Translocator protein ligands based on N-methyl-(quinolin-4-yl)oxypropanamides with properties suitable for PET radioligand development.
Modifications to an N-methyl-(quinolin-4-yl)oxypropanamide scaffold were explored to discover leads for developing new radioligands for PET imaging of brain TSPO (translocator protein), a biomarker of neuroinflammation. Whereas contraction of the quinolinyl portion of the scaffold or cyclization of the tertiary amido group abolished high TSPO affinity, insertion of an extra nitrogen atom into the 2-arylquinolinyl portion was effective in retaining sub-nanomolar affinity for rat TSPO, while also decreasing lipophilicity to within the moderate range deemed preferable for a PET radioligand. Replacement of a phenyl group on the amido nitrogen with an isopropyl group was similarly effective. Among others, compound 20 (N-methyl-N-phenyl-2-[2-(pyridin-2-yl)-1,8-naphthyridin-4-yloxy]propanamide) appears especially appealing for PET radioligand development, based on high selectivity and high affinity (Ki= 0.5 nM) for rat TSPO, moderate lipophilicity (logD = 2.48), and demonstrated amenability to labeling with carbon-11.
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346A, 10 Center Drive, Bethesda, MD 20892, United States.
Chad
C
Brouwer
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346A, 10 Center Drive, Bethesda, MD 20892, United States.
Kimberly J
KJ
Jenko
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346A, 10 Center Drive, Bethesda, MD 20892, United States.
Sami S
SS
Zoghbi
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346A, 10 Center Drive, Bethesda, MD 20892, United States.
Cheryl L
CL
Morse
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346A, 10 Center Drive, Bethesda, MD 20892, United States.
Robert B
RB
Innis
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346A, 10 Center Drive, Bethesda, MD 20892, United States. Electronic address: pikev@mail.nih.gov.
Victor W
VW
Pike
D000577:Amides / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D001923:Brain Chemistry; D008024:Ligands; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D011407:Propane / Q000737:chemistry; D015363:Quinolones / Q000737:chemistry; D011869:Radioligand Assay / Q000379:methods*; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D018079:Receptors, GABA / Q000032:analysis* / Q000378:metabolism
D000577:Amides; D008024:Ligands; D015363:Quinolones; D019275:Radiopharmaceuticals; D018079:Receptors, GABA; C499229:TSPO protein, human; D011407:Propane
Binding affinity; Carbon-11; Ligand; Lipophilic efficiency; PET; Translocator protein