TY - JOUR
T1 - Development of Peptide-Based Probes for Molecular Imaging of the Postsynaptic Density in the Brain
AU - Fernandes, Eduardo F A
AU - Palner, Mikael
AU - Raval, Nakul Ravi
AU - Jeppesen, Troels E
AU - Danková, Daniela
AU - Bærentzen, Simone L
AU - Werner, Christian
AU - Eilts, Janna
AU - Maric, Hans M
AU - Doose, Sören
AU - Aripaka, Sanjay Sagar
AU - Kaalund, Sanne Simone
AU - Aznar, Susana
AU - Kjaer, Andreas
AU - Schlosser, Andreas
AU - Haugaard-Kedström, Linda M
AU - Knudsen, Gitte M
AU - Herth, Matthias M
AU - Stromgaard, Kristian
PY - 2024/7/25
Y1 - 2024/7/25
N2 - 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.
AB - 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.
KW - Animals
KW - Autoradiography
KW - Brain/metabolism
KW - Disks Large Homolog 4 Protein/metabolism
KW - Fluorine Radioisotopes/chemistry
KW - Humans
KW - Male
KW - Molecular Imaging/methods
KW - Molecular Probes/chemistry
KW - Parkinson Disease/metabolism
KW - Peptides/chemistry
KW - Post-Synaptic Density/metabolism
KW - Pyridines
KW - Pyrrolidinones
KW - Rats
KW - Rats, Sprague-Dawley
KW - Tritium
UR - http://www.scopus.com/inward/record.url?scp=85198502011&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.4c00615
DO - 10.1021/acs.jmedchem.4c00615
M3 - Journal article
C2 - 38981131
SN - 0022-2623
VL - 67
SP - 11975
EP - 11988
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 14
ER -