Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE)
The implication of the receptor for advanced glycation end-products (RAGE) in numerous diseases and neurodegenerative disorders makes it interesting both as a therapeutic target and as an inflammatory biomarker. In the context of investigating RAGE as a biomarker, there is interest in developing rad...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-10-01
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| Series: | Journal of Pharmaceutical Analysis |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2095177920310388 |
| _version_ | 1818321138416091136 |
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| author | Lindsey R. Drake Allen F. Brooks Jenelle Stauff Phillip S. Sherman Janna Arteaga Robert A. Koeppe Aimee Reed Timothy J. Montavon Marc B. Skaddan Peter J.H. Scott |
| author_facet | Lindsey R. Drake Allen F. Brooks Jenelle Stauff Phillip S. Sherman Janna Arteaga Robert A. Koeppe Aimee Reed Timothy J. Montavon Marc B. Skaddan Peter J.H. Scott |
| author_sort | Lindsey R. Drake |
| collection | DOAJ |
| description | The implication of the receptor for advanced glycation end-products (RAGE) in numerous diseases and neurodegenerative disorders makes it interesting both as a therapeutic target and as an inflammatory biomarker. In the context of investigating RAGE as a biomarker, there is interest in developing radiotracers that will enable quantification of RAGE using positron emission tomography (PET) imaging. We have synthesized potential small molecule radiotracers for both the intracellular ([18F]InRAGER) and extracellular ([18F]RAGER) domains of RAGE. Herein we report preclinical evaluation of both using in vitro (lead panel screens) and in vivo (rodent and nonhuman primate PET imaging) methods. Both radiotracers have high affinity for RAGE and show good brain uptake, but suffer from off-target binding. The source of the off-target PET signal is not attributable to binding to melatonin receptors, but remains unexplained. We have also investigated use of lipopolysaccharide (LPS)-treated mice as a possible animal model with upregulated RAGE for evaluation of new imaging agents. Immunoreactivity of the mouse brain sections revealed increases in RAGE in the male cohorts, but no difference in the female groups. However, it proves challenging to quantify the changes in RAGE due to off-target binding of the radiotracers. Nevertheless, they are appropriate lead scaffolds for future development of 2nd generation RAGE PET radiotracers because of their high affinity for the receptor and good CNS penetration. |
| first_indexed | 2024-12-13T10:36:08Z |
| format | Article |
| id | doaj.art-7cc4d8c7511c42c49f3782ccdbc29d6c |
| institution | Directory Open Access Journal |
| issn | 2095-1779 |
| language | English |
| last_indexed | 2024-12-13T10:36:08Z |
| publishDate | 2020-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmaceutical Analysis |
| spelling | doaj.art-7cc4d8c7511c42c49f3782ccdbc29d6c2022-12-21T23:50:43ZengElsevierJournal of Pharmaceutical Analysis2095-17792020-10-01105452465Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE)Lindsey R. Drake0Allen F. Brooks1Jenelle Stauff2Phillip S. Sherman3Janna Arteaga4Robert A. Koeppe5Aimee Reed6Timothy J. Montavon7Marc B. Skaddan8Peter J.H. Scott9Department of Radiology, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, 48109, USADepartment of Radiology, University of Michigan, Ann Arbor, MI, 48109, USADepartment of Radiology, University of Michigan, Ann Arbor, MI, 48109, USADepartment of Radiology, University of Michigan, Ann Arbor, MI, 48109, USADepartment of Radiology, University of Michigan, Ann Arbor, MI, 48109, USADepartment of Radiology, University of Michigan, Ann Arbor, MI, 48109, USAAbbVie Process Chemistry, North Chicago, IL, 60064, USAAbbVie Centralized Medicinal Chemistry, North Chicago, IL, 60064, USAAbbVie Translational Imaging, North Chicago, IL, 60064, USADepartment of Radiology, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, 48109, USA; Corresponding author. Department of Radiology, University of Michigan, Ann Arbor, MI, 48109, USA.The implication of the receptor for advanced glycation end-products (RAGE) in numerous diseases and neurodegenerative disorders makes it interesting both as a therapeutic target and as an inflammatory biomarker. In the context of investigating RAGE as a biomarker, there is interest in developing radiotracers that will enable quantification of RAGE using positron emission tomography (PET) imaging. We have synthesized potential small molecule radiotracers for both the intracellular ([18F]InRAGER) and extracellular ([18F]RAGER) domains of RAGE. Herein we report preclinical evaluation of both using in vitro (lead panel screens) and in vivo (rodent and nonhuman primate PET imaging) methods. Both radiotracers have high affinity for RAGE and show good brain uptake, but suffer from off-target binding. The source of the off-target PET signal is not attributable to binding to melatonin receptors, but remains unexplained. We have also investigated use of lipopolysaccharide (LPS)-treated mice as a possible animal model with upregulated RAGE for evaluation of new imaging agents. Immunoreactivity of the mouse brain sections revealed increases in RAGE in the male cohorts, but no difference in the female groups. However, it proves challenging to quantify the changes in RAGE due to off-target binding of the radiotracers. Nevertheless, they are appropriate lead scaffolds for future development of 2nd generation RAGE PET radiotracers because of their high affinity for the receptor and good CNS penetration.http://www.sciencedirect.com/science/article/pii/S2095177920310388RAGENeuroimagingPositron emission tomographyRadiochemistryNeuroinflammation |
| spellingShingle | Lindsey R. Drake Allen F. Brooks Jenelle Stauff Phillip S. Sherman Janna Arteaga Robert A. Koeppe Aimee Reed Timothy J. Montavon Marc B. Skaddan Peter J.H. Scott Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE) Journal of Pharmaceutical Analysis RAGE Neuroimaging Positron emission tomography Radiochemistry Neuroinflammation |
| title | Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE) |
| title_full | Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE) |
| title_fullStr | Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE) |
| title_full_unstemmed | Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE) |
| title_short | Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE) |
| title_sort | strategies for pet imaging of the receptor for advanced glycation endproducts rage |
| topic | RAGE Neuroimaging Positron emission tomography Radiochemistry Neuroinflammation |
| url | http://www.sciencedirect.com/science/article/pii/S2095177920310388 |
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