2. Academic Validation
  3. Development of Peptide-Based Probes for Molecular Imaging of the Postsynaptic Density in the Brain

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

  • J Med Chem. 2024 Jul 25;67(14):11975-11988. doi: 10.1021/acs.jmedchem.4c00615.
Eduardo F A Fernandes 1,  Mikael Palner 2,  Nakul Ravi Raval 2 3 4,  Troels E Jeppesen 5,  Daniela Danková 1,  Simone L Bærentzen 2,  Christian Werner 6,  Janna Eilts 6,  Hans M Maric 1 7,  Sören Doose 6,  Sanjay Sagar Aripaka 2,  Sanne Simone Kaalund 8,  Susana Aznar 8 9,  Andreas Kjaer 3 5,  Andreas Schlosser 6,  Linda M Haugaard-Kedström 1,  Gitte M Knudsen 2 3,  Matthias M Herth 1 2 5,  Kristian Stro Mgaard 1
Affiliations

Affiliations

  • 1 Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark.
  • 2 Neurobiology Research Unit, Rigshospitalet, Blegdamsvej 9, Copenhagen DK-2100, Denmark.
  • 3 Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3, Copenhagen DK-2200, Denmark.
  • 4 Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut 06520, United States.
  • 5 Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital - Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen DK-2200, Denmark.
  • 6 Department of Biotechnology and Biophysics, Biocenter, Julius-Maximilians-University, Am Hubland, Würzburg D-97074, Germany.
  • 7 Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-University, Josef-Schneider-Str. 2, Würzburg 97080, Germany.
  • 8 Center for Neuroscience and Stereology, Bispebjerg University Hospital, Nielsine Nielsens Vej 6B, Copenhagen DK-2400, Denmark.
  • 9 Center for Translational Research, Bispebjerg University Hospital, Nielsine Nielsens Vej 4B, Copenhagen DK-2400, Denmark.
PMID: 38981131 DOI: 10.1021/acs.jmedchem.4c00615
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.

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