Development of Peptide-Based Probes for Molecular Imaging of the Postsynaptic Density in the Brain

Eduardo F.A. Fernandes, Mikael Palner, Nakul Ravi Raval, Troels E. Jeppesen, Daniela Danková, Simone L. Bærentzen, Christian Werner, Janna Eilts, Hans M. Maric, Sören Doose, Sanjay Sagar Aripaka, Sanne Simone Kaalund, Susana Aznar, Andreas Kjaer, Andreas Schlosser, Linda M. Haugaard-Kedström, Gitte M. Knudsen, Matthias M. Herth, Kristian Stro̷mgaard*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

1 Citation (Scopus)

Abstract

The postsynaptic density (PSD) comprises numerous scaffolding proteins, receptors, and signaling molecules that coordinate synaptic transmission in the brain. Postsynaptic density protein 95 (PSD-95) is a master scaffold protein within the PSD and one of its most abundant proteins and therefore constitutes a very attractive biomarker of PSD function and its pathological changes. Here, we exploit a high-affinity inhibitor of PSD-95, AVLX-144, as a template for developing probes for molecular imaging of the PSD. AVLX-144-based probes were labeled with the radioisotopes fluorine-18 and tritium, as well as a fluorescent tag. Tracer binding showed saturable, displaceable, and uneven distribution in rat brain slices, proving effective in quantitative autoradiography and cell imaging studies. Notably, we observed diminished tracer binding in human post-mortem Parkinson’s disease (PD) brain slices, suggesting postsynaptic impairment in PD. We thus offer a suite of translational probes for visualizing and understanding PSD-related pathologies.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume67
Issue number14
Pages (from-to)11975–11988
ISSN0022-2623
DOIs
Publication statusPublished - 2024

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© 2024 American Chemical Society

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