Muneyuki Sakata

High Occupancy of Sigma-1 Receptors in the Human Brain after Single Oral Administration of Fluvoxamine: A Positron Emission Tomography Study Using [11C]SA4503

BACKGROUND Sigma-1 receptors might be implicated in the pathophysiology of psychiatric diseases, as well as in the mechanisms of action of some selective serotonin reuptake inhibitors (SSRIs). Among the several SSRIs, fluvoxamine has the highest affinity for sigma-1 receptors (Ki = 36 nM), whereas paroxetine shows low affinity (Ki = 1893 nM). The present study was undertaken to examine whether fluvoxamine binds to sigma-1 receptors in living human brain. METHODS A dynamic positron emission tomography (PET) data acquisition using the selective sigma-1 receptor ligand [(11)C]SA4503 was performed with arterial blood sampling to evaluate quantitatively the binding of [(11)C]SA4503 to sigma-1 receptors in 15 healthy male volunteers. Each subject had two PET scans before and after randomly receiving a single dose of either fluvoxamine (50, 100, 150, or 200 mg) or paroxetine (20 mg). The binding potential of [(11)C]SA4503 in 9 regions of the brain was calculated by a 2-tissue 3-compartment model. In addition, we examined the effects of functional polymorphisms of the sigma-1 receptor (SIGMAR1) gene on the binding potential of [(11)C]SA4503. RESULTS Fluvoxamine bound to sigma-1 receptors in all brain regions in a dose-dependent manner, whereas paroxetine did not bind to sigma-1 receptors. However, there was no association between the SIGMAR1 gene polymorphism GC-241-240TT and binding potential. CONCLUSIONS The study demonstrated that fluvoxamine bound to sigma-1 receptors in living human brain at therapeutic doses. These findings suggest that sigma-1 receptors may play an important role in the mechanism of action of fluvoxamine.

Adenosine A2A Receptors Measured with [11C]TMSX PET in the Striata of Parkinson's Disease Patients

Adenosine A2A receptors (A2ARs) are thought to interact negatively with the dopamine D2 receptor (D2R), so selective A2AR antagonists have attracted attention as novel treatments for Parkinsons disease (PD). However, no information about the receptor in living patients with PD is available. The purpose of this study was to investigate the relationship between A2ARs and the dopaminergic system in the striata of drug-naïve PD patients and PD patients with dyskinesia, and alteration of these receptors after antiparkinsonian therapy. We measured binding ability of striatal A2ARs using positron emission tomography (PET) with [7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([11C]TMSX) in nine drug-naïve patients with PD, seven PD patients with mild dyskinesia and six elderly control subjects using PET. The patients and eight normal control subjects were also examined for binding ability of dopamine transporters and D2Rs. Seven of the drug-naïve patients underwent a second series of PET scans following therapy. We found that the distribution volume ratio of A2ARs in the putamen were larger in the dyskinesic patients than in the control subjects (p<0.05, Tukey-Kramer post hoc test). In the drug-naïve patients, the binding ability of the A2ARs in the putamen, but not in the head of caudate nucleus, was significantly lower on the more affected side than on the less affected side (p<0.05, paired t-test). In addition, the A2ARs were significantly increased after antiparkinsonian therapy in the bilateral putamen of the drug-naïve patients (p<0.05, paired t-test) but not in the bilateral head of caudate nucleus. Our study demonstrated that the A2ARs in the putamen were increased in the PD patients with dyskinesia, and also suggest that the A2ARs in the putamen compensate for the asymmetrical decrease of dopamine in drug-naïve PD patients and that antiparkinsonian therapy increases the A2ARs in the putamen. The A2ARs may play an important role in regulation of parkinsonism in PD.

High occupancy of σ1 receptors in the human brain after single oral administration of donepezil: a positron emission tomography study using [11C]SA4503

The acetylcholinesterase (AChE) inhibitor donepezil is also a sigma1 receptor agonist. We examined whether donepezil binds to sigma1 receptors in the living human brain after a single oral administration. Dynamic positron emission tomography (PET) data acquisition using the selective sigma1 receptor ligand [11C]SA4503 was performed to evaluate quantitatively the binding of [11C]SA4503 to sigma1 receptors in eight healthy male volunteers. Each subject had a PET scan before and after receiving a single dose of donepezil (5 or 10 mg). The binding potential of [11C]SA4503 was calculated. Doses of 5 mg and 10 mg donepezil bound to sigma1 receptors in the human brain with occupancies of approximately 60% and approximately 75%, respectively, in a dose-dependent manner. This study demonstrated that donepezil binds to sigma1 receptors in the living human brain at therapeutic doses. Therefore, sigma1 receptors may be implicated in the pharmacological mechanism of donepezil in the human brain.

Imaging of Sigma1 Receptors in the Human Brain Using PET and [11C]SA4503

Sigma(1) receptors were imaged in living human brain by positron emission tomography (PET) using [(11)C] SA4503. A dynamic 90-min scan and kinetic analysis enabled quantification of receptor density in the brain. The sigma(1) receptors were distributed throughout the brain in normal subjects, but decreased in the frontal, temporal, and occipital lobes, cerebellum and thalamus in patients with early Alzheimers disease and in the putamen in patients with Parkinsons disease. In addition, rates of receptor occupancy by the neuroleptic haloperidol and the selective serotonin reuptake inhibitor fluvoxamine were evaluated by [(11)C]SA4503-PET and found to be high. [(11)C]SA4503-PET is useful for studying the pathophysiology of neurological and psychiatric disorders such as schizophrenia and for evaluation of the pharmacodynamics of psychiatric drugs.

Changes in cerebral blood flow during steady-state cycling exercise: a study using oxygen-15-labeled water with PET

Cerebral blood flow (CBF) during dynamic exercise has never been examined quantitatively using positron emission tomography (PET). This study investigated changes in CBF that occur over the course of a moderate, steady-state cycling exercise. Global and regional CBF (gCBF and rCBF, respectively) were measured using oxygen-15-labeled water (H215O) and PET in 10 healthy human subjects at rest (Rest), at the onset of exercise (Ex1) and at a later phase in the exercise (Ex2). At Ex1, gCBF was significantly (P<0.01) higher (27.9%) than at Rest, and rCBF was significantly higher than at Rest in the sensorimotor cortex for the bilateral legs (M1Leg and S1Leg), supplementary motor area (SMA), cerebellar vermis, cerebellar hemispheres, and left insular cortex, with relative increases ranging from 37.6% to 70.5%. At Ex2, gCBF did not differ from Rest, and rCBF was significantly higher (25.9% to 39.7%) than at Rest in only the M1Leg, S1Leg, and vermis. The areas showing increased rCBF at Ex1 were consistent with the central command network and the anatomic pathway for interoceptive stimuli. Our results suggest that CBF increases at Ex1 in parallel with cardiovascular responses then recovers to the resting level as the steady-state exercise continues.

A feasibility study of ( 11 C)SA4503-PET for evaluating sigma1 receptor occupancy by neuroleptics: the binding of haloperidol to sigma1 and dopamine D2-like receptors

We investigated feasibility of positron emission tomography (PET) with [11C]SA4503 for evaluating the sigmai receptor occupancy rate by neuroleptics. Haloperidol, which is well known to bind dopamine D2-like receptor (D2R) as well as to be a representative non-selective antagonist for sigmai receptor (σ1R), was selected as a model drug. Three healthy male subjects underwent 60-min [11C]raclopride-PET and 90-min [11C]SA4503-PET scans successively at a 120-min interval twice in a day for baseline measurement and on another day for haloperidol-loading measurement 16 hours after peroral administration of 3 mg of haloperidol. Binding potential (BP) of [11C]raclopride and [11C]SA4503 was quantitatively evaluated and the σ1R and D2R occupancy rates were determined. D2R occupancy rates by haloperidol were 64% and 62% in the caudate and putamen, respectively, 16 h after the administration, while σ1R occupancy rates were approximately 80% in all seven regions investigated including the caudate, putamen and cerebellum 18 h after the administration, suggesting that the σlR receptor occupancy rate by haloperidol was slightly larger than the D2R receptor occupancy rate. We concluded that [11C]SA4503-PET can be used for evaluating the σlR occupancy rates by neuroleptics or other drugs.

Whole-Body Distribution and Brain Tumor Imaging with 11C-4DST: A Pilot Study

Recently, we developed [methyl-11C]4′-thiothymidine (11C-4DST) as an in vivo cell proliferation marker. The present study was performed to determine the safety, distribution, radiation dosimetry, and initial brain tumor imaging of 11C-4DST in humans. Methods: Multiorgan biodistribution and radiation dosimetry of 11C-4DST were assessed in 3 healthy humans, who underwent 2-h whole-body PET scanning. Radiation dosimetry was estimated from the residence times of source organs using the OLINDA program. Six brain tumor patients underwent dynamic 11C-4DST scans with arterial blood sampling. These patients were also evaluated with 11C-methionine PET on the same day (n = 4) as, or 3 wk before (n = 2), 11C-4DST PET studies. Metabolites in plasma and urine samples were analyzed by high-performance liquid chromatography. Breakdown of the blood–brain barrier in tumor tissue was confirmed by gadolinium-enhanced T1-weighted MRI. Results: There were no serious adverse events in any subjects at any time during the study period. 11C-4DST PET demonstrated selective uptake in the bone marrow, which has a high rate of proliferation. In addition, high-level uptake was also seen in the liver. The highest absorbed organ dose was in the urinary bladder wall (17.6 μGy/MBq). The estimated effective dose for 11C-4DST was 4.2 μSv/MBq. 11C-4DST showed little uptake in normal brain tissues, resulting in low background activity for imaging of brain tumors. In contrast, 11C-4DST PET demonstrated rapid uptake in aggressive tumor masses, whereas no signal of 11C-4DST was seen in clinically stable disease in which 11C-methionine uptake was high. The distribution pattern of 11C-methionine in tumor regions was not always identical to that of 11C-4DST. Analysis of plasma samples by high-performance liquid chromatography indicated that more than 60% of the radioactivity was present as unchanged 11C-4DST at 20 min. Conclusion: The initial findings of the present study in a small group of patients indicated that 11C-4DST PET is feasible for imaging of brain tumors. Dosimetry and pharmacologic safety were acceptable at the dose required for adequate PET images.

Biodistribution and radiation dosimetry of the α7 nicotinic acetylcholine receptor ligand [11C]CHIBA-1001 in humans

INTRODUCTION 4-[(11)C]Methylphenyl 2,4-diazabicyclo[3.2.2]nonane-2-carboxylate ([(11)C]CHIBA-1001) is a newly developed positron emission tomography (PET) ligand for mapping α(7) nicotinic acetylcholine receptors. We investigated whole-body biodistribution and radiation dosimetry of [(11)C]CHIBA-1001 in humans and compared the results with those obtained in mice. METHODS Dynamic whole-body PET was carried out for three human subjects after administering a bolus injection of [(11)C]CHIBA-1001. Emission scans were collected in two-dimensional mode over five bed positions. Regions of interest were placed over 12 organs. Radiation dosimetry was estimated from the residence times of these source organs using the OLINDA program. Biodistribution data from mice were also used for the prediction of radiation dosimetry in humans, and results with and those without accommodation of different proportions of organ-to-total-body mass were compared with the results from the human PET study. RESULTS In humans, the highest accumulation was observed in the liver, whereas in mice, the highest accumulation was observed in the urinary bladder. The estimated effective dose from the human PET study was 6.9 μSv/MBq, and that from mice was much underestimated. CONCLUSION Effective dose estimates for [(11)C]CHIBA-1001 were compatible with those associated with other common nuclear medicine tests. Absorption doses among several organs were considerably different between the human and mouse studies. Human dosimetry studies for the investigation of radiation safety are desirable as one of the first clinical trials of new PET probes before their application in subsequent clinical investigations.

In Vivo Evaluation of α7 Nicotinic Acetylcholine Receptor Agonists [11C]A-582941 and [11C]A-844606 in Mice and Conscious Monkeys

Background The α7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimers disease. The goal of this study was to evaluate the two carbon-11-labeled α7 nAChR agonists [11C]A-582941 and [11C]A-844606 for their potential as novel positron emission tomography (PET) tracers. Methodology/Principal Findings The two tracers were synthesized by methylation of the corresponding desmethyl precursors using [11C]methyl triflate. Effects of receptor blockade in mice were determined by coinjection of either tracer along with a carrier or an excess amount of a selective α7 nAChR agonist (SSR180711). Metabolic stability was investigated using radio-HPLC. Dynamic PET scans were performed in conscious monkeys with/without SSR180711-treatment. [11C]A-582941 and [11C]A-844606 showed high uptake in the mouse brain. Most radioactive compounds in the brain were detected as an unchanged form. However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain. On the other hand, the total distribution volume of [11C]A-582941 and [11C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711. Conclusions/Significance A nonhuman primate study suggests that [11C]A-582941 and [11C]A-844606 would be potential PET ligands for imaging α7 nAChRs in the human brain.

Direct comparison of radiation dosimetry of six PET tracers using human whole-body imaging and murine biodistribution studies

ObjectiveWe investigated the whole-body biodistributions and radiation dosimetry of five 11C-labeled and one 18F-labeled radiotracers in human subjects, and compared the results to those obtained from murine biodistribution studies.MethodsThe radiotracers investigated were 11C-SA4503, 11C-MPDX, 11C-TMSX, 11C-CHIBA-1001, 11C-4DST, and 18F-FBPA. Dynamic whole-body positron emission tomography (PET) was performed in three human subjects after a single bolus injection of each radiotracer. Emission scans were collected in two-dimensional mode in five bed positions. Regions of interest were placed over organs identified in reconstructed PET images. The OLINDA program was used to estimate radiation doses from the number of disintegrations of these source organs. These results were compared with the predicted human radiation doses on the basis of biodistribution data obtained from mice by dissection.ResultsThe ratios of estimated effective doses from the human-derived data to those from the mouse-derived data ranged from 0.86 to 1.88. The critical organs that received the highest absorbed doses in the human- and mouse-derived studies differed for two of the six radiotracers. The differences between the human- and mouse-derived dosimetry involved not only the species differences, including faster systemic circulation of mice and differences in the metabolism, but also measurement methodologies.ConclusionsAlthough the mouse-derived effective doses were roughly comparable to the human-derived doses in most cases, considerable differences were found for critical organ dose estimates and pharmacokinetics in certain cases. Whole-body imaging for investigation of radiation dosimetry is desirable for the initial clinical evaluation of new PET probes prior to their application in subsequent clinical investigations.