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Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE)
Lindsey R Drake1,2, Allen F Brooks1, Jenelle Stauff1
1Department of Radiology, University of Michigan, Ann Arbor, MI, 48109, USA.
Abstract:
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.
Insights
Researchers developed novel radiotracers to image the receptor for advanced glycation end-products (RAGE) using PET scans. While showing promise for RAGE biomarker development, off-target binding requires further investigation for improved imaging agents.
Area of Science:
- Neuroscience
- Biomarker Development
- Radiochemistry
Background:
- The receptor for advanced glycation end-products (RAGE) is implicated in various diseases and neurodegenerative disorders.
- RAGE is a potential therapeutic target and an inflammatory biomarker.
- Positron emission tomography (PET) imaging requires specific radiotracers for quantifying biomarkers like RAGE.
Purpose of the Study:
- To synthesize and preclinically evaluate novel small molecule radiotracers for RAGE imaging.
- To assess the potential of these radiotracers for RAGE biomarker quantification via PET.
- To investigate the utility of lipopolysaccharide (LPS)-treated mice as a model for RAGE upregulation.
Main Methods:
- Synthesis of two novel radiotracers ([18F]InRAGER and [18F]RAGER) targeting intracellular and extracellular RAGE domains.
- In vitro lead panel screens and in vivo PET imaging in rodents and nonhuman primates.
- Evaluation of LPS-treated mice for RAGE upregulation and assessment of radiotracer binding.
Main Results:
- Both radiotracers demonstrated high affinity for RAGE and good brain uptake.
- Significant off-target binding was observed, with the source remaining unexplained.
- RAGE levels increased in male LPS-treated mice, but quantification was hindered by off-target binding.
Conclusions:
- The developed radiotracers ([18F]InRAGER and [18F]RAGER) serve as promising lead scaffolds for next-generation RAGE PET imaging agents.
- High affinity and CNS penetration are key strengths for future RAGE radiotracer development.
- Further research is needed to resolve off-target binding issues for accurate RAGE quantification.
