Improved in vivo PET imaging of the adenosine A2A receptor in the brain using [18F]FLUDA, a deuterated radiotracer with high metabolic stability
| Autor: | Winnie Deuther-Conrad, Rareş-Petru Moldovan, Peter Brust, Friedrich-Alexander Ludwig, Sladjana Dukic-Stefanovic, Thu Hang Lai, Barbara Wenzel, Magali Toussaint, Bernhard Sattler, Susann Schröder, Osama Sabri, Björn H. Falkenburger, Daniel Gündel, Rodrigo Teodoro |
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| Jazyk: | němčina |
| Rok vydání: | 2021 |
| Předmět: |
positron emission tomography
medicine.diagnostic_test Chemistry neurodegeneration Adenosine A2A receptor General Medicine Striatum Pharmacology Adenosine receptor In vitro adenosine receptors A2A receptor In vivo Positron emission tomography Toxicity medicine fluorine-18 Radiology Nuclear Medicine and imaging FESCH Receptor |
| Zdroj: | European Journal of Nuclear Medicine and Molecular Imaging 48(2021), 2727-2736 |
| Popis: | Purpose The adenosine A2A receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A2A receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A2A receptor radiotracer and report herein the preclinical evaluation of [18F]FLUDA, a deuterated isotopologue of [18F]FESCH. Methods [18F]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 [18F]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72–180 GBq/μmol. Autoradiography proved A2A receptor–specific accumulation of [18F]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [18F]FLUDA compared to that of [18F]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 [18F]FLUDA towards striatal A2A 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 [18F]FLUDA. Conclusions The new radiotracer [18F]FLUDA is suitable to detect the availability of the A2A receptor in the brain with high target specificity. It is regarded ready for human application. |
| Databáze: | OpenAIRE |
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