Improved in vivo PET imaging of the adenosine A2A receptor in the brain using [18F]FLUDA, a deuterated radiotracer with high metabolic stability
Thu Hang Lai, Magali Toussaint, Rodrigo Teodoro, Sladjana Dukić-Stefanović, Daniel Gündel, Friedrich‐Alexander Ludwig, Barbara Wenzel, Susann Schröder, Bernhard Sattler, Rareş‐Petru Moldovan, Björn Falkenburger, Osama Sabri, Winnie Deuther‐Conrad, Peter Brust
Abstract
Abstract 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.