Abstract
PurposeThe 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.ConclusionsThe 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.
Highlights
The signaling molecule adenosine is an important modulator of neurotransmission, regulating physiological processes such as sleep, motor activity, or sensorimotor gating [1]
Parkinson’s disease (PD) patients with dyskinesias and Huntington’s disease (HD) patients show excessive movements, these findings collectively indicate that A2A is an important reporter - and modulator - of mobility in human basal ganglia
Binding studies were performed by competitive radiotracer binding assays and revealed high-affinity binding of FLUDA towards the human A2A receptor with a Ki value of 0.74 ± 0.26 nM and negligible binding towards the human A1 receptor (Ki > 1 μM)
Summary
The signaling molecule adenosine is an important modulator of neurotransmission, regulating physiological processes such as sleep, motor activity, or sensorimotor gating [1]. Modulating adenosine signaling is an emerging treatment option for neuropsychiatric and neurodegenerative disorders [1]. Adenosine regulates neurotransmission of glutamate, acetylcholine, γ-aminobutyric acid, and dopamine using four Gprotein-coupled plasma membrane receptors - adenosine A1, A2A, A2B, and A3 receptors [1]. Whereas A1, A2B and A3 receptors are widely distributed throughout the brain, the A2A receptor is expressed at high densities in the dorsal. The binding of adenosine to the A2A receptor activates protein kinase A (PKA) via G protein–mediated stimulation of adenylyl cyclase and the corresponding increase in cyclic adenosine monophosphate (cAMP).
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