TY  - JOUR
AU  - Joseph, Emanuel
AU  - Kunze, Lea H
AU  - Schaefer, Rebecca
AU  - Palumbo, Giovanna
AU  - Kugelmann, Benjamin
AU  - Wagner, Stephan
AU  - Lammich, Sven
AU  - Feederle, Regina
AU  - Willem, Michael
AU  - Werner, Rudolf A
AU  - Brendel, Matthias
AU  - Lindner, Simon
TI  - Design, Synthesis and Preclinical Evaluation of a Brain-Permeable PET Tracer for P2Y12 Receptor Imaging in the Brain.
JO  - Journal of medicinal chemistry
VL  - 68
IS  - 15
SN  - 0095-9065
CY  - Washington, DC
PB  - ACS
M1  - DZNE-2025-01041
SP  - 15543 - 15562
PY  - 2025
AB  - Microglia, the innate immune cells of the central nervous system (CNS), act as first responders to brain injury. Their ability to switch between different neuroprotective and neurotoxic phenotypes, plays a central role in maintaining brain homeostasis. Recently, the P2Y12 receptor (P2Y12R) has been identified as a promising molecular biomarker for microglia activity, as its expression level is dependent on microglia phenotype and function. P2Y12R positron emission tomography (PET) might be a valuable diagnostic tool, however, tracers with sufficient brain retention have not been reported so far. Herein, we report a brain-permeable P2Y12R PET tracer for in vivo imaging of P2Y12R-positive microglia. Nicotinate [18F]12 exhibited nanomolar affinity and specificity for the target receptor and showed a reduced uptake in microglia-depleted (PLX) mice, in comparison to WT and Trem2 knockout (Trem2-/-) mice. Ex vivo immunohistochemistry (IHC) and PET data revealed a strong correlation between microglia abundance, P2Y12R expression levels and tracer uptake.
LB  - PUB:(DE-HGF)16
C6  - pmid:40713021
C2  - pmc:PMC12362594
DO  - DOI:10.1021/acs.jmedchem.5c00457
UR  - https://pub.dzne.de/record/280959
ER  -