Radiosynthesis and in vivo Evaluation of Carbon‐11 (2S)‐3‐(1H‐Indol‐3‐yl)‐2‐{[(4‐methoxyphenyl)carbamoyl]amino}‐N‐{[1‐(5‐methoxypyridin‐2‐yl)cyclohexyl]methyl}propanamide: An Attempt to Visualize Brain Formyl Peptide Receptors in Mouse Models of Neuroinflammation

Abstract

Here, we describe the very first attempt to visualize in vivo formyl peptide receptors (FPRs) in mouse brain by positron emission tomography (PET). FPRs are expressed in microglial cells where they mediate chemotactic activity of β-amyloid peptide in Alzheimer disease and, thus, are involved in neuroinflammatory processes. To this purpose, we have selected (2S)-3-(1H-Indol-3-yl)-2-{[(4-methoxyphenyl)carbamoyl]amino}-N-{[1-(5-methoxypyridin-2-yl)cyclohexyl]methyl}propanamide ((S)-1), that we have previously identified as a potent non-peptidic FPR agonist. (S)-[(11) C]-1 has been prepared in high radiochemical yield. (S)-[(11) C]-1 showed very low penetration of blood-brain barrier and, thus, was unable to accumulate into the brain. In addition, (S)-[(11) C]-1 was not able to label FPRs receptors in brain slices of PS19 and APP23 mice, two animal models of Alzheimer disease. Although (S)-[(11) C]-1 was not suitable to visualize FPRs in the brain, this study provides useful information for the design and characterization of future potential PET radioligands for visualization of brain FPRs by PET.

The Role of Formyl Peptide Receptors in Neurological Diseases via Regulating Inflammation

“…Neuroinflammation is reportedly a complex process involving the coordination of different groups of glial cells, which act as a double-edged sword in this process, depending on the progression of the disease and the inflammatory microenvironment ( Shabab et al, 2017 ; Yang and Zhou, 2019 ). The first attempt to visualize in vivo FPRs in mouse brains by positron emission tomography was undertaken by Lacivita et al (2016) . They found that FPRs are expressed in the microglia and mediate the chemotactic activity of Aβ peptides in AD, and they are thus involved in the chronic neuroinflammation process ( Lacivita et al, 2016 ).…”

“…The first attempt to visualize in vivo FPRs in mouse brains by positron emission tomography was undertaken by Lacivita et al (2016) . They found that FPRs are expressed in the microglia and mediate the chemotactic activity of Aβ peptides in AD, and they are thus involved in the chronic neuroinflammation process ( Lacivita et al, 2016 ). The FPR mRNA is generally present in all regions of the brain, with higher expression in the brainstem and spinal cord ( Ho et al, 2018 ).…”

Functional N‐Formyl Peptide Receptor 2 (FPR2) Antagonists Based on the Ureidopropanamide Scaffold Have Potential To Protect Against Inflammation‐Associated Oxidative Stress

“…To date, several classes of chemically diverse FPR2 agonists have been reported in the literature, including pyrazolone derivatives such as mixed FPR1/FPR2 agonist 1 (designated also as “compound 43 ”), N ‐phenylurea derivatives such as compound 2 (also named AG‐10/8), and quinazolinones derivatives exemplified by the highly specific FPR2 agonist Quin C1 (compound 3 ) (Figure ) . Recently, we developed ureidopropanamide derivatives as agonists of human FPR2, exemplified by compounds ( R )‐ and ( S )‐ 4 (Figure ) . Regarding FPR2 antagonists, several peptide and peptidomimetic antagonists, exemplified by compound 5 , have been reported, whereas only a very limited number of small‐molecule antagonists have been described so far (Figure ).…”