Adenosine A2A Receptor Occupancy by Caffeine After Coffee Intake in Parkinson's Disease.

BACKGROUND: Coffee intake can decrease the risk for Parkinson's disease (PD). Its beneficial effects are allegedly mediated by caffeine through adenosine A2A receptor (A2A R) antagonist action. OBJECTIVE: We aimed to calculate occupancy rates of striatal A2A Rs by caffeine after coffee intake in PD. METHODS: Five patients with PD underwent 11 C-preladenant positron emission tomography scanning at baseline and after intake of coffee containing 129.5 mg (n = 3) or 259 mg (n = 2) of caffeine. Concurrently, serum caffeine levels were measured. RESULTS: The mean serum caffeine level (µg/mL) was 0.374 at baseline and increased to 4.48 and 8.92 by 129.5 and 259 mg of caffeine, respectively. The mean occupancy rates of striatal A2A Rs by 129.5 and 259 mg of caffeine were 54.2% and 65.1%, respectively. CONCLUSIONS: A sufficient A2A R occupancy can be obtained by drinking a cup of coffee, which is equivalent to approximately 100 mg of caffeine. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Potential Therapeutic Applications of Adenosine A2A Receptor Ligands and Opportunities for A2A Receptor Imaging.

Adenosine A2A receptors (A2A Rs) are highly expressed in the human striatum, and at lower densities in the cerebral cortex, the hippocampus, and cells of the immune system. Antagonists of these receptors are potentially useful for the treatment of motor fluctuations, epilepsy, postischemic brain damage, or cognitive impairment, and for the control of an immune checkpoint during immunotherapy of cancer. A2A R agonists may suppress transplant rejection and graft-versus-host disease; be used to treat inflammatory disorders such as asthma, inflammatory bowel disease, and rheumatoid arthritis; be locally applied to promote wound healing and be employed in a strategy for transient opening of the blood-brain barrier (BBB) so that therapeutic drugs and monoclonal antibodies can enter the brain. Increasing A2A R signaling in adipose tissue is also a potential strategy to combat obesity. Several radioligands for positron emission tomography (PET) imaging of A2A Rs have been developed in recent years. This review article presents a critical overview of the potential therapeutic applications of A2A R ligands, the use of A2A R imaging in drug development, and opportunities and limitations of PET imaging in future research.

Adenosine A1 receptors measured with 11 C-MPDX PET in early Parkinson's disease.

Adenosine A1 receptors (A1 Rs) interact negatively with dopamine D1 receptors (D1 Rs) in neurons of the basal ganglia's direct pathway, while adenosine A2A receptors (A2A Rs) negatively interact with dopamine D2 receptors (D2 Rs) in indirect-pathway neurons. The aim of this study was to investigate the cerebral density of A1 Rs in Parkinson's disease (PD) in its early stages, using PET scans with the radioligand 8-dicyclopropylmethyl-1-11 C-methyl-3-propylxanthine (11 C-MPDX). We studied 10 drug-naïve patients with early PD. Each patient was also examined for dopamine transporters (DATs) and D2 Rs by PET using 11 C-2-ß-carbomethoxy-3-ß-(4-fluorophenyl)-tropane (11 C-CFT) and 11 C-raclopride (11 C-RAC), respectively. Ten elderly, healthy volunteers were recruited as controls for 11 C-MPDX PET scanning and eight elderly volunteers were recruited as controls for 11 C-CFT and 11 C-RAC PET scanning. The PET scans revealed a decrease in the uptake ratio index (URI) of 11 C-CFT and an increase in the URI of 11 C-RAC in patients. In the temporal lobe, the binding potential for 11 C-MPDX was higher in the patient group than in healthy subjects, but not in the other regions examined, including the striatum. In patients, we observed motor-symptom asymmetry and a relationship between parkinsonism and the striatal density of DATs, but not A1 R density. In the putamen of early PD, asymmetrical down-regulation of A2A Rs is likely a compensatory mechanism in response to a decrease in dopamine. However, our study suggests that A1 Rs are unaltered in the putamen of early PD.

Effects of exercise on brain activity during walking in older adults: a randomized controlled trial.

BACKGROUND: Physical activity may preserve neuronal plasticity, increase synapse formation, and cause the release of hormonal factors that promote neurogenesis and neuronal function. Previous studies have reported enhanced neurocognitive function following exercise training. However, the specific cortical regions activated during exercise training remain largely undefined. In this study, we quantitatively and objectively evaluated the effects of exercise on brain activity during walking in healthy older adults. METHODS: A total of 24 elderly women (75-83 years old) were randomly allocated to either an intervention group or a control group. Those in the intervention group attended 3 months of biweekly 90-min sessions focused on aerobic exercise, strength training, and physical therapy. We monitored changes in regional cerebral glucose metabolism during walking in both groups using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). RESULTS: All subjects completed the 3-month experiment and the adherence to the exercise program was 100%. Compared with the control group, the intervention group showed a significantly greater step length in the right foot after 3 months of physical activity. The FDG-PET assessment revealed a significant post-intervention increase in regional glucose metabolism in the left posterior entorhinal cortex, left superior temporal gyrus, and right superior temporopolar area in the intervention group. Interestingly, the control group showed a relative increase in regional glucose metabolism in the left premotor and supplemental motor areas, left and right somatosensory association cortex, and right primary visual cortex after the 3-month period. We found no significant differences in FDG uptake between the intervention and control groups before vs. after the intervention. CONCLUSION: Exercise training increased activity in specific brain regions, such as the precuneus and entorhinal cortices, which play an important role in episodic and spatial memory. Further investigation is required to confirm whether alterations in glucose metabolism within these regions during walking directly promote physical and cognitive performance. TRIAL REGISTRATION: UMIN-CTR ( UMIN000021829 ). Retrospectively registered 10 April 2016.

Central µ-Opioidergic System Activation Evoked by Heavy and Severe-Intensity Cycling Exercise in Humans: a Pilot Study Using Positron Emission Tomography with 11C-Carfentanil.

The central opioid receptor system likely contributes to the mechanism underlying the changes in affect elicited by exercise. Our aim was to use positron emission tomography (PET) to test whether exercise intensity influences activation of the µ-opioid receptor system in the brain, and whether changes in opioid receptor activation correlate with exercise-induced changes in affect. 7 healthy young male subjects (23±2 years) performed 20-min constant-load cycling exercises at heavy (ExH) and severe-intensity (ExS), and PET was performed using [11C]carfentanil as a tracer before and after each exercise. Exercise elicited the µ-opioidergic system activation in the large areas of the limbic system, particularly in the insular cortex, and cerebellum. Of note, deactivation of the µ-opioidergic system in the pituitary gland was identified as a specific finding in ExS, which evoked a distinctive sensation of fatigue. Within these brain areas, µ-opioid receptor activation correlated positively with increased positive affect (R2=0.67-0.95) in ExH and negative affect (R2=0.63-0.77) in ExS. These findings suggest that central µ-opioidergic neurotransmission evoked by continuous exercise is discriminated by work intensity. Notably, we also observed a possible contribution of the central µ-opioidergic system to the development of the sensation of fatigue during exhaustive exercise.

Potential applications for sigma receptor ligands in cancer diagnosis and therapy.

Sigma receptors (sigma-1 and sigma-2) represent two independent classes of proteins. Their endogenous ligands may include the hallucinogen N,N-dimethyltryptamine (DMT) and sphingolipid-derived amines which interact with sigma-1 receptors, besides steroid hormones (e.g., progesterone) which bind to both sigma receptor subpopulations. The sigma-1 receptor is a ligand-regulated molecular chaperone with various ion channels and G-protein-coupled membrane receptors as clients. The sigma-2 receptor was identified as the progesterone receptor membrane component 1 (PGRMC1). Although sigma receptors are over-expressed in tumors and up-regulated in rapidly dividing normal tissue, their ligands induce significant cell death only in tumor tissue. Sigma ligands may therefore be used to selectively eradicate tumors. Multiple mechanisms appear to underlie cell killing after administration of sigma ligands, and the signaling pathways are dependent both on the type of ligand and the type of tumor cell. Recent evidence suggests that the sigma-2 receptor is a potential tumor and serum biomarker for human lung cancer and an important target for inhibiting tumor invasion and cancer progression. Current radiochemical efforts are focused on the development of subtype-selective radioligands for positron emission tomography (PET) imaging. Right now, the mostpromising tracers are [18F]fluspidine and [18F]FTC-146 for sigma-1 receptors and [11C]RHM-1 and [18F]ISO-1 for the sigma-2 subtype. Nanoparticles coupled to sigma ligands have shown considerable potential for targeted delivery of antitumor drugs in animal models of cancer, but clinical studies exploring this strategy in cancer patients have not yet been reported. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

Alteration of the regional cerebral glucose metabolism in healthy subjects by glucose loading.

High plasma glucose (PG) levels can reduce fluorine-18-labeled fluorodeoxyglucose ((18) F-FDG) uptake, especially in the Alzheimer's disease (AD)-related regions. This fact is supported by studies showing that the resting-state activity in diabetes can be altered in the default mode network (DMN)-related regions, which considerably overlap with the AD-related regions. In order to expand the current knowledge, we aimed to investigate the relationship between increasing PG levels and the regional cerebral metabolic rates for glucose (CMRglc ) as a direct index of brain activity. We performed dynamic (18) F-FDG positron emission tomography with arterial blood sampling once each in the fasting and glucose-loading conditions on 12 young, healthy volunteers without cognitive impairment or insulin resistance. The absolute CMRglc values were calculated for the volume-of-interest (VOI) analysis, and normalized CMRglc maps were generated for the voxelwise analysis. The normalized measurement is known to have smaller intersubject variability than the absolute measurement, and may, thus, lead to greater statistical power. In VOI analysis, no regional difference in the CMRglc was found between the two conditions. In exploratory voxelwise analysis, however, significant clusters were identified in the precuneus, posterior cingulate, lateral parietotemporal, and medial prefrontal regions where the CMRglc decreased upon glucose loading (P < 0.05, corrected). These regions include the representative components of both the DMN and AD pathology. Taken together with the previous knowledge on the relationships between the DMN, AD, and diabetes, it may be inferred that glucose loading induces hypometabolism in the AD-related and DMN-related regions. Hum Brain Mapp 37:2823-2832, 2016. © 2016 Wiley Periodicals, Inc.

Cerebral Functional Response during Eyelid Opening/Closing with Bell's Phenomenon and Volitional Vertical Eye Movements in Humans.

Bell's phenomenon is a physiological phenomenon wherein the eye ball involuntarily rolls upward during eyelid closing. Although this phenomenon occurs in healthy individuals, the neural mechanism related to Bell's phenomenon has not yet been identified. We aimed to investigate the brain regions relevant to Bell's phenomenon and volitional eye movement using [15O] H2O and positron emission tomography (PET). We measured regional cerebral blood flow (rCBF) in 8 normal subjects under 3 conditions: at rest with eyes closed, during opening and closing of the eyelids in response to sound stimuli (lid opening/closing), and during vertical movement of the eyes with lids closed in response to sound stimuli (volitional eye movement). The supplementary motor area (SMA) proper, right superior temporal gyrus, right insular cortex and left angular gyrus were activated during lid opening/closing. The right frontal eye field (FEF), pre-SMA, left primary motor area, right angular gyrus, and SMA proper were activated during volitional eye movement. The SMA proper was active during both tasks, while the FEF and pre-SMA were active during volitional eye movement, but not during eyelid opening/closing. A comparison of activation during volitional eye movements and lid opening/closing tasks revealed a relative increase in rCBF in the FEF. There were no areas that are activated in relation to Bell's phenomenon. In conclusion, activation in the FEF mainly occurs during volitional eye movement. Since Bell's phenomenon is a reflexive eye movement, the FEF is scarcely concerned in Bell's phenomenon.

Radiosynthesis and preliminary biological evaluation of a new (18)F-labeled triethylene glycol derivative of triphenylphosphonium.

Delocalized lipophilic cations such as [(18)F]fluorobenzyltriphenylphosphonium ([(18)F]FBnTP) can accumulate in mitochondria and have been used in myocardial perfusion imaging (MPI). In this study, we established a simplified method for [(18)F]FBnTP synthesis using triphenylphosphine hydrobromide (PPh3 •HBr) without preparing an intermediate that contains benzyl bromide structure. Applying this new method, we synthesized and evaluated a novel (18)F-labeled PEGylated BnTP derivative ([(18)F]FPEGBnTP). In vitro cellular uptake study demonstrated that [(18)F]FPEGBnTP accumulated in cells in proportion to the relative intensity of mitochondrial membrane potential. Biodistribution study revealed that the heart : liver uptake ratio of [(18)F]FPEGBnTP (4.00 at 60 min) was superior to that of [(18)F]FBnTP (1.50 at 60 min). However, [(18)F]FPEGBnTP showed slow blood clearance and high radioactivity uptake in bone at 120-min post-injection. These results imply the possibility of [(18)F]FPEGBnTP being used as a MPI agent. However, there is a need of further structural optimization and flow-dependent uptake study.

Evaluation of [(11)C]CB184 for imaging and quantification of TSPO overexpression in a rat model of herpes encephalitis.

PURPOSE: Evaluation of translocator protein (TSPO) overexpression is considered an attractive research tool for monitoring neuroinflammation in several neurological and psychiatric disorders. [(11)C]PK11195 PET imaging has been widely used for this purpose. However, it has a low sensitivity and a poor signal-to-noise ratio. For these reasons, [(11)C]CB184 was evaluated as a potentially more sensitive PET tracer. METHODS: A model of herpes simplex encephalitis (HSE) was induced in male Wistar rats. On day 6 or 7 after virus inoculation, [(11)C]CB184 PET scans were acquired followed by ex vivo evaluation of biodistribution. In addition, [(11)C]CB184 and [(11)C]PK11195 PET scans with arterial blood sampling were acquired to generate input for pharmacokinetic modelling. Differences between the saline-treated control group and the virus-treated HSE group were explored using volumes of interest and voxel-based analysis. RESULTS: The biodistribution study showed significantly higher [(11)C]CB184 uptake in the amygdala, olfactory bulb, medulla, pons and striatum (p < 0.05) in HSE rats than in control rats, and the voxel-based analysis showed higher bilateral uptake in the pons and medulla (p < 0.05, corrected at the cluster level). A high correlation was found between tracer uptake in the biodistribution study and on the PET scans (p < 0.001, r (2) = 0.71). Pretreatment with 5 mg/kg of unlabelled PK11195 effectively reduced (p < 0.001) [(11)C]CB184 uptake in the whole brain. Both, [(11)C]CB184 and [(11)C]PK11195, showed similar amounts of metabolites in plasma, and the binding potential (BPND) was not significantly different between the HSE rats and the control rats. In HSE rats BPND for [(11)C]CB184 was significantly higher (p < 0.05) in the amygdala, hypothalamus, medulla, pons and septum than in control rats, whereas higher uptake of [(11)C]PK11195 was only detected in the medulla. CONCLUSION: [(11)C]CB184 showed nonspecific binding to healthy tissue comparable to that observed for [(11)C]PK11195, but it displayed significantly higher specific binding in those brain regions affected by the HSE. Our results suggest that [(11)C]CB184 PET is a good alternative for imaging of neuroinflammatory processes.

Cerebral glucose metabolism in the striate cortex positively correlates with fractional anisotropy values of the optic radiation in patients with glaucoma.

BACKGROUND: It has recently become clear that glaucoma is not only an ocular disease, but involves central visual pathways as well. The purpose of this study was to examine functional and structural alterations in the brains of glaucoma patients. DESIGN: Case-control study in a hospital. PARTICIPANTS: A total of 32 glaucoma patients and 19 healthy controls. METHODS: All participants underwent positron emission tomography with (18)F-fluorodeoxyglucose, diffusion-tensor magnetic resonance imaging, and the 30-2 program of the Humphrey Visual Field Analyzer. MAIN OUTCOME MEASURES: Fractional anisotropy values of the optic radiation were compared between the two groups by defining regions of interests. Cerebral glucose metabolism was compared using statistical parametric mapping software. The correlation coefficients were calculated between the average of the total deviation of hemivisual fields of both eyes, fractional anisotropy values of the contralateral optic radiation and glucose metabolism in the contralateral striate cortex. RESULTS: Fractional anisotropy values in the bilateral optic radiations were significantly lower in patients with glaucoma. A significant glucose hypometabolism in the bilateral striate cortex was also observed in the glaucoma group. Regression analyses for glaucoma patients demonstrated that the average of the total deviation of hemivisual fields significantly correlated with both fractional anisotropy value of the contralateral optic radiation and glucose metabolism in the contralateral striate cortex. Moreover, there were significant correlations between fractional anisotropy values of the optic radiation and ipsilateral striatal glucose metabolism. CONCLUSION: We observed structural alterations in the bilateral optic radiations and glucose hypometabolism in the bilateral striate cortex of glaucoma patients.

Cerebral adenosine A1 receptors are upregulated in rodent encephalitis.

Adenosine A1 receptors (A1Rs) are implied in the modulation of neuroinflammation. Activation of cerebral A1Rs acts as a brake on the microglial response after traumatic brain injury and has neuroprotective properties in animal models of Parkinson's disease and multiple sclerosis. Neuroinflammatory processes in turn may affect the expression of A1Rs, but the available data is limited and inconsistent. Here, we applied an animal model of encephalitis to assess how neuroinflammation affects the expression of A1Rs. Two groups of animals were studied: Infected rats (n=7) were intranasally inoculated with herpes simplex virus-1 (HSV-1, 1 × 10(7) plaque forming units), sham-infected rats (n=6) received only phosphate-buffered saline. Six or seven days later, microPET scans (60 min with arterial blood sampling) were made using the tracer 8-dicyclopropyl-1-(11)C-methyl-3-propyl-xanthine ((11)C-MPDX). Tracer clearance from plasma and partition coefficient (K1/k2 estimated from a 2-tissue compartment model fit) were not significantly altered after virus infection. PET tracer distribution volume calculated from a Logan plot was significantly increased in the hippocampus (+37%) and medulla (+27%) of virus infected rats. Tracer binding potential (k3/k4 estimated from the model fit) was significantly increased in the cerebellum (+87%) and the medulla (+148%) which may indicate increased A1R expression. This was confirmed by immunohistochemical analysis showing a strong increase of A1R immunoreactivity in the cerebellum of HSV-1-infected rats. Both the quantitative PET data and immunohistochemical analysis indicate that A1Rs are upregulated in brain areas where active virus is present.

Regional analysis of striatal and cortical amyloid deposition in patients with Alzheimer's disease.

We aimed to analyse the detailed distribution pattern of amyloid-ß (Aß) in the striatum, and to examine whether there is any correlation between Aß deposition levels in the striatum and cortical regions. Twenty patients with Alzheimer's disease underwent positron emission tomography using (11) C-Pittsburgh Compound B ((11) C-PiB) to quantify the Aß deposition. Volumes-of-interest analyses were performed on the ventral striatum (VST), pre-commissural dorsal caudate (pre-DCA), post-commissural caudate (post-CA), pre-commissural dorsal putamen (pre-DPU), and post-commissural putamen (post-PU), followed by exploratory voxel-wise analyses. Volumes-of-interest analyses of (11) C-PiB binding showed: VST > pre-DPU (P = 0.004), VST > pre-DCA (P < 0.0001), pre-DPU > post-PU (P < 0.0001), and pre-DCA > post-CA (P < 0.0001), consistent with visual inspection of the (11) C-PiB images. Exploratory voxel-wise analyses of (11) C-PiB binding showed a positive correlation between the VST and the medial part of the orbitofrontal area (P < 0.01 family-wise error corrected). This study confirmed that there were ventral > dorsal, and anterior > posterior gradients of Aß deposition in patients with Alzheimer's disease, and provided the first evidence of a robust correlation between Aß deposition levels in the VST and the medial part of the orbitofrontal area. There are well-known anatomical and functional links between these areas. These findings indicated that brain Aß deposition was not randomly distributed, but had characteristic patterns related to anatomical connectivity and/or functional networks.

Glucose hypermetabolism in the thalamus of patients with hemifacial spasm.

The purpose of this study was investigate functional alteration in the brains of patients with hemifacial spasm using positron emission tomography (PET). We studied cerebral glucose metabolism using PET with (18) F-fluorodeoxyglucose in 13 patients with right lateral hemifacial spasm and 13 with left lateral hemifacial spasm. All patients underwent 2 PET scans before treatment (active state) and after treatment (suppressive state) with the botulinum neurotoxin type A. At the time of the PET scans, the severity of the spasm was rated according to the Jankovic Disability Rating Scale. We also used magnetic resonance imaging to evaluate the grade of neurovascular compression in each patient using scores of 1 to 3 (1 = mild, 3 = severe). Fifty-two normal volunteers were examined as controls. Compared with controls, patients with right and left hemifacial spasm showed bilateral cerebral glucose hypermetabolism in the thalamus in both the active and suppressive states. However, thalamic glucose metabolism after the suppressive state was significantly reduced compared with that in the active state using region of interest analysis. There was a positive correlation between the severity of the spasm in the active state and the score of neurovascular compression (rs = 0.65) that was estimated using Spearman order correlation coefficient. We observed bilateral cerebral glucose hypermetabolism in the thalamus of patients with hemifacial spasm. The thalamic glucose hypermetabolism may be attributed to multiple sources, including afferent input from the skin and muscle spindle, antidromic conduction of the facial nerve, and secondary alteration in the central nervous system.

Differential effects of age on human striatal adenosine A1 and A(2A) receptors.

The aim of this study was to investigate the effect of age on the distribution of adenosine A1 receptors (A1Rs) and adenosine A(2A) receptors (A(2A)Rs) in the striatum of healthy subjects using PET imaging with 8-dicyclopropylmethyl-1-[¹¹C]methyl-3-propylxanthine ([¹¹C]MPDX) and [7-methyl-¹¹C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([¹¹C]TMSX), respectively. We recruited 8 young (22.0 ± 1.7 years) and 10 elderly (65.4 ± 7.6 years) volunteers to undergo [¹¹C]MPDX PET scanning, and 11 young (22.7 ± 2.7 years) and six elderly (60.7 ± 8.5 years) volunteers to undergo [¹¹C]TMSX PET scanning. A dynamic series of decay-corrected PET scans was performed for 60 min following injection of [¹¹C]MPDX or [¹¹C]TMSX. We calculated the binding potential (BP(ND) ) of [¹¹C]MPDX and distribution volume ratio (DVR) of [¹¹C]TMSX in the striatum. The BP(ND) of [¹¹C]MPDX was significantly lower in elderly than in young subjects, both in the putamen and head of the caudate nucleus. The BP(ND) was negatively correlated with age in both the putamen and the head of the caudate nucleus. However, no difference was found between the DVR of [¹¹C]TMSX in the striata of young and elderly subjects, nor was there a correlation between age and the DVR of [¹¹C]TMSX. The effect of age on the distribution of A1Rs in the human striatum described herein is similar to previous reports of age-related decreases in dopamine D1 and D2 receptors. Unlike A1Rs, however, this study suggests that the distribution of A(2A) Rs does not change with age.

[18F]FDG uptake in axillary lymph nodes and deltoid muscle after COVID-19 mRNA vaccination: a cohort study to determine incidence and contributing factors using a multivariate analysis.

PURPOSE: Reactive FDG uptake in the axillary lymph nodes (ALN) and deltoid muscle (DM) after COVID-19 mRNA vaccination has been recognized, although the actual situation in the Japanese population remains unknown. To determine the incidence of reactive FDG uptake and its contributing factors, we retrospectively studied a cohort of subjects who were vaccinated at our hospital. METHODS: Whole-body FDG-PET/CT examinations performed in 237 subjects out of 240 subjects with a definite history of COVID-19 vaccination (BNT162b2; BioNTech-Pfizer) were analyzed. Positivity and SUVmax of FDG uptake in the ALN and DM ipsilateral to vaccination, various subject characteristics, and the grade of the pathological FDG-PET/CT findings were evaluated using a multivariate analysis. RESULTS: FDG uptake in the ALN and DM ipsilateral to vaccination was seen in about 60% of the subjects even soon (0-4 days) after the first vaccination, with percentages reaching 87.5% and 75.0%, respectively, after the second vaccination. DM uptake had almost disappeared at around 2 weeks, while ALN uptake persisted for 3 weeks or longer. A multivariate analysis showed that a short duration since vaccination, a younger age, a female sex, and a low FDG-PET/CT grade (minimal pathological FDG uptake) contributed significantly to positive ALN uptake, while a short duration since vaccination and a female sex were the only significant contributors to positive DM uptake. This study is the first to identify factors contributing to positive FDG uptake in ALN and DM after COVID-19 vaccination. CONCLUSION: A high incidence of FDG uptake in ALN and DM was observed after vaccination. ALN uptake seemed to be associated with a younger age, a female sex, and minimal pathological FDG uptake. After vaccination, an acute inflammatory reaction in DM followed by immune reaction in ALN linked to humoral immunity may be speculated.

Test-retest reproducibility of cerebral adenosine A2A receptor quantification using [11C]preladenant.

OBJECTIVE: To evaluate the reproducibility of cerebral adenosine A2A receptor (A2AR) quantification using [11C]preladenant ([11C]PLN) and PET in a test-retest study. METHODS: Eight healthy male volunteers were enrolled. Dynamic 90 min PET scans were performed twice at the same time of the day to avoid the effect of diurnal variation. Subjects refrained from caffeine from 12 h prior to scanning, and serum caffeine was measured before radioligand injection. Arterial blood was sampled repeatedly during scanning and the fraction of the parent compound in plasma was determined. Total distribution volume (VT) was estimated using 1- and 2-tissue compartment models (1-TCM and 2-TCM, respectively) and Logan graphical analysis (Logan plot) (t* = 30 min). Plasma-free fraction (fP) of [11C]PLN was measured and used for correction of VT values. Distribution volume ratio (DVR) was calculated from VT of target and reference regions and obtained by noninvasive Logan graphical reference tissue model (LGAR) (t* = 30 min). Absolute test-retest variability (aTRV), and intra-class correlation coefficient (ICC) of VT and DVR were calculated as indexes of repeatability. Correlation between DVR and serum concentration of caffeine (a nonselective A2AR blocker) was analyzed by Pearson's correlation analysis. RESULTS: Regional time-activity curves were well described by 2-TCM models. Estimation of VT by 2-TCM produced some erroneous values; therefore, the more robust Logan plot was selected as the appropriate model. Global mean aTRV was 20% for VT and 14% for VT/fP (ICC, 0.72 for VT and 0.87 for VT/fP). Global mean aTRV of DVR was 13% for Logan plot and 10% for LGAR (ICC, 0.70 for Logan plot and 0.81 for LGAR). DVR estimates using LGAR and Logan plot were in good agreement (r2 = 0.96). Coefficients of variation for VT, VT/fP, DVR (Logan plot), and DVR (LGAR) were 47%, 47%, 27%, and 18%, respectively. Despite low serum caffeine levels, significant concentration-dependent effects on [11C]PLN binding to target regions were observed (p < 0.01). CONCLUSIONS: In this study, moderate test-retest reproducibility and large inter-subject differences were observed with [11C]PLN PET, possibly attributable to competition by baseline amount of caffeine. Analysis of plasma caffeine concentration is recommended during [11C]PLN PET studies. TRIAL REGISTRATION: UMIN000030040.

¹¹C-labeled analogs of indomethacin esters and amides for brain cyclooxygenase-2 imaging: radiosynthesis, in vitro evaluation and in vivo characteristics in mice.

There is great potential in the use of positron emission tomography (PET) and suitable radiotracers for the study of cyclooxygenase type 2 (COX-2) enzyme in living subjects. In the present study, we prepared and evaluated five ¹¹C-labeled ester and amide analogs derived from indomethacin as potential PET imaging agents for the in vivo visualization of the brain COX-2 enzyme. Five ¹¹C-labeled COX-2 inhibitors, with different lipophilicities and moderate COX-2 inhibitory activity, were prepared by treatment of the corresponding O-desmethyl precursors with [¹¹C]methyl triflate and purified by HPLC (radiochemical yields of 55-71%, radiochemical purity of >93%, and the specific activities of 22-331 GBq/µmol). In mice, radioactivity in the brain for all radiotracers was low, with very low brain-to-blood ratios. A clear inverse relationship was observed between brain uptake at 1 min postinjection and the lipophilicity (experimental log P7.4) of the studied ¹¹C-radiotracers. Pretreatment of mice with cyclosporine A to block P-glycoproteins caused a significant increase in brain uptake of radioactivity following injection of the ¹¹C-radiotracer compared to control. HPLC analysis showed that each radiotracer was rapidly metabolized, and a few metabolites, which were more polar than the original radiotracers, were found in both plasma and brain. No specific binding of the tracers towards the COX-2 enzyme in the brain was clearly revealed by in vivo blocking study. Further structural refinement of the tracer agent is necessary for better enhancement of brain uptake and for sufficient metabolic stability.

Validation of cardiac (123)I-MIBG scintigraphy in patients with Parkinson's disease who were diagnosed with dopamine PET.

PURPOSE: The aim of this study was to evaluate the diagnostic potential of cardiac (123)I-labelled metaiodobenzylguanidine ((123)I-MIBG) scintigraphy in idiopathic Parkinson's disease (PD). The diagnosis was confirmed by positron emission tomography (PET) imaging with (11)C-labelled 2beta-carbomethoxy-3beta-(4-fluorophenyl)-tropane ((11)C-CFT) and (11)C-raclopride (together designated as dopamine PET). METHODS: Cardiac (123)I-MIBG scintigraphy and dopamine PET were performed for 39 parkinsonian patients. To estimate the cardiac (123)I-MIBG uptake, heart to mediastinum (H/M) ratios in early and delayed images were calculated. On the basis of established clinical criteria and our dopamine PET findings, 24 patients were classified into the PD group and 15 into the non-PD (NPD) group. RESULTS: Both early and delayed images showed that the H/M ratios were significantly lower in the PD group than in the NPD group. When the optimal cut-off levels of the H/M ratio were set at 1.95 and 1.60 in the early and delayed images, respectively, by receiver-operating characteristic analysis, the sensitivity of cardiac (123)I-MIBG scintigraphy for the diagnosis of PD was 79.2 and 70.8% and the specificity was 93.3 and 93.3% in the early and delayed images, respectively. In the Hoehn and Yahr 1 and 2 PD patients, the sensitivity decreased by 69.2 and 53.8% in the early and delayed images, respectively. CONCLUSION: In early PD cases, cardiac (123)I-MIBG scintigraphy is of limited value in the diagnosis, because of its relatively lower sensitivity. However, because of its high specificity for the overall cases, cardiac (123)I-MIBG scintigraphy may assist in the diagnosis of PD in a complementary role with the dopaminergic neuroimaging.