Small-Molecule Ligands as Challenge for Positron Emission Tomography of Peptide Receptors in Neurons and Microglia of the Brain

Abstract

Neuropeptide and chemokine receptors of the G protein-coupled receptor (GPCR) family belong to different classes and subgroups providing different docking sites and special binding behavior at extracellular and also transmembrane domains for small molecules potentially suitable for positron emission tomography (PET). The contribution gives an overview updating developments of small-molecule, nonpeptide ligands at a selection of peptide and chemokine receptors, expressed in neurons and microglia of the brain, regarding the last five years. Orexin 1 and orexin 2 receptors (OX1R; OX2R) and neuropeptide Y1 and Y2 receptors (NPY1R, NPY2R) were chosen as representatives of Class A neuropeptide receptors, chemokine receptor CX3C (CX3CR1) as Class A, protein-activated receptor, highly expressed in activated microglia, and corticotropin releasing factor receptor 1 (CRFR1) as representative Class B1 receptor. Structural differences between binding domains and their endogenous ligands as well as parallel expression in different types of cells and generally low density of these receptors in brain tissue are factors making the search for selective and sensitive ligands more difficult than for classical GPCR receptors. Main progress in ligand development is observed for NPY receptor antagonists and orexin receptor antagonists. For orexin receptors, search for suitable ligands can be supported with modelling approaches, as recently the complete molecular structure of these receptors is available. Small molecules, binding at CRFR1, as for other Class B1 receptor ligands, in PET and investigations of pharmacodynamics revealed rather allosteric binding modes, although, the complete crystal structure of CRFR1 as prototype of Class B1 provides, hitherto, improved possibilities for understanding binding mechanisms. Highly specific as a marker of microglia among How to cite this paper: Pissarek, M. (2019) Small-Molecule Ligands as Challenge for Positron Emission Tomography of Peptide Receptors in Neurons and Microglia of the Brain. World Journal of Neuroscience, 9, 294-327.

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

“…326 Initial PET imaging studies in mice demonstrated the ability to cross the BBB, but further information about in vitro and in vivo validation remains to be reported (Figure 13). 109,327 In addition, a 64 Cu-labeled macromolecule ([ 64 Cu]vMIP-II-comb) was synthesized by conjugating the viral macrophage inflammatory protein-II (vMIP-II) with a 64 Cu-linked nanoparticle. 328 [ 64 Cu]vMIP-IIcomb was specific for chemokine receptors and proved to be useful for an in vivo macrophage mapping in mouse models of peripheral diseases, such as vascular injury and inflammatory atherosclerosis.…”