Characterization of (R)- and (S)-[¹⁸F]OF-NB1 in Rodents as Positron Emission Tomography Probes for Imaging GluN2B Subunit-Containing N-Methyl-d-Aspartate Receptors
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2023-12-20
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Journal Article
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Abstract
The N-methyl-d-aspartate receptor (NMDAR) subtype 2B (GluN1/2B) is implicated in various neuropathologies. Given the lack of a validated radiofluorinated positron emission tomography (PET) probe for the imaging of GluN1/2B receptors, we comprehensively investigated the enantiomers of [¹⁸F]-OF-NB1 in rodents. Particularly, the (R)- and (S)- enantiomers were evaluated using in silico docking, in vitro autoradiography, in vivo PET imaging, and ex vivo biodistribution studies. A select panel of GluN1/2B antagonists (CP-101,606, CERC-301, and eliprodil) and the off-target sigma-1 receptor ligands (fluspidine and SA4503) were used to determine the specificity and selectivity of the tested enantiomers. Additionally, a nonmetal-mediated radiofluorination strategy was devised that harnesses the potential of diaryliodoniums in the nucleophilic radiofluorination of nonactivated aromatic compounds. Both enantiomers exhibited known GluN1/2B binding patterns; however, the R-enantiomer showed higher GluN1/2B-specific accumulation in rodent autoradiography and higher brain uptake in PET imaging experiments compared to the S-enantiomer. Molecular simulation studies provided further insights with respect to the difference in binding, whereby a reduced ligand-receptor interaction was observed for the S-enantiomer. Nonetheless, both enantiomers showed dose dependency when two different doses (1 and 5 mg/kg) of the GluN1/2B antagonist, CP-101,606, were used in the PET imaging study. Taken together, (R)-[¹⁸F]-OF-NB1 appears to exhibit the characteristics of a suitable PET probe for imaging of GluN2B-containing NMDARs in clinical studies.
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14 (24)
Pages / Article No.
4323 - 4334
Publisher
American Chemical Society
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Subject
GluN2B subunit; NMDA; PET imaging; rodents; molecular modeling; neurodegeneration
Organisational unit
03688 - Schibli, Roger / Schibli, Roger
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Funding
160403 - Development of fluorinated GluN2B receptorantagonists for positron emission tomography (SNF)
182872 - Development of fluorinated GluN2B-NMDA receptor ligands for positron emission tomography (PET) (SNF)
182872 - Development of fluorinated GluN2B-NMDA receptor ligands for positron emission tomography (PET) (SNF)