Synthesis and characterization of ¹¹C‐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 11C‐labeled N‐benzyl amidine derivatives 2‐[11C]methoxybenzyl) cinnamamidine ([11C]CBA), N‐(2‐[11C]methoxybenzyl)‐2‐naphthamidine ([11C]NBA), and N‐(2‐[11C]methoxybenzyl)quinoline‐3‐carboxamidine ([11C]QBA) as PET radioligands for these receptors. The 11C‐benzyl amidines were synthesized via conventional methylation of corresponding des‐methyl precursors with [11C]CH3I. 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 11C‐labeled benzyl amidines showed high‐specific binding to the GluN2B subunit at in vitro. In particular, the quinoline derivative [11C]QBA had the best binding properties in terms of high‐brain localization to GluN2B‐rich regions and specificity to the GluN2B subunit. Conversely, these 11C‐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 11C‐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.

A Review of Molecular Imaging of Glutamate Receptors

“…The N -benzyl amidine derivatives 2-[ 11 C]methoxybenzyl) cinnamamidine ([ 11 C]CBA, 45 ), N -(2-[ 11 C]methoxybenzyl)-2-naphthamidine ([ 11 C]NBA, 46 ), and N -(2-[ 11 C]methoxybenzyl)quinoline-3-carboxamidine ([ 11 C]QBA, 47 ) were tested as PET radioligands for GluN2B binding sites [ 84 ]. The three compounds were strongly displaced from rat brain sections by addition of the GluN2B blocker CP-101,606, and by spermine and Zn 2+ , but were unaffected by σ-ligands.…”

Synthesis and Biological Evaluation of Enantiomerically Pure (R)- and (S)-[18F]OF-NB1 for Imaging the GluN2B Subunit-Containing NMDA Receptors

“…While numerous probes exhibited high in vitro specificity and selectivity toward the GluN2B subunit, the vast majority of reported ligands were plagued by unfavorable in vivo performance characteristics . Major drawbacks included low brain penetration, lack of in vivo specificity and selectivity, and the presence of radiometabolites in the CNS. , We have recently reported on the first successful GluN2B subunit-selective PET radioligand, ( R ) - [ 11 C]­Me-NB1, that proved to be suitable for visualizing GluN2B in vitro and in vivo . The structure of ( R ) - [ 11 C]­Me-NB1 belongs to a class of 3-benzazepine-based ligands, encompassing a series of high-affinity GluN2B antagonists, that were first reported by Tewes et al Of note, ( R ) - [ 11 C]­Me-NB1 was successfully translated to humans, rendering it the first and only GluN2B-targeted PET radioligand to be clinically validated to date .…”

Cyanoquinolines and Furo[3,4-b]quinolinones Formation via On-The-Spot 2,3-Functionalization of Quinolines with Cyanopropargylic Alcohols

“…In particular, they are seen in the molecules of such commercial drugs as bosutinib (Bosulif@), Neratinib (Nerlynx@), and pelitinib (tyrosine kinase inhibitor), 6 which are used as anticancer agents 7 (Figure 1) and for the treatment of the Wnt signaling pathway. 8 Besides, quinolines functionalized with the cyano group are valuable building blocks for the synthesis of acridinic acid 9 and its derivatives−2,3-dihydropyridazino[4,5-b]quinoline-1,4dione 10 (neuroactive agents), quinoline-3-carboxamides (hematopoietic prostaglandin D synthase (H-PGDS) inhibitors), 11 N-(2-[ 11 C]methoxybenzyl)quinoline-3-carboxamidine ([PET radioligands for GluN2B-containing NMDA receptors), 12 quinolonedihydrooxazoles (effective against bronchial carcinoma), 13 3-acylaminotetrahydroquinolines (versatile bioisosteres of tetralin for melatonin receptor ligands), 14 and so forth.…”

“…Besides, quinolines functionalized with the cyano group are valuable building blocks for the synthesis of acridinic acid and its derivatives–2,3-dihydropyridazino­[4,5- b ]­quinoline-1,4-dione (neuroactive agents), quinoline-3-carboxamides (hematopoietic prostaglandin D synthase (H-PGDS) inhibitors), N -(2-[ 11 C]­methoxybenzyl)­quinoline-3-carboxamidine ([PET radioligands for GluN2B-containing NMDA receptors), quinolonedihydrooxazoles (effective against bronchial carcinoma), 3-acylaminotetrahydroquinolines (versatile bioisosteres of tetralin for melatonin receptor ligands), and so forth.…”