Increased Binding Potential of Brain Adenosine A₁Receptor in Chronic Stages of Patients with Diffuse Axonal Injury Measured with [1-methyl-¹¹C] 8-dicyclopropylmethyl-1-methyl-3-propylxanthine Positron Emission Tomography Imaging

Abstract

The positron emission tomography (PET) radioligand for adenosine A receptor (A1R) [1-methyl-C] 8-dicyclopropylmethyl-1-methyl-3-propylxanthine (MPDX) has recently been developed for human brain imaging. In the present study, we evaluated the alteration of the A1R in patients with diffuse axonal injury (DAI) in chronic stage in vivo. Ten patients with DAI (7 men and 3 women) were included in this study. Three PET examinations were sequentially performed to measure A1R binding with C-MPDX, glucose metabolism withF-fluorodeoxyglucose (FDG), and central benzodiazepine receptor binding with C-flumazenil (FMZ), and decreases ofC-FMZ uptake indicate neuronal loss. C- MPDX did not depict any lesion with significantly decreased nondisplaceable binding potential (BP) in comparison to healthy controls (14 men) in region of interest (ROI) analysis. Instead, it showed a significant increase of BP in the lower frontal and posterior cingulate cortexes and rolandic area (p < 0.05) in ROI analysis. In F-FDG PET, the standardized uptake values (SUVs) ratio to the whole brain were decreased in anterior and posterior cingulate gyrus compared to controls (14 men and 9 women; p< 0.01). In C-FMZ PET, the SUV ratio to the cerebellum was decreased in anterior cingulate gyrus in ROI analysis (controls, 9 men and 6 women; p< 0.01). The area with significantly increased C-MPDX binding, lower frontal cortex, rolandic area, and posterior cingulate gyrus, did not overlap with the areas of neuronal loss detected by decreasedC-FMZ binding and did not completely overlap with area of reducedF-FDG uptake. We obtained the first C-MPDX PET images reflecting the A1R BP in human DAI brain in vivo. C-MPDX depicted increased A1R BP in the areas surrounding the injured brain, whereas F-FDG demonstrated reduction throughout the brain. The results suggested that A1R might continuously confer neuroprotective or neuromodulatory effects in DAI even in the chronic stage.

Chemical Probes for the Adenosine Receptors

“…One of the most studied derivatives is xanthine derivative [1-methyl- 11 C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine ( 11 C-MPDX, 2). This compound has been utilized for various studies [26][27][28]. For example, Paul and coworkers performed in vivo binding studies in rats hypothesizing that agonists and antagonists may bind in different sites at the A 1 receptor [26].…”

“…For example, Paul and coworkers performed in vivo binding studies in rats hypothesizing that agonists and antagonists may bind in different sites at the A 1 receptor [26]. The same derivative was also utilized to evaluate A 1 AR alterations in patients with chronic diffuse axonal injury [27] or to investigate the density of A 1 ARs in patients with early-stage Parkinson's disease [28].…”

Purinergic Receptors of the Central Nervous System: Biology, PET Ligands, and Their Applications

“…The first PET radiotracer was developed by 11 C radiolabeling of the xanthene-derived A 1 R antagonist KF15372, [ 11 C]KF15372, and showed a specific and reversible brain uptake but an unacceptable high fraction of nonspecific binding that limited its use in preclinical evaluation of the A 1 R. 83,84 [ 11 C]MPDX, another analog of A 1 R antagonist KF15372, was developed to measure regional A 1 R densities in the brain of rodent and in patients with diffuse axonal injury, a model for TBI. 85 It detected an increase in A 1 R expression in areas surrounding the injuries in the brain, emphasizing on neuroprotective and neuromodulatory effects of A 1 R in TBI. 85 Moreover, [ 11 C]MPDX was also used to investigate the cerebral density of A 1 Rs in early stages of PD and showed a higher binding potential in the temporal lobe of the patients with PD compared to the healthy controls.…”

“…85 It detected an increase in A 1 R expression in areas surrounding the injuries in the brain, emphasizing on neuroprotective and neuromodulatory effects of A 1 R in TBI. 85 Moreover, [ 11 C]MPDX was also used to investigate the cerebral density of A 1 Rs in early stages of PD and showed a higher binding potential in the temporal lobe of the patients with PD compared to the healthy controls. 86 Similarly, [ 11 C]MPDX was used for mapping of the A 1 Rs in the brain of aged human compared to the young subjects and showed a significantly lower BP ND in the frontal, temporal, occipital, parietal cortices, and thalamus of aged subjects.…”

“…84 Despite this fact, [ 18 F]CPFPX has been used for imaging of A 1 Rs in the human brain 93 and is currently a standard PET radioligand for evaluation of the A 1 R density in CNS disorders such as sleep-wake research. 84,[94][95][96] In order to improve metabolic stability inherent in [ 18 88 Despite stated limitations, these tracers 85 have presented promising imaging tools for mapping of A 1 R in the brain 86,87,96 . A list of all aforementioned A 1 R PET radioligands is presented in Table 1.…”