabetes: State of the Art".

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Synthesis and biological evaluation of an 111In-labeled exendin-4 derivative as a single-photon emission computed tomography probe for imaging pancreatic β-cells

Cited by 20 publications

References 16 publications

Association of glucagon‐like peptide‐1 receptor‐targeted imaging probe with in vivo glucagon‐like peptide‐1 receptor agonist glucose‐lowering effects

Association of glucagon‐like peptide‐1 receptor‐targeted imaging probe with in vivo glucagon‐like peptide‐1 receptor agonist glucose‐lowering effects

Investigation of the preservation effect of canagliflozin on pancreatic beta cell mass using SPECT/CT imaging with 111In-labeled exendin-4

Molecular imaging of β-cells: diabetes and beyond

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