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, [(11)C]31 entered brain to give a high proportion of TSPO-specific binding. These findings augur well for the future application of [(11)C]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, [(11)C]31 represents a promising new chemotype for developing novel TSPO radioligands as biomarkers of neuroinflammation.
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 n class="Gene">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, [(11)C]31 entered brain to give a high proportion of TSPO-specific binding. These findings augur well for the future application of [(11)C]31 in humans. Consequently, the binding of 31 to humanTSPO 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, [(11)C]31 represents a promising new chemotype for developing novel TSPO radioligands as biomarkers of neuroinflammation.
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Authors: A Costanzo; G Guerrini; G Ciciani; F Bruni; S Selleri; B Costa; C Martini; A Lucacchini; P M Aiello; A Ipponi Journal: J Med Chem Date: 1999-06-17 Impact factor: 7.446
Authors: Emmanuelle Briard; Sami S Zoghbi; Fabrice G Siméon; Masao Imaizumi; Jonathan P Gourley; H Umesha Shetty; Shuiyu Lu; Masahiro Fujita; Robert B Innis; Victor W Pike Journal: J Med Chem Date: 2009-02-12 Impact factor: 7.446
Authors: Filomena Mattner; Andrew Katsifis; Thomas Bourdier; Christian Loc'h; Paula Berghofer; Christopher Fookes; Tzong-Tyng Hung; Timothy Jackson; David Henderson; Tien Pham; Brendan J Lee; Rachael Shepherd; Ivan Greguric; Naomi Wyatt; Thanh Le; Jackson Poon; Carl Power; Michael Fulham Journal: RSC Med Chem Date: 2021-04-19