Development of a Novel PET Radioligand for Imaging the Adenosine A_2A Receptor in the Brain

The adenosine A_2A receptor (A_2AAR) is implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, due to its involvement in neuroinflammatory processes and synaptic function. However, suitable positron emission tomography (PET) radioligands for direct imaging of A_2AAR in the living brain remain limited. In this study, we describe the synthesis and preclinical evaluation of [¹¹C]2, a novel PET radioligand developed to target A_2AAR with moderate affinity and selectivity. [¹¹C]2 was synthesized with high radiochemical purity and satisfactory molar activity. In vivo PET imaging in wild-type mice demonstrated that [¹¹C]2 efficiently crossed the blood-brain barrier and distributed throughout the brain. Blocking studies with unlabeled compound 2 confirmed the specificity of [¹¹C]2 binding in vivo. In vitro autoradiography further revealed regional binding patterns in both wild-type and Alzheimer's disease model mice. Slightly higher in vitro signals in AD model mice suggest a potential link to neuroinflammatory mechanisms, although further investigation is required. Notably, during the initial 0.5-2.5 min after injection, striatal uptake was modestly higher than in other brain regions; however, this advantage became indistinct at later time points. Thus, while [¹¹C]2 enables very early phase mapping of A_2AAR distribution, the transient nature of its striatal preference indicates that further structural optimization is required to enhance sustained striatal selectivity and overall imaging performance.