Preclinical Evaluation and Quantification of F-18-Fluoroethyl and F-18-Fluoropropyl Analogs of SCH442416 as Radioligands for PET Imaging of the Adenosine A(2A) Receptor in Rat Brain

The cerebral adenosine A(2A) receptor is an attractive therapeutic target for neuropsychiatric disorders. F-18-fluoroethyl and F-18-fluoropropyl analogs of F-18-labeled pyrazolo[4,3-e]-1,2,4-triazolo [1,5-c] pyrimidine (SCH442416) (F-18-FESCH and F-18-FPSCH, respectively) were developed as A(2A) receptor-specific PET ligands. Our aim was to determine an appropriate compartmental model for tracer kinetics, evaluate a reference tissue approach, and select the most suitable PET ligand. Methods: A 90-min dynamic PET scan with arterial blood sampling and metabolite analysis was acquired for 22 healthy male Wistar rats starting at the time of F-18-FESCH (n = 12) and F-18-FPSCH (n = 10) injection. For each tracer, half the animals were vehicle-treated whereas the other half were pretreated with the A(2A) receptor-selective antagonist KW-6002, inducing full blocking. Regional tissue total volume of distribution (V-T) was estimated by 1- and 2-tissue-compartment modeling (1TCM and 2TCM, respectively) and Logan graphical analysis. Midbrain, cerebellum, and hippocampus were evaluated as the reference region by comparing baseline V-T with V-T under full blocking conditions and comparing striatal nondisplaceable binding potential (BPND) using a simplified reference tissue model (SRTM) with distribution volume ratio minus 1 (DVR - 1) for 60- and 90-min scans. Results: On the basis of the Akaike information criterion, 1TCM and 2TCM were the most appropriate models for F-18-FPSCH (baseline striatal VT, 3.7 6 1.1) and F-18-FESCH (baseline striatal V-T, 5.0 6 2.0), respectively. Baseline striatal V-T did not significantly differ between tracers. After pretreatment, striatal V-T was reduced significantly, with no significant decrease in hippocampus, midbrain, or cerebellum V-T. Baseline striatal SRTM BPND did not differ significantly from DVR - 1 except for F-18-FPSCH when using a 60-min scan and midbrain as the reference region, whereas Bland-Altman analysis found a smaller bias for F-18-FESCH and a 60-min scan. After pretreatment, striatal SRTM BPND did not significantly differ from zero except for F-18-FPSCH when using hippocampus as the reference region. Striatal SRTM BPND using midbrain or cerebellum as the reference region was significantly lower for F-18-FPSCH (range, 1.41-2.62) than for F-18-FESCH (range, 1.64-3.36). Conclusion: Dynamic PET imaging under baseline and blocking conditions determined F-18-FESCH to be the most suitable PET ligand for quantifying A(2A) receptor expression in the rat brain. Accurate quantification is achieved by a 60-min dynamic PET scan and the use of either cerebellum or midbrain as the reference region.