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[ 18 F]FLUDA is a selective radiotracer for in vivo imaging of the adenosine A 2A receptor (A 2A R) by positron emission tomography (PET). Promising preclinical results obtained by neuroimaging of mice and piglets suggest the translation of [ 18 F]FLUDA to human PET studies. Thus, we report herein a remotely controlled automated radiosynthesis of [ 18 F]FLUDA using a GE TRACERlab FX2 N radiosynthesizer. The radiotracer was obtained by a one-pot two-step radiofluorination procedure with a radiochemical yield of 9±1%, a radiochemical purity of ≥99%, and molar activities in the range of 69-333 GBq/μmol at the end of synthesis within a total synthesis time of approx. 95 min (n = 16). Altogether, we successfully established a reliable and reproducible procedure for the automated production of [ 18 F]FLUDA., (© 2022 The Authors. Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons Ltd.)

A 2A adenosine receptors (A 2A -AR) have a cardio-protective function upon ischemia and reperfusion, but on the other hand, their stimulation could lead to arrhythmias. Our aim was to investigate the potential use of the PET radiotracer [ 18 F]FLUDA to non-invasively determine the A 2A -AR availability for diagnosis of the A 2A R status. Therefore, we compared mice with cardiomyocyte-specific overexpression of the human A 2A -AR (A 2A -AR TG) with the respective wild type (WT). We determined: (1) the functional impact of the selective A 2A R ligand FLUDA on the contractile function of atrial mouse samples, (2) the binding parameters ( B max and   K D ) of [ 18 F]FLUDA on mouse and human atrial tissue samples by autoradiographic studies, and (3) investigated the in vivo uptake of the radiotracer by dynamic PET imaging in A 2A -AR TG and WT. After A 2A -AR stimulation by the A 2A -AR agonist CGS 21680 in isolated atrial preparations, antagonistic effects of FLUDA were found in A 2A -AR-TG animals but not in WT. Radiolabelled [ 18 F]FLUDA exhibited a K D of 5.9 ± 1.6 nM and a B max of 455 ± 78 fmol/mg protein in cardiac samples of A 2A -AR TG, whereas in WT, as well as in human atrial preparations, only low specific binding was found. Dynamic PET studies revealed a significantly higher initial uptake of [ 18 F]FLUDA into the myocardium of A 2A -AR TG compared to WT. The hA 2A -AR-specific binding of [ 18 F]FLUDA in vivo was verified by pre-administration of the highly affine A 2A AR-specific antagonist istradefylline. Conclusion: [ 18 F]FLUDA is a promising PET probe for the non-invasive assessment of the A 2A -AR as a marker for pathologies linked to an increased A 2A -AR density in the heart, as shown in patients with heart failure.

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.

The adenosine A 2A receptor (A 2A R) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the A 2A R-tailored therapy, we designed a library of fluorinated analogs based on a recently published lead compound ( PPY ). Among those, the highly affine 4-fluorobenzyl derivate ( PPY1 ; K i ( h A 2A R) = 5.3 nM) and the 2-fluorobenzyl derivate ( PPY2 ; K i ( h A 2A R) = 2.1 nM) were chosen for 18 F-labeling via an alcohol-enhanced copper-mediated procedure starting from the corresponding boronic acid pinacol ester precursors. Investigations of the metabolic stability of [ 18 F] PPY 1 and [18F] PPY2 in CD-1 mice by radio-HPLC analysis revealed parent fractions of more than 76% of total activity in the brain. Specific binding of [ 18 F] PPY 2 on mice brain slices was demonstrated by in vitro autoradiography. In vivo PET/magnetic resonance imaging (MRI) studies in CD-1 mice revealed a reasonable high initial brain uptake for both radiotracers, followed by a fast clearance.

The adenosine A 2A receptor (A 2A R) 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 A 2A R-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 A 2A R antagonist tozadenant , and the preclinical evaluation of [ 18 F] TOZ1 . Autoradiography proved A 2A R-specific in vitro binding of [ 18 F] 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 A 2A R-specific in vivo binding.

The adenosine A 2A receptor (A 2A R) is regarded as a particularly appropriate target for non-dopaminergic treatment of Parkinson's disease (PD). An increased A 2A R availability has been found in the human striatum at early stages of PD and in patients with PD and dyskinesias. The aim of this small animal positron emission tomography/magnetic resonance (PET/MR) imaging study was to investigate whether rotenone-treated mice reflect the aspect of striatal A 2A R upregulation in PD. For that purpose, we selected the known A 2A R-specific radiotracer [ 18 F] FESCH and developed a simplified two-step one-pot radiosynthesis. PET images showed a high uptake of [ 18 F] FESCH in the mouse striatum. Concomitantly, metabolism studies with [ 18 F] FESCH revealed the presence of a brain-penetrant radiometabolite. In rotenone-treated mice, a slightly higher striatal A 2A R binding of [ 18 F] FESCH was found. Nonetheless, the correlation between the increased A 2A R levels within the proposed PD animal model remains to be further investigated.