Synthesis and characterization of 11 C-labeled benzyl amidine derivatives as PET radioligands for GluN2B subunit of the NMDA receptors
| Autor: | Takashi Okauchi, Takahiro Mukai, Noriko Fujimoto, Jun Maeda, Yumiko Nojiri, Terushi Haradahira, Tetsuya Suhara, Minoru Maeda, Takeshi Fuchigami, Morio Nakayama, Fumihiko Yamamoto |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Biodistribution Stereochemistry Organic Chemistry Quinoline Methylation Biochemistry In vitro Analytical Chemistry Amidine 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine chemistry In vivo Drug Discovery NMDA receptor Radiology Nuclear Medicine and imaging Receptor 030217 neurology & neurosurgery Spectroscopy |
| Zdroj: | Journal of Labelled Compounds and Radiopharmaceuticals. 61:1095-1105 |
| ISSN: | 0362-4803 |
| DOI: | 10.1002/jlcr.3691 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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