Abstract
The adenosine A2A receptor (A2AR) has emerged as a potential non-dopaminergic target for the treatment of Parkinson’s disease and, thus, the non-invasive imaging with positron emission tomography (PET) is of utmost importance to monitor the receptor expression and occupancy during an A2AR-tailored therapy. Aiming at the development of a PET radiotracer, we herein report the design of a series of novel fluorinated analogs (TOZ1-TOZ7) based on the structure of the A2AR antagonist tozadenant, and the preclinical evaluation of [18F]TOZ1. Autoradiography proved A2AR-specific in vitro binding of [18F]TOZ1 to striatum of mouse and pig brain. Investigations of the metabolic stability in mice revealed parent fractions of more than 76% and 92% of total activity in plasma and brain samples, respectively. Dynamic PET/magnetic resonance imaging (MRI) studies in mice revealed a brain uptake but no A2AR-specific in vivo binding.
Highlights
Adenosine is an endogenous ubiquitous molecule involved in many aspects of cellular physiology pertaining to neuronal activity, vascular function, platelet aggregation and immune cell regulation
The A2A receptor (A2AR) is highly enriched in the dorsal and ventral striatum, where it is involved in the indirect basal ganglia pathway and can form heteromeric complexes with other G protein-coupled receptors, including dopamine D2, glutamate mGluR5, cannabinoid CB1 and A1 [1,2,3,4]
In particular for positron emission tomography (PET) radiotracer development, we investigated fluoropyridyl groups in the tozadenant scaffold since pyridine substituted with fluorine in positions 2 and 4 favor the radiofluorination via the aromatic nucleophilic substitution of known leaving groups [24,25]
Summary
Adenosine is an endogenous ubiquitous molecule involved in many aspects of cellular physiology pertaining to neuronal activity, vascular function, platelet aggregation and immune cell regulation. It exerts its signaling by binding to four subtypes of purinergic P1 receptors, namely A1R, A2AR, A2BR and A3R, which are coupled to different G proteinmediated intracellular pathways. Among these receptors, the A2AR has emerged as an important non-dopaminergic target for the treatment of Parkinson’s disease (PD) based on its unique central nervous system distribution. The A2AR is highly enriched in the dorsal and ventral striatum, where it is involved in the indirect basal ganglia pathway and can form heteromeric complexes with other G protein-coupled receptors, including dopamine D2, glutamate mGluR5, cannabinoid CB1 and A1 [1,2,3,4]. Co-administration with a low dose of L-DOPA induces an improvement of motor symptoms and a reduction in adverse effects from long-term L-DOPA treatment including dyskinesia, on-time shortening and psychotic syndromes [6,7]
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