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Development of N-methyl-(2-arylquinolin-4-yl)oxypropanamides as leads to PET radioligands for translocator protein (18 kDa).

Brouwer C, Jenko K, Zoghbi SS, Innis RB, Pike VW - J. Med. Chem. (2014)

Bottom Line: Radioligands with PET accurately quantify TSPO in neuroinflammatory conditions.There is an unmet need for genotype-insensitive, high-affinity, and moderately lipophilic TSPO ligands that may serve as leads for PET radioligand development.To address this need, we varied the known high-affinity TSPO ligand (l)-N,N-diethyl-2-methyl-3-(2-phenylquinolin-4-yl)propanamide in its aryl scaffold, side chain tether, and pendant substituted amido group while retaining an N-methyl group as a site for labeling with carbon-11.

View Article: PubMed Central - PubMed

Affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health , Building 10, Room B3 C346A, 10 Center Drive, Bethesda, Maryland 20892, United States.

ABSTRACT
Translocator protein (18 kDa), known as TSPO, is a recognized biomarker of neuroinflammation. Radioligands with PET accurately quantify TSPO in neuroinflammatory conditions. However, the existence of three human TSPO genotypes that show differential affinity to almost all useful TSPO PET radioligands hampers such studies. There is an unmet need for genotype-insensitive, high-affinity, and moderately lipophilic TSPO ligands that may serve as leads for PET radioligand development. To address this need, we varied the known high-affinity TSPO ligand (l)-N,N-diethyl-2-methyl-3-(2-phenylquinolin-4-yl)propanamide in its aryl scaffold, side chain tether, and pendant substituted amido group while retaining an N-methyl group as a site for labeling with carbon-11. From this effort, oxygen-tethered N-methyl-aryloxypropanamides emerged as new high-affinity TSPO ligands with attenuated lipophilicity, including one example with attractive properties for PET radioligand development, namely N-methyl-N-phenyl-2-{[2-(pyridin-2-yl)quinolin-4-yl]oxy}propanamide (22a; rat Ki=0.10 nM; human TSPO genotypes Ki=1.4 nM; clogD=4.18).

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Generalized structure of compounds tested in this study.
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fig1: Generalized structure of compounds tested in this study.

Mentions: Ligands were synthesized in one of threegeneral ways, depending on the tether X in the general structure (Figure 1).


Development of N-methyl-(2-arylquinolin-4-yl)oxypropanamides as leads to PET radioligands for translocator protein (18 kDa).

Brouwer C, Jenko K, Zoghbi SS, Innis RB, Pike VW - J. Med. Chem. (2014)

Generalized structure of compounds tested in this study.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4216211&req=5

fig1: Generalized structure of compounds tested in this study.
Mentions: Ligands were synthesized in one of threegeneral ways, depending on the tether X in the general structure (Figure 1).

Bottom Line: Radioligands with PET accurately quantify TSPO in neuroinflammatory conditions.There is an unmet need for genotype-insensitive, high-affinity, and moderately lipophilic TSPO ligands that may serve as leads for PET radioligand development.To address this need, we varied the known high-affinity TSPO ligand (l)-N,N-diethyl-2-methyl-3-(2-phenylquinolin-4-yl)propanamide in its aryl scaffold, side chain tether, and pendant substituted amido group while retaining an N-methyl group as a site for labeling with carbon-11.

View Article: PubMed Central - PubMed

Affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health , Building 10, Room B3 C346A, 10 Center Drive, Bethesda, Maryland 20892, United States.

ABSTRACT
Translocator protein (18 kDa), known as TSPO, is a recognized biomarker of neuroinflammation. Radioligands with PET accurately quantify TSPO in neuroinflammatory conditions. However, the existence of three human TSPO genotypes that show differential affinity to almost all useful TSPO PET radioligands hampers such studies. There is an unmet need for genotype-insensitive, high-affinity, and moderately lipophilic TSPO ligands that may serve as leads for PET radioligand development. To address this need, we varied the known high-affinity TSPO ligand (l)-N,N-diethyl-2-methyl-3-(2-phenylquinolin-4-yl)propanamide in its aryl scaffold, side chain tether, and pendant substituted amido group while retaining an N-methyl group as a site for labeling with carbon-11. From this effort, oxygen-tethered N-methyl-aryloxypropanamides emerged as new high-affinity TSPO ligands with attenuated lipophilicity, including one example with attractive properties for PET radioligand development, namely N-methyl-N-phenyl-2-{[2-(pyridin-2-yl)quinolin-4-yl]oxy}propanamide (22a; rat Ki=0.10 nM; human TSPO genotypes Ki=1.4 nM; clogD=4.18).

Show MeSH