Improved in vivo PET imaging of the adenosine A(2A) receptor in the brain using [(18)F]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 [(18)F]FLUDA, a deuterated isotopologue of [(18)F]FESCH. METHODS: [(18)F]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: [(18)F]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72–180 GBq/μmol. Autoradiography proved A(2A) receptor–specific accumulation of [(18)F]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [(18)F]FLUDA compared to that of [(18)F]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 [(18)F]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 μg/kg, ~ 4000-fold the dose applied in human PET studies using [(18)F]FLUDA. CONCLUSIONS: The new radiotracer [(18)F]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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-020-05164-4.