Development and Validation of [3H]OF-NB1 for Preclinical Assessment of GluN1/2B Candidate Drugs
GluN2B-enriched N-methyl-D-aspartate receptors (NMDARs) are implicated in several neurodegenerative and psychiatric diseases, such as Alzheimer’s disease. No clinically valid GluN1/2B therapeutic exists due to a lack of selective GluN2B imaging tools, and the state-of-the-art [3H]ifenprodil shows po...
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Published in | Pharmaceuticals (Basel, Switzerland) Vol. 15; no. 8; p. 960 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Basel
MDPI AG
02.08.2022
MDPI |
Subjects | |
Online Access | Get full text |
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Summary: | GluN2B-enriched N-methyl-D-aspartate receptors (NMDARs) are implicated in several neurodegenerative and psychiatric diseases, such as Alzheimer’s disease. No clinically valid GluN1/2B therapeutic exists due to a lack of selective GluN2B imaging tools, and the state-of-the-art [3H]ifenprodil shows poor selectivity in drug screening. To this end, we developed a tritium-labeled form of OF-NB1, a recently reported selective GluN1/2B positron emission tomography imaging (PET) agent, with a molar activity of 1.79 GBq/µmol. The performance of [3H]OF-NB1 and [3H]ifenprodil was compared through head-to-head competitive binding experiments, using the GluN1/2B ligand CP-101,606 and the sigma-1 receptor (σ1R) ligand SA-4503. Contrary to [3H]ifenprodil, the usage of [3H]OF-NB1 differentiated between GluN1/2B and σ1R binding components. These results were corroborated by observations from PET imaging experiments in Wistar rats using the σ1R radioligand [18F]fluspidine. To unravel the binding modes of OF-NB1 and ifenprodil in GluN1/2B and σ1Rs, we performed a retrospective in silico study using a molecular operating environment. OF-NB1 maintained similar interactions to GluN1/2B as ifenprodil, but only ifenprodil successfully fitted in the σ1R pocket, thereby explaining the high GluN1/2B selectivity of OF-NB1 compared to ifenprodil. We successfully showed in a proof-of-concept study the superiority of [3H]OF-NB1 over the gold standard [3H]ifenprodil in the screening of potential GluN1/2B drug candidates. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. |
ISSN: | 1424-8247 1424-8247 |
DOI: | 10.3390/ph15080960 |