Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue 1, Pages 366-373Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm101230g
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Funding
- National Institutes of Health (NIH)
- National Institute of Mental Health (NIMH)
- Tuscan Cancer Institute (Istituto Toscano Tumori, ITT) [2007]
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A novel series of N-1-methyl-(2-phenylindol-3-yl)glyoxylamides, 19-31, designed in accordance with our previously reported pharmacophore/topological model, showed high affinity for the 18 kDa translocator protein (TSPO) and paved the way for developing a new radiolabeled probe Thus ligand 31, N,N-di-n-propyl-(N-1-methyl-2-(4'-nitrophenyl)indol-3-yl)glyoxylamide, featuring the best combination of affinity and lipophilicity, was labeled with carbon-11 for evaluation with positron emission tomography (PET) in monkey After intravenous injection, [C-11]31 entered brain to give a high proportion of TSPO-specific binding These findings augur well for the future application of [C-11]31 in humans Consequently, the binding of 31 to human TSPO was tested on samples of brain membranes from deceased subjects who through ethically approved in vitro study had previously been established to be high-affinity binders (HABs), mixed-affinity binders (MABs), or low-affinity binders (LABs) for the known TSPO ligand, PBR28 (2) 31 showed high affinity for HABs, MABs, and LABs In conclusion, [C-11]31 represents a promising new chemotype for developing novel TSPO radioligands as biomarkers of neuroinflammation
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