Synthesis and characterization of 11 C-labeled benzyl amidine derivatives as PET radioligands for GluN2B subunit of the NMDA receptors.
ABSTRACT
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]CH3
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.