Improved in vivo PET imaging of the adenosine A2A receptor in the brain using [18F]FLUDA, a deuterated radiotracer with high metabolic stability

Purpose The adenosine A(2A) receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A(2A) receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A(2A) receptor radiotracer and report herein the preclinical evaluation of [F-18]FLUDA, a deuterated isotopologue of [F-18]FESCH. Methods [F-18]FLUDA was synthesized by a two-step one-pot approach and evaluated in vitro by autoradiographic studies as well as in vivo by metabolism and dynamic PET/MRI studies in mice and piglets under baseline and blocking conditions. A single-dose toxicity study was performed in rats. Results [F-18]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72-180 GBq/mu mol. Autoradiography proved A(2A) receptor-specific accumulation of [F-18]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [F-18]FLUDA compared to that of [F-18]FESCH, resulting in the absence of brain-penetrant radiometabolites. Furthermore, the radiometabolites detected in piglets are expected to have a low tendency for brain penetration. PET/MRI studies confirmed high specific binding of [F-18]FLUDA towards striatal A(2A) receptor with a maximum specific-to-non-specific binding ratio in mice of 8.3. The toxicity study revealed no adverse effects of FLUDA up to 30 mu g/kg, similar to 4000-fold the dose applied in human PET studies using [F-18]FLUDA. Conclusions The new radiotracer [F-18]FLUDA is suitable to detect the availability of the A(2A) receptor in the brain with high target specificity. It is regarded ready for human application.

Automated summary

The study developed a metabolically stable radiotracer, [F-18]FLUDA, for the non-invasive imaging of the A(2A) receptor in the brain. Preclinical evaluation in mice and piglets showed high target specificity and low toxicity, indicating its readiness for human application in diagnosing and developing drugs targeting the A(2A) receptor.