Assessment of 18F-Fluoroethyl and 18F-Fluoropropyl Analogs for A2A Receptor PET Imaging in Rats

The cerebral adenosine A2A receptor has potential as a target for treating neuropsychiatric conditions. Two A2A receptor-specific PET tracers, 18F-FESCH and 18F-FPSCH, were developed and tested in a study involving 22 healthy male Wistar rats. The study involved a 90-minute dynamic PET scan, arterial blood sampling, and metabolite analysis. Half of the rats received a vehicle treatment, while the other half were pre-treated with the A2A receptor antagonist KW-6002 to achieve full receptor blocking.

The tracer kinetics were analyzed using 1-tissue-compartment modeling (1TCM) and 2-tissue-compartment modeling (2TCM), as well as the Logan graphical analysis. The midbrain, cerebellum, and hippocampus were considered as potential reference regions. The total volume of distribution (VT) in these regions was compared under baseline and full blocking conditions, and the striatal nondisplaceable binding potential (BPND) was assessed using a simplified reference tissue model (SRTM) with distribution volume ratio minus 1 (DVR - 1) for both 60- and 90-minute scans.

The Akaike information criterion indicated that 1TCM was suitable for 18F-FPSCH, and 2TCM was suitable for 18F-FESCH. The baseline striatal VT was not significantly different between the two tracers. After pretreatment with KW-6002, there was a significant reduction in striatal VT, but no significant change in the VT of the hippocampus, midbrain, or cerebellum. The baseline striatal SRTM BPND was not significantly different from DVR - 1 for both tracers, except for a 60-minute scan with midbrain as the reference region for 18F-FPSCH. The Bland-Altman analysis showed a smaller bias for 18F-FESCH with a 60-minute scan. After pretreatment, the striatal SRTM BPND for 18F-FPSCH was significantly lower than for 18F-FESCH when using the midbrain or cerebellum as the reference region.

The conclusion of the study is that 18F-FESCH is the most appropriate PET ligand for quantifying A2A receptor expression in the rat brain under baseline and blocking conditions. Accurate quantification can be achieved with a 60-minute dynamic PET scan using either the cerebellum or midbrain as the reference region.