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

Autor: Fernandes EFA; Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark., Palner M; Neurobiology Research Unit, Rigshospitalet, Blegdamsvej 9, Copenhagen DK-2100, Denmark., Raval NR; Neurobiology Research Unit, Rigshospitalet, Blegdamsvej 9, Copenhagen DK-2100, Denmark.; Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3, Copenhagen DK-2200, Denmark.; Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut 06520, United States., Jeppesen TE; 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., Danková D; Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark., Bærentzen SL; Neurobiology Research Unit, Rigshospitalet, Blegdamsvej 9, Copenhagen DK-2100, Denmark., Werner C; Department of Biotechnology and Biophysics, Biocenter, Julius-Maximilians-University, Am Hubland, Würzburg D-97074, Germany., Eilts J; Department of Biotechnology and Biophysics, Biocenter, Julius-Maximilians-University, Am Hubland, Würzburg D-97074, Germany., Maric HM; Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark.; Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-University, Josef-Schneider-Str. 2, Würzburg 97080, Germany., Doose S; Department of Biotechnology and Biophysics, Biocenter, Julius-Maximilians-University, Am Hubland, Würzburg D-97074, Germany., Aripaka SS; Neurobiology Research Unit, Rigshospitalet, Blegdamsvej 9, Copenhagen DK-2100, Denmark., Kaalund SS; Center for Neuroscience and Stereology, Bispebjerg University Hospital, Nielsine Nielsens Vej 6B, Copenhagen DK-2400, Denmark., Aznar S; Center for Neuroscience and Stereology, Bispebjerg University Hospital, Nielsine Nielsens Vej 6B, Copenhagen DK-2400, Denmark.; Center for Translational Research, Bispebjerg University Hospital, Nielsine Nielsens Vej 4B, Copenhagen DK-2400, Denmark., Kjaer A; Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3, Copenhagen DK-2200, Denmark.; 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., Schlosser A; Department of Biotechnology and Biophysics, Biocenter, Julius-Maximilians-University, Am Hubland, Würzburg D-97074, Germany., Haugaard-Kedström LM; Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark., Knudsen GM; Neurobiology Research Unit, Rigshospitalet, Blegdamsvej 9, Copenhagen DK-2100, Denmark.; Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3, Copenhagen DK-2200, Denmark., Herth MM; Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark.; Neurobiology Research Unit, Rigshospitalet, Blegdamsvej 9, Copenhagen DK-2100, Denmark.; 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., Stro Mgaard K; Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Jul 25; Vol. 67 (14), pp. 11975-11988. Date of Electronic Publication: 2024 Jul 09.
DOI: 10.1021/acs.jmedchem.4c00615
Abstrakt: 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.
Databáze: MEDLINE