PET imaging of adenosine A2A receptors

This thesis describes the development and evaluation of [11C]preladenant as a novel radioligand for in vivo imaging of adenosine A2A receptors in the brain with positron-emission tomography (PET). The 11C-labeled drug [11C]preladenant was produced with high radiochemical yield and specific activity. The tracer uptake was in accordance with A2A receptor distribution in the brain. [11C]preladenant displayed favorable pharmacokinetics and radiation dosimetry and proved to be a suitable tracer for the in vivo quantification of striatal A2A receptors in rat and monkey brain. [11C]preladenant-PET was also used to investigate A2A receptor availability in a rat model for Parkinson’s disease. We demonstrated that [11C]preladenant-PET is able to show changes of A2A receptor availability during the course of Parkinson’s disease, and that A2A receptor availability positively correlated with dopamine D2 receptor availability in rats with levodopa-induced dyskinesia. These findings could contribute to our knowledge about the molecular mechanisms underlying Parkinson’s disease. Thus, this study provides a useful tool to map A2A receptors in the living brain, which could be of help in exploring the functions of A2A receptors in physiological and pathological conditions. [11C]preladenant-PET could facilitate linking changes in A2A receptor availability with clinical symptoms, measuring drug-related A2A receptor occupancy in drug development and determining the best regimen of A2A receptor-targeting treatment. Now this tracer is ready for validation in human subjects. If the validation is successful, [11C]preladenant-PET can be applied to study the behavior and functions of A2A receptors in the human brain in various conditions.