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Dale O. Kiesewetter - One of the best experts on this subject based on the ideXlab platform.
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improving the theranostic potential of Exendin 4 by reducing the renal radioactivity through brush border membrane enzyme mediated degradation
Bioconjugate Chemistry, 2019Co-Authors: Mingru Zhang, Hongzhang Deng, Lixin Lang, Dale O. Kiesewetter, Longguang Tang, Fei Kang, Zhantong Wang, Orit Jacobson, Weijing YangAbstract:As highly expressed in insulinomas, the glucagon-like peptide-1 receptor (GLP-1R) is believed to be an attractive target for diagnosis, localization, and treatment with radiolabeled Exendin 4. However, the high and persistent radioactivity accumulation of Exendin 4 in the kidneys limits accurate diagnosis and safe, as well as effective, radiotherapy in insulinomas. In this study, we intend to reduce the renal accumulation of radiolabeled Exendin 4 through degradation mediated by brush border membrane enzymes. A new Exendin 4 ligand NOTA-MVK-Cys40-Leu14-Exendin 4 containing Met-Val-Lys (MVK) linker between the peptide and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator was synthesized and labeled with 68Ga. The in vitro mouse serum stability and cell binding affinity of the tracer were evaluated. Initial in vitro cleavage of the linker was determined by incubation of a model compound Boc-MVK-Dde with brush border membrane vesicles (BBMVs) with and without the inhibitor of neutral endopeptidase (NEP). Further cleavage studies were performed with the full structure of NOTA-MVK-Cys40-Leu14-Exendin 4. Kidney and urine samples were collected in the in vivo metabolism study after intravenous injection of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4. The microPET images were acquired in INS-1 tumor model at different time points; the radioactivity uptake of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 in tumor and kidneys were determined and compared with the control radiotracer without MVK linker. 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 was stable in mouse serum. The MVK modification did not affect the affinity of NOTA-MVK-Cys40-Leu14-Exendin 4 toward GLP-1R. The in vitro cleavage study and in vivo metabolism study confirmed that the MVK sequence can be recognized by BBM enzymes and cleaved at the amide bond between Met and Val, thus releasing the small fragment containing Met. MicroPET images showed that the tumor uptake of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 was comparable to that of the control, while the kidney uptake was significantly reduced. As a result, more favorable tumor to kidney ratios were achieved. In this study, a novel Exendin 4 analogue, NOTA-MVK-Cys40-Leu14-Exendin 4, was successfully synthesized and labeled with 68Ga. With the cleavable MVK sequence, this ligand could be cleaved by the enzymes on kidneys, and releasing the fragment of 68Ga-NOTA-Met-OH, which will rapidly excrete from urine. As the high and consistent renal radioactivity accumulation could be significantly reduced, NOTA-MVK-Cys40-Leu14-Exendin 4 shows great potential in the diagnosis and radiotherapy for insulinoma.
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improving the theranostic potential of Exendin 4 by reducing the renal radioactivity through brush border membrane enzyme mediated degradation
Bioconjugate Chemistry, 2019Co-Authors: Lixin Lang, Mingru Zhang, Dale O. Kiesewetter, Longguang Tang, Fei Kang, Zhantong Wang, Orit Jacobson, Hongzhang DengAbstract:As highly expressed in insulinomas, the glucagon-like peptide-1 receptor (GLP-1R) is believed to be an attractive target for diagnosis, localization, and treatment with radiolabeled Exendin 4. However, the high and persistent radioactivity accumulation of Exendin 4 in the kidneys limits accurate diagnosis and safe, as well as effective, radiotherapy in insulinomas. In this study, we intend to reduce the renal accumulation of radiolabeled Exendin 4 through degradation mediated by brush border membrane enzymes. A new Exendin 4 ligand NOTA-MVK-Cys40-Leu14-Exendin 4 containing Met-Val-Lys (MVK) linker between the peptide and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator was synthesized and labeled with 68Ga. The in vitro mouse serum stability and cell binding affinity of the tracer were evaluated. Initial in vitro cleavage of the linker was determined by incubation of a model compound Boc-MVK-Dde with brush border membrane vesicles (BBMVs) with and without the inhibitor of neutral endopeptidase...
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glucagon like peptide 1 receptor pet ct with 68ga nota Exendin 4 for detecting localized insulinoma a prospective cohort study
The Journal of Nuclear Medicine, 2016Co-Authors: Yaping Luo, Dale O. Kiesewetter, Yupei Zhao, Qingqing Pan, Shaobo Yao, Huadan Xue, Zhaohui Zhu, Xiaoyuan ChenAbstract:Preoperative localization of insulinoma is a clinical dilemma. We aimed to investigate whether glucagon-like peptide-1 receptor (GLP-1R) PET/CT with 68Ga-NOTA-MAL-cys40-Exendin-4 (68Ga-NOTA-Exendin-4) is efficient in detecting insulinoma. Methods: In our prospective cohort study, patients with endogenous hyperinsulinemic hypoglycemia were enrolled. CT, MRI, endoscopic ultrasound, and 99mTc-hydrazinonicotinamide-TOC SPECT/CT were done according to standard protocols. GLP-1R PET/CT was performed 30–60 min after the injection of 68Ga-NOTA-Exendin-4. The gold standard for diagnosis was the histopathologic results after surgery. Results: Of 52 recruited patients, 43 patients with histopathologically proven insulinomas were included for the imaging studies. Nine patients did not undergo surgical intervention. 68Ga-NOTA-Exendin-4 PET/CT correctly detected insulinomas in 42 of 43 patients with high tumor uptake (mean SUVavg ± SD, 10.2 ± 4.9; mean SUVmax ± SD, 23.6 ± 11.7), resulting in sensitivity of 97.7%. In contrast, 99mTc-hydrazinonicotinamide-TOC SPECT/CT showed a low sensitivity of 19.5% (8/41) in this group of patients; however, it successfully localized the tumor that was false-negative with GLP-1R PET/CT. The sensitivities of CT, MR, and endoscopic ultrasonography were 74.4% (32/43), 56.0% (14/25), and 84.0% (21/25), respectively. Conclusion:68Ga-NOTA-Exendin-4 PET/CT is a highly sensitive imaging technique for the localization of insulinoma.
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glucagon like peptide 1 receptor pet ct with 68ga nota Exendin 4 for detecting localized insulinoma a prospective cohort study
The Journal of Nuclear Medicine, 2016Co-Authors: Miao Yu, Dale O. Kiesewetter, Yupei Zhao, Wenming Wu, Fang Li, Xiaoyuan ChenAbstract:UNLABELLED: Preoperative localization of insulinoma is a clinical dilemma. We aimed to investigate whether glucagon-like peptide-1 receptor (GLP-1R) PET/CT with (68)Ga-NOTA-MAL-cys(40)-Exendin-4 ((68)Ga-NOTA-Exendin-4) is efficient in detecting insulinoma. METHODS: In our prospective cohort study, patients with endogenous hyperinsulinemic hypoglycemia were enrolled. CT, MRI, endoscopic ultrasound, and (99m)Tc-hydrazinonicotinamide-TOC SPECT/CT were done according to standard protocols. GLP-1R PET/CT was performed 30-60 min after the injection of (68)Ga-NOTA-Exendin-4. The gold standard for diagnosis was the histopathologic results after surgery. RESULTS: Of 52 recruited patients, 43 patients with histopathologically proven insulinomas were included for the imaging studies. Nine patients did not undergo surgical intervention. (68)Ga-NOTA-Exendin-4 PET/CT correctly detected insulinomas in 42 of 43 patients with high tumor uptake (mean SUVavg ± SD, 10.2 ± 4.9; mean SUVmax ± SD, 23.6 ± 11.7), resulting in sensitivity of 97.7%. In contrast, (99m)Tc-hydrazinonicotinamide-TOC SPECT/CT showed a low sensitivity of 19.5% (8/41) in this group of patients; however, it successfully localized the tumor that was false-negative with GLP-1R PET/CT. The sensitivities of CT, MR, and endoscopic ultrasonography were 74.4% (32/43), 56.0% (14/25), and 84.0% (21/25), respectively. CONCLUSION: (68)Ga-NOTA-Exendin-4 PET/CT is a highly sensitive imaging technique for the localization of insulinoma.
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68ga nota Exendin 4 pet ct in localization of an occult insulinoma and appearance of coexisting esophageal carcinoma
Clinical Nuclear Medicine, 2016Co-Authors: Yaping Luo, Dale O. Kiesewetter, Xiaoyuan ChenAbstract:A 61-year-old woman with biochemically proven endogenous hyperinsulinemic hypoglycemia and negative conventional imaging underwent 68Ga-NOTA-Exendin-4 PET/CT for localization of insulinoma. Focal intense radioactivity in the tail of the pancreas was observed that was subsequently confirmed as insulinoma pathologically after surgical resection. In addition, esophageal carcinoma with lymph node and hepatic metastases was found by FDG PET/CT in the same patient. Neither the primary carcinoma nor the metastases showed increased radioactivity on 68Ga-NOTA-Exendin-4 PET/CT.
Xiaoyuan Chen - One of the best experts on this subject based on the ideXlab platform.
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long acting release formulation of Exendin 4 based on biomimetic mineralization for type 2 diabetes therapy
ACS Nano, 2017Co-Authors: Wei Chen, Guohao Wang, Bryant C Yung, Gang Liu, Zhiyong Qian, Xiaoyuan ChenAbstract:Exendin-4 has been clinically exploited for treating type 2 diabetes, but the short circulation half-life and multiple daily injections limit its widespread application with respect to poor patient compliance, low efficacy, and high treatment cost. In this study, a potent long-acting release system based on biomimetic mineralization was constructed for biocompatible and sustained Exendin-4 delivery. Similar to natural biomineralization, Exendin-4 can be mineralized to form nanosized mineral solids by means of the reaction between acidic amino acid residues and calcium ions in a supersaturated environment with negligible influence on peptide bioactivity. Mineralized Exendin-4 particles may be spontaneously absorbed by a living body under physiologically supersaturated conditions, resulting in gradual dissociation and sustained drug release. In such a way, the glucose level of diabetic mice may be effectively controlled for a long period of time by mineralized Exendin-4 without obvious side effects. We beli...
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glucagon like peptide 1 receptor pet ct with 68ga nota Exendin 4 for detecting localized insulinoma a prospective cohort study
The Journal of Nuclear Medicine, 2016Co-Authors: Yaping Luo, Dale O. Kiesewetter, Yupei Zhao, Qingqing Pan, Shaobo Yao, Huadan Xue, Zhaohui Zhu, Xiaoyuan ChenAbstract:Preoperative localization of insulinoma is a clinical dilemma. We aimed to investigate whether glucagon-like peptide-1 receptor (GLP-1R) PET/CT with 68Ga-NOTA-MAL-cys40-Exendin-4 (68Ga-NOTA-Exendin-4) is efficient in detecting insulinoma. Methods: In our prospective cohort study, patients with endogenous hyperinsulinemic hypoglycemia were enrolled. CT, MRI, endoscopic ultrasound, and 99mTc-hydrazinonicotinamide-TOC SPECT/CT were done according to standard protocols. GLP-1R PET/CT was performed 30–60 min after the injection of 68Ga-NOTA-Exendin-4. The gold standard for diagnosis was the histopathologic results after surgery. Results: Of 52 recruited patients, 43 patients with histopathologically proven insulinomas were included for the imaging studies. Nine patients did not undergo surgical intervention. 68Ga-NOTA-Exendin-4 PET/CT correctly detected insulinomas in 42 of 43 patients with high tumor uptake (mean SUVavg ± SD, 10.2 ± 4.9; mean SUVmax ± SD, 23.6 ± 11.7), resulting in sensitivity of 97.7%. In contrast, 99mTc-hydrazinonicotinamide-TOC SPECT/CT showed a low sensitivity of 19.5% (8/41) in this group of patients; however, it successfully localized the tumor that was false-negative with GLP-1R PET/CT. The sensitivities of CT, MR, and endoscopic ultrasonography were 74.4% (32/43), 56.0% (14/25), and 84.0% (21/25), respectively. Conclusion:68Ga-NOTA-Exendin-4 PET/CT is a highly sensitive imaging technique for the localization of insulinoma.
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glucagon like peptide 1 receptor pet ct with 68ga nota Exendin 4 for detecting localized insulinoma a prospective cohort study
The Journal of Nuclear Medicine, 2016Co-Authors: Miao Yu, Dale O. Kiesewetter, Yupei Zhao, Wenming Wu, Fang Li, Xiaoyuan ChenAbstract:UNLABELLED: Preoperative localization of insulinoma is a clinical dilemma. We aimed to investigate whether glucagon-like peptide-1 receptor (GLP-1R) PET/CT with (68)Ga-NOTA-MAL-cys(40)-Exendin-4 ((68)Ga-NOTA-Exendin-4) is efficient in detecting insulinoma. METHODS: In our prospective cohort study, patients with endogenous hyperinsulinemic hypoglycemia were enrolled. CT, MRI, endoscopic ultrasound, and (99m)Tc-hydrazinonicotinamide-TOC SPECT/CT were done according to standard protocols. GLP-1R PET/CT was performed 30-60 min after the injection of (68)Ga-NOTA-Exendin-4. The gold standard for diagnosis was the histopathologic results after surgery. RESULTS: Of 52 recruited patients, 43 patients with histopathologically proven insulinomas were included for the imaging studies. Nine patients did not undergo surgical intervention. (68)Ga-NOTA-Exendin-4 PET/CT correctly detected insulinomas in 42 of 43 patients with high tumor uptake (mean SUVavg ± SD, 10.2 ± 4.9; mean SUVmax ± SD, 23.6 ± 11.7), resulting in sensitivity of 97.7%. In contrast, (99m)Tc-hydrazinonicotinamide-TOC SPECT/CT showed a low sensitivity of 19.5% (8/41) in this group of patients; however, it successfully localized the tumor that was false-negative with GLP-1R PET/CT. The sensitivities of CT, MR, and endoscopic ultrasonography were 74.4% (32/43), 56.0% (14/25), and 84.0% (21/25), respectively. CONCLUSION: (68)Ga-NOTA-Exendin-4 PET/CT is a highly sensitive imaging technique for the localization of insulinoma.
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68ga nota Exendin 4 pet ct in localization of an occult insulinoma and appearance of coexisting esophageal carcinoma
Clinical Nuclear Medicine, 2016Co-Authors: Yaping Luo, Dale O. Kiesewetter, Xiaoyuan ChenAbstract:A 61-year-old woman with biochemically proven endogenous hyperinsulinemic hypoglycemia and negative conventional imaging underwent 68Ga-NOTA-Exendin-4 PET/CT for localization of insulinoma. Focal intense radioactivity in the tail of the pancreas was observed that was subsequently confirmed as insulinoma pathologically after surgical resection. In addition, esophageal carcinoma with lymph node and hepatic metastases was found by FDG PET/CT in the same patient. Neither the primary carcinoma nor the metastases showed increased radioactivity on 68Ga-NOTA-Exendin-4 PET/CT.
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evaluation of an 18 f alf nota analog of Exendin 4 for imaging of glp 1 receptor in insulinoma
Theranostics, 2012Co-Authors: Dale O. Kiesewetter, Lei Zhu, Ning Guo, Jinxia Guo, Haokao Gao, Gang Niu, Xiaoyuan ChenAbstract:Introduction: The GLP-1 receptor plays an important role in glucose homeostasis and thus is a very important target for diabetes therapy. The receptor is also overexpressed in insulinoma, a tumor of pancreatic beta-cells. We previously evaluated two fluorine-18-labeled analogs of Exendin-4 prepared by conjugation with [18F]FBEM (N-[2-(4-[18F]fluorobenzamide)ethyl]maleimide). Both compounds demonstrated good tumor uptake, but the synthesis of the radiotracers was time consuming. To overcome this challenge, we developed a NOTA analog and performed radiolabeling using aluminum [18F]fluoride complexation. Methods: Cys40-Exendin-4 was conjugated with NOTA mono N-ethylmaleimide. [18F]AlF conjugation was conducted and the radiolabeled product purified by preparative HPLC. Dynamic and static PET imaging scans were conducted on nude mice with established INS-1 xenografts. Uptake of tumor and other major organs in static images was quantitated (%ID/g) and comparison with blocking studies was made. PET quantification was also compared with ex vivo biodistribution results. Results: The radiosynthesis provided [18F]AlF-NOTA-MAL-cys40-Exendin-4 in 23.6 ± 2.4 % radiochemical yield (uncorrected, n = 3) after HPLC; the process required about 55 min. The specific activity at time of injection ranged from 19.6 to 31.4 GBq (0.53-0.85 Ci)/µmol. Tumor uptake had reached its maximum (16.09 ± 1.18% ID/g, n = 4) by 5 min and remained nearly constant for the duration of the study. Kidney uptake continued to increase throughout the entire one hour time course. Pre-injection of Exendin-4 caused a marked reduction in tissue uptake with the major exception of liver and kidneys, in which uptake was not affected. HPLC analysis of the radioactive components in extracts of the tumor and plasma showed primarily parent compound at 60 min post-injection, whereas extracts of kidney and urine contained exclusively one polar radioactive component. Conclusion: The radiotracer is prepared in a simple one-step procedure and obtained in high specific activity after HPLC purification. [18F]AlF-NOTA-MAL-Exendin-4 shows high tumor uptake and highly selective GLP-1 tissue uptake (INS-1 tumor, lung, pancreas), but still suffers from high kidney uptake.
Helmut R Macke - One of the best experts on this subject based on the ideXlab platform.
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Exendin 4 based radiopharmaceuticals for glucagonlike peptide 1 receptor pet ct and spect ct
The Journal of Nuclear Medicine, 2010Co-Authors: Damian Wild, Andreas Wicki, Rosalba Mansi, Martin Behe, Boris Keil, Peter Bernhardt, Gerhard Christofori, Helmut R MackeAbstract:Strong overexpression of glucagonlike peptide-1 (GLP-1) receptors in human insulinoma provides an attractive target for imaging. The first clinical trials demonstrated that GLP-1 receptor SPECT/CT using [Lys(40)(Ahx [6-aminohexanoic acid]-DOTA-(111)In)NH(2)]-Exendin-4 can localize hardly detectable insulinomas. However, [Lys(40)(Ahx-DOTA-(111)In)NH(2)]-Exendin-4 imaging has drawbacks related to the use of (111)In in that it is costly and carries a relatively high radiation burden for the patient. The aim of this study was the preclinical evaluation of [Lys(40)(Ahx-DOTA-(68)Ga)NH(2)]-Exendin-4 for PET/CT and [Lys(40)(Ahx-hydrazinonicotinamide [HYNIC]-(99m)Tc)NH(2)]-Exendin-4 for SPECT/CT.
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lys40 ahx dtpa 111in nh2 Exendin 4 is a highly efficient radiotherapeutic for glucagon like peptide 1 receptor targeted therapy for insulinoma
Clinical Cancer Research, 2007Co-Authors: Andreas Wicki, Damian Wild, Martin Behe, Daniel Storch, Martin Gotthardt, Jean Claude Reubi, Christian Seemayer, Stefan Kneifel, Michael J Mihatsch, Helmut R MackeAbstract:PURPOSE: Although metabolic changes make diagnosis of insulinoma relatively easy, surgical removal is hampered by difficulties in locating it, and there is no efficient treatment for malignant insulinoma. We have previously shown that the high density of glucagon-like peptide-1 receptors (GLP-1R) in human insulinoma cells provides an attractive target for molecular imaging and internal radiotherapy. In this study, we investigated the therapeutic potential of [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4, an (111)In-labeled agonist of GLP-1, in a transgenic mouse model of human insulinoma. EXPERIMENTAL DESIGN: [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4 was assessed in the Rip1Tag2 mouse model of pancreatic beta-cell carcinogenesis, which exhibits a GLP-1R expression comparable with human insulinoma. Mice were injected with 1.1, 5.6, or 28 MBq of the radiopeptide and sacrificed 7 days after injection. Tumor uptake and response, the mechanism of action of the radiopeptide, and therapy toxicity were investigated. RESULTS: Tumor uptake was >200% injected activity per gram, with a dose deposition of 3 Gy/MBq at 40 pmol [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4. Other GLP-1R-positive organs showed > or =30 times lower dose deposition. A single injection of [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4 resulted in a reduction of the tumor volume by up to 94% in a dose-dependent manner without significant acute organ toxicity. The therapeutic effect was due to increased tumor cell apoptosis and necrosis and decreased proliferation. CONCLUSIONS: The results suggest that [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4 is a promising radiopeptide capable of selectively targeting insulinoma. Furthermore, Auger-emitting radiopharmaceuticals such as (111)In are able to produce a marked therapeutic effect if a high tumor uptake is achieved.
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lys40 ahx dtpa 111in nh2 Exendin 4 a very promising ligand for glucagon like peptide 1 glp 1 receptor targeting
The Journal of Nuclear Medicine, 2006Co-Authors: Damian Wild, Andreas Wicki, Martin Behe, Boris Keil, Gerhard Christofori, Daniel Storch, Beatrice Waser, Martin Gotthardt, Jean Claude Reubi, Helmut R MackeAbstract:High levels of glucagon-like peptide-1 (GLP-1) receptor expression in human insulinomas and gastrinomas provide an attractive target for imaging, therapy, and intraoperative tumor localization, using receptor-avid radioligands. The goal of this study was to establish a tumor model for GLP-1 receptor targeting and to use a newly designed Exendin-4-DTPA (DTPA is diethylenetriaminepentaacetic acid) conjugate for GLP-1 receptor targeting. METHODS: Exendin-4 was modified C-terminally with Lys(40)-NH(2), whereby the lysine side chain was conjugated with Ahx-DTPA (Ahx is aminohexanoic acid). The GLP-1 receptor affinity (50% inhibitory concentration [IC(50)] value) of [Lys(40)(Ahx-DTPA)NH(2)]Exendin-4 as well as the GLP-1 receptor density in tumors and different organs of Rip1Tag2 mice were determined. Rip1Tag2 mice are transgenic mice that develop insulinomas in a well-defined multistage tumorigenesis pathway. This animal model was used for biodistribution studies, pinhole SPECT/MRI, and SPECT/CT. Peptide stability, internalization, and efflux studies were performed in cultured beta-tumor cells established from tumors of Rip1Tag2 mice. RESULTS: The GLP-1 receptor affinity of [Lys(40)(Ahx-DTPA)NH(2)]Exendin-4 was found to be 2.1 +/- 1.1 nmol/L (mean +/- SEM). Because the GLP-1 receptor density in tumors of Rip1Tag2 mice was very high, a remarkably high tumor uptake of 287 +/- 62 %IA/g (% injected activity per gram tissue) was found 4 h after injection. This resulted in excellent tumor visualization by pinhole SPECT/MRI and SPECT/CT. In accordance with in vitro data, [Lys(40)(Ahx-DTPA-(111)In)NH(2)]Exendin-4 uptake in Rip1Tag2 mice was also found in nonneoplastic tissues such as pancreas and lung. However, lung and pancreas uptake was distinctly lower compared with that of tumors, resulting in a tumor-to-pancreas ratio of 13.6 and in a tumor-to-lung ratio of 4.4 at 4 h after injection. Furthermore, in vitro studies in cultured beta-tumor cells demonstrated a specific internalization of [Lys(40)(Ahx-DTPA-(111)In)NH(2)]Exendin-4, whereas peptide stability studies indicated a high metabolic stability of the radiopeptide in beta-tumor cells and human blood serum. CONCLUSION: The high density of GLP-1 receptors in insulinomas as well as the high specific uptake of [Lys(40)(Ahx-DTPA-(111)In)NH(2)]Exendin-4 in the tumor of Rip1Tag2 mice indicate that targeting of GLP-1 receptors in insulinomas may become a useful imaging method to localize insulinomas in patients, either preoperatively or intraoperatively. In addition, Rip1Tag2 transgenic mice represent a suitable animal tumor model for GLP-1 receptor targeting.
Burkhard Göke - One of the best experts on this subject based on the ideXlab platform.
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stable expression of the rat glp i receptor in cho cells activation and binding characteristics utilizing glp i 7 36 amide oxyntomodulin Exendin 4 and Exendin 9 39
Peptides, 1994Co-Authors: Hans Christoph Fehmann, Jiwen Jiang, Johannes Schweinfurth, Michael B. Wheeler, Aubrey E. Boyd, Burkhard GökeAbstract:Abstract Glucagon-like peptide-I (GLP-I) is a potent insulinotropic peptide that mediates its actions at pancreatic B-cells via specific receptors. In the present study we stably expressed the rat B-cell GLP-I receptor in CHO cells and studied binding characteristics and receptor activation utilizing the naturally occuring receptor agonist GLP-I(7–36)-amide (GLP-I), the proglucagon-derived GLP-I-related peptide oxyntomodulin, the GLP-I receptor agonist Exendin-4, and the specific antagonist Exendin(9–39). The potencies to displace [ 125 I]GLP-I from the receptor were GLP-I > Exendin-4 > Exendin(9–39) > oxyntomodulin , and to displace [ 125 I]Exendin-4 GLP-I = Exendin-4 > Exendin(9–39) > oxyntomodulin . cAMP production was stimulated equally by GLP-I and Exendin-4. Oxyntomodulin was less potent to stimulate cAMP generation. Exendin(9–39) blocked the stimulatory action of GLP-I and Exendin-4 on cAMP production, but not that of oxyntomodulin. This study shows that GLP-I and Exendin-4 are potent agonists at the transfected rat B-cell GLP-I receptor whereas oxyntomodulin is only a weak GLP-I receptor agonist. Furthermore, Exendin(9–39) is a potent GLP-I receptor antagonist. This peptide is a valuable tool to further study the physiological actions of GLP-I.
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rat gastric somatostatin and gastrin release interactions of Exendin 4 and truncated glucagon like peptide 1 glp 1 amide
Life Sciences, 1994Co-Authors: R. Eissele, Burkhard Göke, E Bothesandfort, J Eng, R Arnold, H KoopAbstract:The effect of Exendin-4, a peptide of the secretin-glucagon family with high homology of amino acid sequence with glucagon-like peptide-1 (GLP-1), on gastric hormone release was investigated in the isolated perfused rat stomach. Exendin-4 dose dependently stimulated somatostatin release up to 9-fold at a concentration of 10(-7) M whereas gastrin release was inversely inhibited by up to 63%. These effects could partially be reduced by concomitant perfusion of truncated Exendin-4, Exendin(9-39)amide. Similarly, stimulation of somatostatin secretion and inhibition of gastrin release induced by GLP-1(7-36)amide was partially reversed by Exendin-4 (9-39)amide. These data are consistent with the assumption that Exendin-4 and truncated GLP-1amide exert their effects on gastric D and G cell by interaction with the same receptor.
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Exendin 4 is a high potency agonist and truncated Exendin 9 39 amide an antagonist at the glucagon like peptide 1 7 36 amide receptor of insulin secreting beta cells
Journal of Biological Chemistry, 1993Co-Authors: Rudiger Goke, Hans Christoph Fehmann, T Linn, Harald Schmidt, M Krause, Burkhard GökeAbstract:Abstract Exendin-4 purified from Heloderma suspectum venom shows structural relationship to the important incretin hormone glucagon-like peptide 1-(7-36)-amide (GLP-1). We demonstrate that Exendin-4 and truncated Exendin-(9-39)-amide specifically interact with the GLP-1 receptor on insulinoma-derived cells and on lung membranes. Exendin-4 displaced 125I-GLP-1, and unlabeled GLP-1 displaced 125I-Exendin-4 from the binding site at rat insulinoma-derived RINm5F cells. Exendin-4 had, like GLP-1, a pronounced effect on intracellular cAMP generation, which was reduced by Exendin-(9-39)-amide. When combined, GLP-1 and Exendin-4 showed additive action on cAMP. They each competed with the radio-labeled version of the other peptide in cross-linking experiments. The apparent molecular mass of the respective ligand-binding protein complex was 63,000 Da. Exendin-(9-39)-amide abolished the cross-linking of both peptides. Exendin-4, like GLP-1, stimulated dose dependently the glucose-induced insulin secretion in isolated rat islets, and, in mouse insulinoma beta TC-1 cells, both peptides stimulated the proinsulin gene expression at the level of transcription. Exendin-(9-39)-amide reduced these effects. In conclusion, Exendin-4 is an agonist and Exendin-(9-39)-amide is a specific GLP-1 receptor antagonist.
Mingru Zhang - One of the best experts on this subject based on the ideXlab platform.
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improving the theranostic potential of Exendin 4 by reducing the renal radioactivity through brush border membrane enzyme mediated degradation
Bioconjugate Chemistry, 2019Co-Authors: Mingru Zhang, Hongzhang Deng, Lixin Lang, Dale O. Kiesewetter, Longguang Tang, Fei Kang, Zhantong Wang, Orit Jacobson, Weijing YangAbstract:As highly expressed in insulinomas, the glucagon-like peptide-1 receptor (GLP-1R) is believed to be an attractive target for diagnosis, localization, and treatment with radiolabeled Exendin 4. However, the high and persistent radioactivity accumulation of Exendin 4 in the kidneys limits accurate diagnosis and safe, as well as effective, radiotherapy in insulinomas. In this study, we intend to reduce the renal accumulation of radiolabeled Exendin 4 through degradation mediated by brush border membrane enzymes. A new Exendin 4 ligand NOTA-MVK-Cys40-Leu14-Exendin 4 containing Met-Val-Lys (MVK) linker between the peptide and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator was synthesized and labeled with 68Ga. The in vitro mouse serum stability and cell binding affinity of the tracer were evaluated. Initial in vitro cleavage of the linker was determined by incubation of a model compound Boc-MVK-Dde with brush border membrane vesicles (BBMVs) with and without the inhibitor of neutral endopeptidase (NEP). Further cleavage studies were performed with the full structure of NOTA-MVK-Cys40-Leu14-Exendin 4. Kidney and urine samples were collected in the in vivo metabolism study after intravenous injection of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4. The microPET images were acquired in INS-1 tumor model at different time points; the radioactivity uptake of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 in tumor and kidneys were determined and compared with the control radiotracer without MVK linker. 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 was stable in mouse serum. The MVK modification did not affect the affinity of NOTA-MVK-Cys40-Leu14-Exendin 4 toward GLP-1R. The in vitro cleavage study and in vivo metabolism study confirmed that the MVK sequence can be recognized by BBM enzymes and cleaved at the amide bond between Met and Val, thus releasing the small fragment containing Met. MicroPET images showed that the tumor uptake of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 was comparable to that of the control, while the kidney uptake was significantly reduced. As a result, more favorable tumor to kidney ratios were achieved. In this study, a novel Exendin 4 analogue, NOTA-MVK-Cys40-Leu14-Exendin 4, was successfully synthesized and labeled with 68Ga. With the cleavable MVK sequence, this ligand could be cleaved by the enzymes on kidneys, and releasing the fragment of 68Ga-NOTA-Met-OH, which will rapidly excrete from urine. As the high and consistent renal radioactivity accumulation could be significantly reduced, NOTA-MVK-Cys40-Leu14-Exendin 4 shows great potential in the diagnosis and radiotherapy for insulinoma.
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improving the theranostic potential of Exendin 4 by reducing the renal radioactivity through brush border membrane enzyme mediated degradation
Bioconjugate Chemistry, 2019Co-Authors: Lixin Lang, Mingru Zhang, Dale O. Kiesewetter, Longguang Tang, Fei Kang, Zhantong Wang, Orit Jacobson, Hongzhang DengAbstract:As highly expressed in insulinomas, the glucagon-like peptide-1 receptor (GLP-1R) is believed to be an attractive target for diagnosis, localization, and treatment with radiolabeled Exendin 4. However, the high and persistent radioactivity accumulation of Exendin 4 in the kidneys limits accurate diagnosis and safe, as well as effective, radiotherapy in insulinomas. In this study, we intend to reduce the renal accumulation of radiolabeled Exendin 4 through degradation mediated by brush border membrane enzymes. A new Exendin 4 ligand NOTA-MVK-Cys40-Leu14-Exendin 4 containing Met-Val-Lys (MVK) linker between the peptide and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator was synthesized and labeled with 68Ga. The in vitro mouse serum stability and cell binding affinity of the tracer were evaluated. Initial in vitro cleavage of the linker was determined by incubation of a model compound Boc-MVK-Dde with brush border membrane vesicles (BBMVs) with and without the inhibitor of neutral endopeptidase...