Design, Synthesis and Preclinical Evaluation of a Brain-Permeable PET Tracer for P2Y12 Receptor Imaging in the Brain

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.