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Synthesis and characterization of 11 C‐labeled benzyl amidine derivatives as PET radioligands for GluN2B subunit of the NMDA receptors
Author(s) -
Fuchigami Takeshi,
Fujimoto Noriko,
Haradahira Terushi,
Nojiri Yumiko,
Okauchi Takashi,
Maeda Jun,
Suhara Tetsuya,
Yamamoto Fumihiko,
Nakayama Morio,
Maeda Minoru,
Mukai Takahiro
Publication year - 2018
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.3691
Subject(s) - chemistry , amidine , nmda receptor , protein subunit , receptor , stereochemistry , ligand (biochemistry) , in vitro , in vivo , biochemistry , microbiology and biotechnology , biology , gene
GluN2B‐containing NMDA receptors (NMDARs) play fundamental roles in learning and memory, although they are also associated with various brain disorders. In this study, we synthesized and evaluated three 11 C‐labeled N ‐benzyl amidine derivatives 2‐[ 11 C]methoxybenzyl) cinnamamidine ([ 11 C]CBA), N ‐(2‐[ 11 C]methoxybenzyl)‐2‐naphthamidine ([ 11 C]NBA), and N ‐(2‐[ 11 C]methoxybenzyl)quinoline‐3‐carboxamidine ([ 11 C]QBA) as PET radioligands for these receptors. The 11 C‐benzyl amidines were synthesized via conventional methylation of corresponding des‐methyl precursors with [ 11 C]CH 3 I. In vitro binding characteristics were examined in brain sagittal sections using various GluN2B modulators and off‐target ligands. Further, in vivo brain distribution studies were performed in normal mice. The 11 C‐labeled benzyl amidines showed high‐specific binding to the GluN2B subunit at in vitro. In particular, the quinoline derivative [ 11 C]QBA had the best binding properties in terms of high‐brain localization to GluN2B‐rich regions and specificity to the GluN2B subunit. Conversely, these 11 C‐radioligands showed the brain distributions were inconsistent with GluN2B expression in biodistribution experiments. The majority of the radiolabeled compounds were identified as metabolized forms of which amido derivatives seemed to be the major species. Although these 11 C‐ligands had high‐specific binding to the GluN2B subunit, significant improvement in metabolic stability is necessary for successful positron emission tomography (PET) imaging of the GluN2B subunit of NMDARs.