Characterization of the rotenone mouse model of Parkinson’s disease using radioligands for the adenosine A_2A receptor ([¹⁸F]FESCH) and the nicotinic α₄β₂ receptor ((‐)‐[¹⁸F]Flubatine)

Objectives
Rotenone-treated mice are regarded as a model for Parkinson´s disease (PD). Increased availability of the adenosine A2A receptor (A2AR) and decreased availability of the α4β2 nicotinic acetylcholine receptor (nAChR) have been found in the striatum and thalamus, respectively, of patients with PD [1,2]. Therefore, we evaluated the potential of [18F]FESCH (for A2AR) and (-)-[18F]Flubatine (for α4β2nAChR) to characterize similar receptor changes in the mouse model of PD with small animal PET/MR imaging.
Methods
Two groups of 18-months-old male C57BL/6JRj mice (28-35 g) (Janvier labs, France) were investigated: a control group (n=5) treated with a vehicle solution (2% carboxymethyl cellulose, 1.25% chloroform) and a PD group (n=7) treated with rotenone (Sigma-Aldrich, Germany) during 4 months (5 days/week, 5 mg/kg p.o.). [18F]FESCH (5.0±1.8 MBq; Am: 116±19 GBq/µmol, EOS) or (-)-[18F]Flubatine (6.5±2.4 MBq; Am: 1080±2156 GBq/µmol, EOS) were injected intravenously followed by 60 min dynamic PET scans (Mediso nanoScan®, PET/MRI 1T, Hungary). Time-activity curves from the striatum, cerebellum, and thalamus were analyzed (PMOD v3.9, PMOD Technologies LLC, Switzerland). The cerebellum was used as a reference tissue.
Results
PET scans revealed high uptake of (-)-[18F]Flubatine in thalamus (SUV ~3.5 at 40 min p.i.) and considerably lower uptake in cerebellum (SUV ~1.2 at 40 min p.i.). The SUV ratio (SUVR) thalamus/cerebellum, indicating specific radiotracer binding, is significantly decreased in the rotenone-treated group compared to the control (Figure 1A).
Also for [18F]FESCH much higher uptake was observed in striatum (SUV ~0.9 at 5 min p.i.) compared to cerebellum (SUV ~0.2 at 5 min p.i.). Although not significant for this rather small and highly variable data set, the SUVR striatum/cerebellum is increased in the rotenone-treated group compared to the control suggesting a higher specific binding in striatum (Figure 1B). These findings are in accordance with a recent publication [3].
Conclusion
We have established a concordance between clinical imaging findings in PD and small animal PET/MR in rotenone-treated mice. Thus, we assume the rotenone mouse model to be suitable for further investigation of molecular aspects of PD in particular related to A2AR and α4β2nAChR.
Acknowledgments
The European Regional Development Fund and Sächsische Aufbaubank are acknowledged for financial support (Project No. 100226753).
References
[1] Vuorimaa et al. Contrast Media Mol Imaging 2017; 6975841. [2] Meyer et al., Arch Gen Psych 2009, 66: 866-877. [3] Khanapur et al., J Nucl Med 2017; 58: 466–472.