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Purpose: (18)F-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ((18)F-CPFPX) is a potent radioligand to study human cerebral A(1) adenosine receptors and their neuromodulatory and neuroprotective functions with positron emission tomography (PET). The purpose of this study was to determine the biodistribution and the radiation dose of (18)F-CPFPX by whole-body scans in humans., Methods: Six normal volunteers were examined with 12 whole-body PET scans from 1.5 min to 4.5 h after injection. Volumes of interest were defined over all visually identifiable organs, i.e. liver, gallbladder, kidneys, small intestines, heart, and brain to obtain the organs' volumes and time-activity curves (TACs). TACs were fitted with exponential functions, extrapolated, multiplied with the physical decay and normalized to injected activities so that the residence times could be computed as area under the curve. Radiation doses were calculated using the OLINDA/EXM software for internal dose assessment in nuclear medicine., Results: The liver uptake shows peak values (decay-corrected) of up to 35% of the injected radioactivity. About 30% is eliminated by bladder voiding. The highest radiation dose is received by the gallbladder (136.2 +/- 66.1 muSv/MBq), followed by the liver (84.4 +/- 10.6 muSv/MBq) and the urinary bladder (78.3 +/- 7.1 muSv/MBq). The effective dose was 17.6 +/- 0.5 muSv/MBq., Conclusions: With 300 MBq of injected (18)F-CPFPX a subject receives an effective dose (ICRP 60) of 5.3 mSv. Thus the effective dose of an (18)F-CPFPX study is comparable to that of other (18)F-labelled neuroreceptor ligands.

Cerebral A(1) adenosine receptors (A(1)AR) fulfill important neuromodulatory and homeostatic functions. The present study examines possible age-related A(1)AR changes in living humans by positron emission tomography (PET) and the A(1)AR ligand [(18)F]CPFPX. Thirty-six healthy volunteers aged 22-74 years were included. The apparent binding potential (BP'2) of [(18)F]CPFPX in various cerebral regions was calculated non-invasively using the cerebellum as reference region. In addition, the total distribution volume (DV't) was assessed in 10 subjects undergoing arterial blood sampling. There was no significant association between regional DV't and age, gender, caffeine consumption or sleep duration. BP'2 showed a significant age-dependent decrease in all regions except cingulate gyrus (p=0.062). The BP'2 decline ranged from -17% (striatum) to -34% (postcentral gyrus), the average cortical decline being -23%. There was no significant effect of gender, caffeine consumption and sleep duration on BP'2. In line with in vitro animal studies, the present in vivo PET study detected an age-dependent A(1)AR loss in humans that may be of pathophysiological importance in various neurological diseases associated with aging. Because of the discrepant results of the invasive (DV't) and the non-invasive (BP'2) analyses the present study needs further validation.

Background: Imaging of cerebral A(1) adenosine receptors (A(1)AR) with positron emission tomography (PET) has recently become available for neurological research. To date, it has still not been unraveled if there is a valid reference region without specific radioligand binding that may be used to improve image quantification. We conducted in vivo displacement studies in humans to elucidate this important question using the A(1)AR ligand [(18)F]CPFPX., Methods: Five healthy male volunteers underwent [(18)F]CPFPX bolus/infusion PET with short infusion of unlabelled CPFPX as competitor (n = 4; 0.9 to 4.0 mg) or vehicle (n = 1; control condition) after equilibrium of [(18)F]CPFPX distribution was attained., Results: Infusion of CPFPX induced a rapid displacement of [(18)F]CPFPX binding in all regions, including the cerebellum (region with lowest binding). Even at the highest competitor dose, no full displacement was reached. Displacement was dose-dependent in all regions except the cerebellum where floor effects and/or noise might have obscured dose dependency. Specific binding was estimated to account for about one third and two thirds of total equilibrium uptake in cerebellum and cortex, respectively., Conclusions: Although the cerebellum is the region with lowest in vivo [(18)F]CPFPX binding, it is not an ideal reference region devoid of specific binding. Nevertheless, as will be discussed, the use of a reference region analysis may be a useful, non-invasive alternative analysis method in carefully selected applications.

Unlabelled: 8-cyclopentyl-3-(3-18F-fluoropropyl)-1-propylxanthine (18F-CPFPX) is a novel PET ligand for in vivo quantification of cerebral A1 adenosine receptors. The present study investigated the applicability of voxelwise graphical analysis to the generation of parametric images of the total volume of distribution (DVt) of 18F-CPFPX as a prerequisite for voxel-by-voxel statistical analysis. The benefit of spatial smoothing for reduction of noise-dependent negative bias in graphical analysis was examined. Additionally, the effect of scan duration on the accuracy of analyses based on volumes of interest (VOIs) and individual voxels was explored., Methods: Ten healthy male volunteers underwent bolus-injection 18F-CPFPX PET (90 min). The data were analyzed using a 2-tissue-compartment model and graphical analysis. Voxelwise graphical analysis was performed with and without preceding spatial gaussian smoothing., Results: Voxelwise graphical analysis yielded high-quality parametric images. However, voxelwise graphical analysis suffered from a negative bias (mean bias in cortical regions, -9.6% to -7.5%), which could be attenuated considerably by spatial smoothing (using a kernel of 5 mm in full width at half maximum, bias of -4.0% to -1.9%). Shortening the total scan duration to 60 min had minor effects on the accuracy of VOI-based analysis (15 VOIs x 10 subjects); the resulting error only occasionally exceeded +/-5% in individual regions (n = 6 for 2-tissue-compartment model, n = 10 for VOI-based graphical analysis, always within +/-7.5%). Quantification accuracy was acceptable with scan durations of 60 and 75 min in voxelwise graphical analysis with spatial smoothing (mean bias in cortical regions, -8.4% to -5.9%) and without spatial smoothing (bias, -9.2% to -11.6%), respectively., Conclusion: High-quality DVt parametric images of 18F-CPFPX can be generated by voxelwise graphical analysis. The noise-dependent negative bias of voxelwise graphical analysis is greatly reduced by spatial smoothing. A shortened scan of 60 min will enhance the clinical applicability of 18F-CPFPX PET.