title: Preclinical Evaluation and Quantification of18F-Fluoroethyl and18F-Fluoropropyl Analogs of SCH442416 as Radioligands for PET Imaging of the Adenosine A2AReceptor in Rat Brain.
abstract: The cerebral adenosine A2Areceptor is an attractive therapeutic target for neuropsychiatric disorders.18F-fluoroethyl and18F-fluoropropyl analogs of18F-labeled pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH442416) (18F-FESCH and18F-FPSCH, respectively) were developed as A2Areceptor-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 of18F-FESCH (n= 12) and18F-FPSCH (n= 10) injection. For each tracer, half the animals were vehicle-treated whereas the other half were pretreated with the A2Areceptor-selective antagonist KW-6002, inducing full blocking. Regional tissue total volume of distribution (VT) 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 VTwith VTunder 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 for18F-FPSCH (baseline striatal VT, 3.7 ± 1.1) and18F-FESCH (baseline striatal VT, 5.0 ± 2.0), respectively. Baseline striatal VTdid not significantly differ between tracers. After pretreatment, striatal VTwas reduced significantly, with no significant decrease in hippocampus, midbrain, or cerebellum VTBaseline striatal SRTM BPNDdid not differ significantly from DVR - 1 except for18F-FPSCH when using a 60-min scan and midbrain as the reference region, whereas Bland-Altman analysis found a smaller bias for18F-FESCH and a 60-min scan. After pretreatment, striatal SRTM BPNDdid not significantly differ from zero except for18F-FPSCH when using hippocampus as the reference region. Striatal SRTM BPNDusing midbrain or cerebellum as the reference region was significantly lower for18F-FPSCH (range, 1.41-2.62) than for18F-FESCH (range, 1.64-3.36).Conclusion:Dynamic PET imaging under baseline and blocking conditions determined18F-FESCH to be the most suitable PET ligand for quantifying A2Areceptor 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.
authors: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and.
authors: Shivashankar
authors: S
authors: Khanapur
authors: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and.
authors: Aren
authors: A
authors: van Waarde
authors: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and.
authors: Rudi A J O
authors: RA
authors: Dierckx
authors: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and.
authors: Philip H
authors: PH
authors: Elsinga
authors: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and michel.koole@kuleuven.be.|Department of Nuclear Medicine and Molecular Imaging, KU Leuven, Leuven, Belgium.
authors: Michel J B
authors: MJ
authors: Koole
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D057054:Molecular Imaging / Q000379:methods; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods*; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D005462:Fluorine Radioisotopes; D011720:Pyrazoles; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D043705:Receptor, Adenosine A2A; C416650:SCH 442416
keywords: 18F-SCH442416 analogs; cerebral adenosine A2A receptor; kinetic analysis; preclinical positron emission tomography (μPET); rat brain