TY - JOUR
T1 - Evaluation of novel N 1-methyl-2-phenylindol-3-ylglyoxylamides as a new chemotype of 18 kDa translocator protein-selective ligand suitable for the development of positron emission tomography radioligands
AU - Pike, Victor W.
AU - Taliani, Sabrina
AU - Lohith, Talakad G.
AU - Owen, David R.J.
AU - Pugliesi, Isabella
AU - Da Pozzo, Eleonora
AU - Hong, Jinsoo
AU - Zoghbi, Sami S.
AU - Gunn, Roger N.
AU - Parker, Christine A.
AU - Rabiner, Eugenii A.
AU - Fujita, Masahiro
AU - Innis, Robert B.
AU - Martini, Claudia
AU - Da Settimo, Federico
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2011/1/13
Y1 - 2011/1/13
N2 - A novel series of N1-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-(N1-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, [11C]31 entered brain to give a high proportion of TSPO-specific binding. These findings augur well for the future application of [11C]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, [11C]31 represents a promising new chemotype for developing novel TSPO radioligands as biomarkers of neuroinflammation.
AB - A novel series of N1-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-(N1-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, [11C]31 entered brain to give a high proportion of TSPO-specific binding. These findings augur well for the future application of [11C]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, [11C]31 represents a promising new chemotype for developing novel TSPO radioligands as biomarkers of neuroinflammation.
UR - http://www.scopus.com/inward/record.url?scp=78651065665&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78651065665&partnerID=8YFLogxK
U2 - 10.1021/jm101230g
DO - 10.1021/jm101230g
M3 - Article
C2 - 21133364
AN - SCOPUS:78651065665
SN - 0022-2623
VL - 54
SP - 366
EP - 373
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 1
ER -