While antisense oligonucleotide (ASOs) therapies have emerged as promising tools to modulate gene expression in neurological diseases, these new agents face challenges in the context of the central nervous system, particularly regarding distribution and duration of action. Translational approaches that enable the tracking of ASO effects in the whole brain are therefore needed to guide their preclinical and clinical development. In the present study, we used PET imaging as a translational tool to study the pharmacodynamics of an ASO targeting a metabotropic receptor, namely, the dopamine D2 receptor. We selected an ASO sequence directed toward D2 mRNA in the rat brain and optimized its chemical backbone by a gapmer design. This anti-D2R ASO was administered directly into the striatum of adult rats via intracerebral stereotaxic injection at different doses. The longitudinal pharmacodynamic effects of the ASO were assessed using successive PET acquisitions with the D2R radiotracer 11Craclopride to quantify changes in D2R receptor expression in the striatum. Our PET findings indicated a reduction of D2R availability from 3 weeks to 10 weeks postinjection. The apomorphine-induced rotation test confirmed that the postsynaptic striatal dopaminergic imbalance was behaviorally relevant and persisted for three months after the ASO injection. This work provides novel insights into the potential of PET neuroimaging to explore the in vivo efficacy and longevity of modified ASOs delivered directly into the brain, opening translational applications.
Cheataini et al. (Mon,) studied this question.