Comparison of desferrioxamine and NODAGA for the gallium-68 labeling of exendin-4

Introduction Radiolabeled exendin-4 (Ex4) derivatives are used to target the glucagon-like peptide-1 receptor (GLP-1R) for the clinical diagnosis of insulinomas, a rare type of neuroendocrine tumor. Gallium-68 is an ideal diagnostic nuclide for this application and a study evaluating an exendin-4-NO...

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Published in:EJNMMI radiopharmacy and chemistry 2019-05, Vol.4 (1), p.9-9, Article 9
Main Authors: Kaeppeli, Simon A. M., Schibli, Roger, Mindt, Thomas L., Behe, Martin
Format: Article
Language:English
Subjects:
Acids
Butane
Deferoxamine
DFO
Exendin-4
Gallium
GLP-1R
Glucagon
Glucagon-like peptide 1
Hypoglycemia
Imaging
Insulinoma
Kidneys
Labeling
Medicine
Medicine & Public Health
Molecular Medicine
Neuroendocrine tumors
NODAGA
Nuclear Chemistry
Nuclear Medicine
Peptides
Pharmacotherapy
Protein purification
Quality control
Radiology
Research Article
β-cells
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description Introduction Radiolabeled exendin-4 (Ex4) derivatives are used to target the glucagon-like peptide-1 receptor (GLP-1R) for the clinical diagnosis of insulinomas, a rare type of neuroendocrine tumor. Gallium-68 is an ideal diagnostic nuclide for this application and a study evaluating an exendin-4-NODAGA conjugate is currently underway. However, in complexion with the chelator DFO, its in vivo stability has been a matter of dispute. The aim of this work was to directly compare [ 68 Ga]Ga-Ex4NOD with [ 68 Ga]Ga-Ex4DFO in vitro and in vivo. Methods In our approach, we directly compared N′ -[5-(acetyl-hydroxy-amino)pentyl]- N -[5-[3-(5-aminopentyl-hydroxy-carbamoyl)propanoylamino]pentyl]- N -hydroxy-butane diamide (desferriox-amine B, DFO) and 2-(4,7-bis (carboxymethyl)-1,4,7-triazonan-1-yl) pentanedioic acid (NODAGA) conjugated to exendin-4 in vitro and in vivo . We radiolabeled the peptides with gallium-68, followed by HPLC quality control. In vitro characterization was performed in CHL cells overexpressing the GLP-1R and in vivo studies were conducted with CD1 nu/nu mice carrying tumors derived from these cells. Results We found that both peptides could be radiolabeled with a molar activity of about 9.33 MBq/nmol without further purification. They internalized equally well into GLP-1R-expressing cells and their IC 50 was similar with 15.6 ± 7.8 nM and 18.4 ± 3.0 nM for [ nat Ga]Ga-Ex4NOD and [ nat Ga]Ga-Ex4DFO, respectively. In vivo, [ 68 Ga]Ga-Ex4NOD accumulated more in all tissue, while [ 68 Ga]Ga-Ex4DFO exhibited a more favorable target-to-kidney ratio. Conclusion and relevance DFO is a suitable chelator for the radiolabeling of exendin-4 derivatives with gallium-68 for in vitro and preclinical in vivo studies. DFO performed better in vivo due to its significantly lower kidney accumulation ( p  
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M. ; Schibli, Roger ; Mindt, Thomas L. ; Behe, Martin</creator><creatorcontrib>Kaeppeli, Simon A. M. ; Schibli, Roger ; Mindt, Thomas L. ; Behe, Martin</creatorcontrib><description>Introduction Radiolabeled exendin-4 (Ex4) derivatives are used to target the glucagon-like peptide-1 receptor (GLP-1R) for the clinical diagnosis of insulinomas, a rare type of neuroendocrine tumor. Gallium-68 is an ideal diagnostic nuclide for this application and a study evaluating an exendin-4-NODAGA conjugate is currently underway. However, in complexion with the chelator DFO, its in vivo stability has been a matter of dispute. The aim of this work was to directly compare [ 68 Ga]Ga-Ex4NOD with [ 68 Ga]Ga-Ex4DFO in vitro and in vivo. Methods In our approach, we directly compared N′ -[5-(acetyl-hydroxy-amino)pentyl]- N -[5-[3-(5-aminopentyl-hydroxy-carbamoyl)propanoylamino]pentyl]- N -hydroxy-butane diamide (desferriox-amine B, DFO) and 2-(4,7-bis (carboxymethyl)-1,4,7-triazonan-1-yl) pentanedioic acid (NODAGA) conjugated to exendin-4 in vitro and in vivo . We radiolabeled the peptides with gallium-68, followed by HPLC quality control. In vitro characterization was performed in CHL cells overexpressing the GLP-1R and in vivo studies were conducted with CD1 nu/nu mice carrying tumors derived from these cells. Results We found that both peptides could be radiolabeled with a molar activity of about 9.33 MBq/nmol without further purification. They internalized equally well into GLP-1R-expressing cells and their IC 50 was similar with 15.6 ± 7.8 nM and 18.4 ± 3.0 nM for [ nat Ga]Ga-Ex4NOD and [ nat Ga]Ga-Ex4DFO, respectively. In vivo, [ 68 Ga]Ga-Ex4NOD accumulated more in all tissue, while [ 68 Ga]Ga-Ex4DFO exhibited a more favorable target-to-kidney ratio. Conclusion and relevance DFO is a suitable chelator for the radiolabeling of exendin-4 derivatives with gallium-68 for in vitro and preclinical in vivo studies. DFO performed better in vivo due to its significantly lower kidney accumulation ( p  &lt; 0.0001). It was also found to be stable in vivo in mice, contrary to earlier reports. 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M.</creatorcontrib><creatorcontrib>Schibli, Roger</creatorcontrib><creatorcontrib>Mindt, Thomas L.</creatorcontrib><creatorcontrib>Behe, Martin</creatorcontrib><title>Comparison of desferrioxamine and NODAGA for the gallium-68 labeling of exendin-4</title><title>EJNMMI radiopharmacy and chemistry</title><addtitle>EJNMMI radiopharm. chem</addtitle><addtitle>EJNMMI Radiopharm Chem</addtitle><description>Introduction Radiolabeled exendin-4 (Ex4) derivatives are used to target the glucagon-like peptide-1 receptor (GLP-1R) for the clinical diagnosis of insulinomas, a rare type of neuroendocrine tumor. Gallium-68 is an ideal diagnostic nuclide for this application and a study evaluating an exendin-4-NODAGA conjugate is currently underway. However, in complexion with the chelator DFO, its in vivo stability has been a matter of dispute. The aim of this work was to directly compare [ 68 Ga]Ga-Ex4NOD with [ 68 Ga]Ga-Ex4DFO in vitro and in vivo. Methods In our approach, we directly compared N′ -[5-(acetyl-hydroxy-amino)pentyl]- N -[5-[3-(5-aminopentyl-hydroxy-carbamoyl)propanoylamino]pentyl]- N -hydroxy-butane diamide (desferriox-amine B, DFO) and 2-(4,7-bis (carboxymethyl)-1,4,7-triazonan-1-yl) pentanedioic acid (NODAGA) conjugated to exendin-4 in vitro and in vivo . We radiolabeled the peptides with gallium-68, followed by HPLC quality control. In vitro characterization was performed in CHL cells overexpressing the GLP-1R and in vivo studies were conducted with CD1 nu/nu mice carrying tumors derived from these cells. Results We found that both peptides could be radiolabeled with a molar activity of about 9.33 MBq/nmol without further purification. They internalized equally well into GLP-1R-expressing cells and their IC 50 was similar with 15.6 ± 7.8 nM and 18.4 ± 3.0 nM for [ nat Ga]Ga-Ex4NOD and [ nat Ga]Ga-Ex4DFO, respectively. In vivo, [ 68 Ga]Ga-Ex4NOD accumulated more in all tissue, while [ 68 Ga]Ga-Ex4DFO exhibited a more favorable target-to-kidney ratio. Conclusion and relevance DFO is a suitable chelator for the radiolabeling of exendin-4 derivatives with gallium-68 for in vitro and preclinical in vivo studies. DFO performed better in vivo due to its significantly lower kidney accumulation ( p  &lt; 0.0001). It was also found to be stable in vivo in mice, contrary to earlier reports. 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M.</au><au>Schibli, Roger</au><au>Mindt, Thomas L.</au><au>Behe, Martin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comparison of desferrioxamine and NODAGA for the gallium-68 labeling of exendin-4</atitle><jtitle>EJNMMI radiopharmacy and chemistry</jtitle><stitle>EJNMMI radiopharm. chem</stitle><addtitle>EJNMMI Radiopharm Chem</addtitle><date>2019-05-16</date><risdate>2019</risdate><volume>4</volume><issue>1</issue><spage>9</spage><epage>9</epage><pages>9-9</pages><artnum>9</artnum><issn>2365-421X</issn><eissn>2365-421X</eissn><abstract>Introduction Radiolabeled exendin-4 (Ex4) derivatives are used to target the glucagon-like peptide-1 receptor (GLP-1R) for the clinical diagnosis of insulinomas, a rare type of neuroendocrine tumor. Gallium-68 is an ideal diagnostic nuclide for this application and a study evaluating an exendin-4-NODAGA conjugate is currently underway. However, in complexion with the chelator DFO, its in vivo stability has been a matter of dispute. The aim of this work was to directly compare [ 68 Ga]Ga-Ex4NOD with [ 68 Ga]Ga-Ex4DFO in vitro and in vivo. Methods In our approach, we directly compared N′ -[5-(acetyl-hydroxy-amino)pentyl]- N -[5-[3-(5-aminopentyl-hydroxy-carbamoyl)propanoylamino]pentyl]- N -hydroxy-butane diamide (desferriox-amine B, DFO) and 2-(4,7-bis (carboxymethyl)-1,4,7-triazonan-1-yl) pentanedioic acid (NODAGA) conjugated to exendin-4 in vitro and in vivo . We radiolabeled the peptides with gallium-68, followed by HPLC quality control. In vitro characterization was performed in CHL cells overexpressing the GLP-1R and in vivo studies were conducted with CD1 nu/nu mice carrying tumors derived from these cells. Results We found that both peptides could be radiolabeled with a molar activity of about 9.33 MBq/nmol without further purification. They internalized equally well into GLP-1R-expressing cells and their IC 50 was similar with 15.6 ± 7.8 nM and 18.4 ± 3.0 nM for [ nat Ga]Ga-Ex4NOD and [ nat Ga]Ga-Ex4DFO, respectively. In vivo, [ 68 Ga]Ga-Ex4NOD accumulated more in all tissue, while [ 68 Ga]Ga-Ex4DFO exhibited a more favorable target-to-kidney ratio. Conclusion and relevance DFO is a suitable chelator for the radiolabeling of exendin-4 derivatives with gallium-68 for in vitro and preclinical in vivo studies. DFO performed better in vivo due to its significantly lower kidney accumulation ( p  &lt; 0.0001). It was also found to be stable in vivo in mice, contrary to earlier reports. Based on our results, the DFO chelating system in combination with exendin-4 would be an interesting option for clinical imaging of insulinomas.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>31659487</pmid><doi>10.1186/s41181-019-0060-9</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record>
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subjects Acids
Butane
Deferoxamine
DFO
Exendin-4
Gallium
GLP-1R
Glucagon
Glucagon-like peptide 1
Hypoglycemia
Imaging
Insulinoma
Kidneys
Labeling
Medicine
Medicine & Public Health
Molecular Medicine
Neuroendocrine tumors
NODAGA
Nuclear Chemistry
Nuclear Medicine
Peptides
Pharmacotherapy
Protein purification
Quality control
Radiology
Research Article
β-cells
title Comparison of desferrioxamine and NODAGA for the gallium-68 labeling of exendin-4
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