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

摘要

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.