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

The cerebral adenosine A receptor is an attractive therapeutic target for neuropsychiatric disorders. F-fluoroethyl and F-fluoropropyl analogs of F-labeled pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH442416) (F-FESCH and F-FPSCH, respectively) were developed as A 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. 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-FESCH ( = 12) and F-FPSCH ( = 10) injection. For each tracer, half the animals were vehicle-treated whereas the other half were pretreated with the A receptor-selective antagonist KW-6002, inducing full blocking. Regional tissue total volume of distribution (V) 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 with V under full blocking conditions and comparing striatal nondisplaceable binding potential (BP) using a simplified reference tissue model (SRTM) with distribution volume ratio minus 1 (DVR - 1) for 60- and 90-min scans. On the basis of the Akaike information criterion, 1TCM and 2TCM were the most appropriate models for F-FPSCH (baseline striatal V, 3.7 ± 1.1) and F-FESCH (baseline striatal V, 5.0 ± 2.0), respectively. Baseline striatal V did not significantly differ between tracers. After pretreatment, striatal V was reduced significantly, with no significant decrease in hippocampus, midbrain, or cerebellum V Baseline striatal SRTM BP did not differ significantly from DVR - 1 except for F-FPSCH when using a 60-min scan and midbrain as the reference region, whereas Bland-Altman analysis found a smaller bias for F-FESCH and a 60-min scan. After pretreatment, striatal SRTM BP did not significantly differ from zero except for F-FPSCH when using hippocampus as the reference region. Striatal SRTM BP using midbrain or cerebellum as the reference region was significantly lower for F-FPSCH (range, 1.41-2.62) than for F-FESCH (range, 1.64-3.36). Dynamic PET imaging under baseline and blocking conditions determined F-FESCH to be the most suitable PET ligand for quantifying A 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.