PET Imaging of the Adenosine A2A Receptor in the Rotenone-Based Mouse Model of Parkinson’s Disease with [18F]FESCH Synthesized by a Simplified Two-Step One-Pot Radiolabeling Strategy

Abstract

The adenosine A2A receptor (A2AR) is regarded as a particularly appropriate target for non-dopaminergic treatment of Parkinson’s disease (PD). An increased A2AR 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 A2AR upregulation in PD. For that purpose, we selected the known A2AR-specific radiotracer [18F]FESCH and developed a simplified two-step one-pot radiosynthesis. PET images showed a high uptake of [18F]FESCH in the mouse striatum. Concomitantly, metabolism studies with [18F]FESCH revealed the presence of a brain-penetrant radiometabolite. In rotenone-treated mice, a slightly higher striatal A2AR binding of [18F]FESCH was found. Nonetheless, the correlation between the increased A2AR levels within the proposed PD animal model remains to be further investigated.

Synthesis and Biological Evaluation of a Novel 18F-Labeled Radiotracer for PET Imaging of the Adenosine A2A Receptor

“…In comparison to the A 2A R radiotracer [ 18 F] FESCH (15 min post injection (p.i. ): parent fractions of 71% and 41% in brain and plasma samples, respectively) [ 17 ], [ 18 F] TOZ1 seems to have a remarkable metabolic stability in mice.…”

“…All these results raise the question of the suitability of the selected animal model for A 2A R imaging. In previous studies, we already investigated another A 2A R radioligand in mice: [ 18 F] FESCH , an 18 F-labeled derivative of the clinically used SCH442416 [ 15 , 16 , 17 ]. [ 18 F] FESCH presented an inferior metabolism (15 min p.i.…”

“…To assess the suitability of PET for detection of changes in the availability of A 2A R in PD, our group performed dynamic PET studies in a rotenone-based mouse model of Parkinson’s disease with [ 18 F] MRS5425 , (also known as [ 18 F] FESCH ) [ 15 , 16 ]. However, the study yielded inconclusive data, at least in part due to the presence of a non-negligible fraction of a brain-penetrating radiometabolite [ 17 ]. Therefore, we selected tozadenant as lead compound for the development of an A 2A R-specific radiotracer based on its high affinity and its extensive evaluation in clinical trials.…”

Development of 18F-Labeled Radiotracers for PET Imaging of the Adenosine A2A Receptor: Synthesis, Radiolabeling and Preliminary Biological Evaluation

“…A maximum receptor density ( B max ) value of 430 fmol/mg wet weight in mouse striatum was described by using [ 3 H] ZM241385 [ 59 ]. As a general rule, the K d value of a PET radiotracer should be 5–10 times lower than the B max value and, thus, the affinity of [ 18 F] PPY1 and [ 18 F] PPY2 might probably be sufficient to clearly visualize the A 2A R in the brain [ 60 ]. The non-specific binding of [ 18 F] PPY1 as well as [ 18 F] PPY2 is presumably not related to significant binding to the A 1 R ( Table 1 ), but to other off-targets.…”

Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016

“…[ 123 ]. It was supposed that this radiometabolite represents [ 18 F]fluoroacetate, which is known to enter the brain and to be frequently formed from radioligands bearing a [ 18 F]fluoroethoxy group [ 1 , 18 , 74 , 123 , 179 ]. Overall, these findings indicate that [ 18 F] 39 and [ 18 F] 40 might show an improved metabolic profile compared to [ 18 F] 30 in the brain [ 123 ].…”