Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE)

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 ([ 18 F]InRAGER) and extracellular ([ 18 F]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.

Advanced glycation end-products reduce lipopolysaccharide uptake by macrophages

“…In the present study, we did not confirm the involvement of RAGE using knockout or knockdown experiments. High concentration of FPS-ZM1 at 10 μM has inhibitory effect on androgen receptor, benzodiazepine receptor, kappa opioid receptor and melatonin receptor [ 55 ]. However, none of these receptors bind to AGEs.…”

Brain‐targeting drug delivery systems

“…In the early pathological studies of AD, it has been reported that RAGE is highly expressed in the brain lesions and upregulated with the progression of the disease (Kong et al, 2020). In addition, this target has been used to develop PET probes for imaging AD disease progression (Drake et al, 2020). Therefore, targeting RAGE for drug delivery can realize the specific accumulation of the delivery system in the lesion.…”

The Repertoire of Small-Molecule PET Probes for Neuroinflammation Imaging: Challenges and Opportunities beyond TSPO

“…Most recently, [ 18 F]95 ([ 18 F]InRAGER) was reported as a selective PET ligand for flRAGE (K d = 1 nM), which was achieved via an isotopic exchange with [ 18 F]KF. 97 Although a high initial brain uptake (SUV max = ca. 2.0) was observed in rats, the development of new radiosynthetic methods is necessary to address poor radiochemical yield and low molar activity.…”

“…Subsequently, [ 11 C]­FPS-ZM1 was successfully synthesized by palladium-catalyzed carbonylation with [ 11 C]­CO. , However, a high nonspecific binding was observed for [ 11 C] 94 ([ 11 C]­FPS-ZM1) in both wild-type and AD mice by in vitro autoradiography experiments, which was possibly attributed to its high lipophilicity (cLogP = 5.25). Most recently, [ 18 F] 95 ([ 18 F]­InRAGER) was reported as a selective PET ligand for flRAGE ( K d = 1 nM), which was achieved via an isotopic exchange with [ 18 F]­KF . Although a high initial brain uptake (SUV max = ca.…”