Investigation of [18F]FESCH for PET imaging of the adenosine A2A receptor in a rotenone-based mouse model of Parkinson´s disease and development of a two-step one-pot radiolabeling strategy


Investigation of [18F]FESCH for PET imaging of the adenosine A2A receptor in a rotenone-based mouse model of Parkinson´s disease and development of a two-step one-pot radiolabeling strategy

Schröder, S.; Lai, T. H.; Kranz, M.; Toussaint, M.; Shang, Q.; Dukic-Stefanovic, S.; Pan-Montojo, F.; Brust, P.

Objectives:

Rotenone-treated mice are regarded as a model for Parkinson´s disease (PD). Increased availability of the adenosine A2A receptor (A2AR) has been found in the striatum of patients with PD and dyskinesias [1]. The aim of this study was to investigate whether similar alterations are found in the mouse model of PD using small animal PET/MR imaging. For that purpose, [18F]FESCH [2] was the radiotracer of choice due to its high A2AR specificity and excellent PET imaging properties [2-5]. Furthermore, we intended to develop a simplified one-pot strategy for the radiosynthesis of [18F]FESCH.
Methods:
The published two-step procedures for the radiosynthesis of [18F]FESCH start with the nucleophilic 18F-labeling of ethane-1,2-diol bis(3,4-dibromobenzenesulfonate) [4] or ethane-1,2-diol bis(4-methylbenzenesulfonate) [2]. The respective [18F]fluoroethyl synthon is isolated either by semi-preparative HPLC [4] or cartridge [2] and, only then, reacted with the phenol precursor desmethyl SCH442416. In our novel one-pot approach, desmethyl SCH442416 was treated with 40% TBAOHaq. to generate the activated phenolate which was directly reacted with the non-isolated 2-[18F]fluoroethyl tosylate in MeCN at 120 °C for 10 min (see Figure 1). [18F]FESCH was purified by semi-preparative HPLC, concentrated using solid-phase extraction on a pre-conditioned RP cartridge and eluted with absolute EtOH. After evaporation of the solvent at 75 °C, the radiotracer was finally formulated in isotonic saline ready for injection. [18F]FESCH (5.0±1.8 MBq) was administered to C57BL/6JRj mice (control n=5, rotenone-treated n=7, 18 month, 28-35 g) and whole body scans were performed for 60 min in listmode with a Mediso nanoScan® PET/MR scanner followed by dynamic reconstruction. Time-activity curves (TACs) were generated for regions of interest such as striatum (Figure 1) and cerebellum as reference region.
Results:
The herein described one-pot strategy provided [18F]FESCH (Ki hA2A=0.6 nM) with an overall radiochemical yield of 16.1±1.5% (n=9, EOB), a radiochemical purity of ≥98% and compared to the published two-pot procedure with a notably increased molar activity of 116±18.5 GBq/µmol (n=7, EOS). The PET images over 60 min showed high uptake of [18F]FESCH in the striatum (Figure 1) which is consistent with the known A2AR distribution pattern in the brain. Although not significant, slightly higher striatal A2AR binding was found in rotenone-treated mice.
Conclusions:
The radiotracer [18F]FESCH proved to be suitable for in vivo imaging of the adenosine A2A receptor in the mouse brain. Since the increased A2AR availability appears to be related to dyskinesia, it has to be proven whether the investigated mouse model of PD reflects this aspect.
Acknowledgments:
The European Regional Development Fund (ERDF) and Sächsische Aufbaubank (SAB) are acknowledged for financial support (Project No. 100226753).
References:
[1] Ramlackhansingh et al., Neurology, 76, 2011
[2] Khanapur et al., J. Med. Chem., 57, 2014
[3] Shinkre et al., Bioorg. Med. Chem. Lett., 20, 2010
[4] Bhattacharjee et al., Nucl. Med. Biol., 38, 2011
[5] Khanapur et al., J. Nucl. Med., 58, 2017

  • Open Access Logo Poster
    23rd International Symposium on Radiopharmaceutical Sciences (ISRS 2019), 26.-31.05.2019, Beijing, China
    DOI: 10.1002/jlcr.3725

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Publ.-Id: 28932