Synaptic phenotypes in living patients with psychiatric disorders are poorly characterized. Excitatory glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a fundamental component for neurotransmission. We recently developed a positron emission tomography (PET) tracer for AMPAR, [11C]K-2, the first technology to visualize and quantify AMPARs density in living human brain. In this study, we characterized patients with major psychiatric disorders with [11C]K-2. One hundred forty-nine patients with psychiatric disorders (schizophrenia, n = 42; bipolar disorder, n = 37; depression, n = 35; and autism spectrum disorder, n = 35) and 70 healthy participants underwent a PET scan with [11C]K-2 for measurement of AMPAR density. We detected brain regions that showed correlation between AMPAR density and symptomatology scores in each of four disorders. We also found brain areas with significant differences in AMPAR density between patients with each psychiatric disorder and healthy participants. Some of these areas were observed across diseases, indicating that these are commonly affected areas throughout psychiatric disorders. Schizophrenia, bipolar disorder, depression, and autism spectrum disorder are uniquely characterized by AMPAR distribution patterns. Our approach to psychiatric disorders using [11C]K-2 can elucidate the biological mechanisms across diseases and pave the way to develop novel diagnostics and therapeutics based on the synapse physiology.

Dopamine (DA) is involved in neurological and physiological functions such as motor control. L-3,4-dihydroxyphenylalanine (L-DOPA), a precursor of DA, is conventionally believed to be an inert amino acid precursor of DA, and its major therapeutic effects in Parkinson's disease (PD) are mediated through its conversion to DA. On the contrary, accumulating evidence suggests that L-DOPA itself is a neurotransmitter. We here show that L-DOPA potentiates DA D2 receptor (DRD2) signaling through GPR143, the gene product of X-linked ocular albinism 1, a G-protein-coupled receptor for L-DOPA. In Gpr143-gene-deficient (Gpr143-/y ) mice, quinpirole, a DRD2/DRD3 agonist, -induced hypolocomotion was attenuated compared to wild-type (WT) mice. Administration of non-effective dose of L-DOPA methyl ester augmented the quinpirole-induced hypolocomotion in WT mice but not in Gpr143-/y mice. In cells co-expressing GPR143 and DRD2, L-DOPA enhanced the interaction between GPR143 and DRD2 and augmented quinpirole-induced decrease in cAMP levels. This augmentation by L-DOPA was not observed in cells co-expressing GPR143 and DRD1 or DRD3. Chimeric analysis in which the domain of GPR143 was replaced with GPR37 revealed that GPR143 interacted with DRD2 at the fifth transmembrane domain. Intracerebroventricular administration of a peptide that disrupted the interaction mitigated quinpirole-induced behavioral changes in WT mice but not in Gpr143-/y mice. These findings provide evidence that coupling between GPR143 and DRD2 is required for selective DRD2 modulation by L-DOPA in the dorsal striatum.

The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) contribute to epileptogenesis. Thirty patients with epilepsy and 31 healthy controls are scanned using positron emission tomography with our recently developed radiotracer for AMPARs, [11C]K-2, which measures the density of cell-surface AMPARs. In patients with focal-onset seizures, an increase in AMPAR trafficking augments the amplitude of abnormal gamma activity detected by electroencephalography. In contrast, patients with generalized-onset seizures exhibit a decrease in AMPARs coupled with increased amplitude of abnormal gamma activity. Patients with epilepsy had reduced AMPAR levels compared with healthy controls, and AMPARs are reduced in larger areas of the cortex in patients with generalized-onset seizures compared with those with focal-onset seizures. Thus, epileptic brain function can be regulated by the enhanced trafficking of AMPAR due to Hebbian plasticity with increased simultaneous neuronal firing and compensational downregulation of cell-surface AMPARs by the synaptic scaling.

Introduction: AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) receptors play a central role in neurotransmission and neuronal function. A positron emission tomography (PET) tracer for AMPA re-ceptors, [C-11]K-2, was recently developed by us to visualize AMPA receptors in the living human brain. [C-11]K-2 is a derivative of 4-[2-(phenylsulphonylamino)ethylthio]-2,6-difuluoro-phenoxyacetamide (PEPA), and is labeled with the radioactive isotope C-11, which has a short half-life. PET drugs are usually labeled with F-18 because of its long half-life. Therefore, we screened and identified potential F-18-labeled PET drugs for AMPA receptors (AMPA-PET drugs), which could provide an image equivalent to that of [C-11]K-2. Methods: Derivatives of K-2 labeled with F-18 were synthesized and administered to rats and PET imaging was performed. The transferability of each compound to the brain and its correlation with the PET image of [C-11]K-2 were evaluated from the obtained PET images. Furthermore, the specific binding ability of promising compounds to the AMPA receptor was evaluated by the PET imaging of rats, which we specifically knocked down the expression of AMPA by the lentivirus-mediated introduction of short hairpin RNA (shRNA) targeted to subunits of the AMPA receptor (GluA1-A3). The specific binding ability was also evaluated through electrophysiological experiments with acute brain slices. Results: Some of the synthesized F-18-labeled candidate compounds showed a distribution similar to that of K-2, with reasonable transferability to the brain. In addition, from the evaluation of the specific binding ability to the AMPA receptor, a promising structure of an 18F-labeled AMPA PET drug was identified. This study also revealed that the alkylation of the sulfonamide group of PEPA enhances brain transferability.

The glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) is an important molecule in neurotransmission. We have recently developed the first positron emission tomography (PET) tracer [11C]K-2 to visualize and quantify AMPARs in the living human brain. After injection, [11C]K-2 is hydrolyzed at the terminal amide (and is thus metabolized to a major metabolite, [11C]K-2OH) within 10 min, representing the PET image in rodents and humans. Here, we found that K-2OH did not penetrate the cell membrane but slowly passed through the blood brain barrier (BBB) with paracellular transport. Furthermore, major efflux transporters in the BBB did not carry K-2OH. Logan graphical analysis exhibited reversible binding kinetics of this radiotracer in healthy individuals; these results demonstrated that the PET image of this tracer represents cell surface AMPARs with passive penetration of [11C]K-2OH through the BBB, resulting in reversible binding kinetics. Thus, PET images with this tracer depict the physiologically crucial fraction of AMPARs.

[ 11 C]K-2, a radiotracer exhibiting high affinity and selectivity for α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), is suitable for the quantification of AMPARs in living human brains and potentially useful in the identification of epileptogenic foci in patients. This study aimed to estimate the radiation doses of [ 11 C]K-2 in various organs and calculate the effective dose after injection of [ 11 C]K-2 in healthy human subjects. Twelve healthy male subjects were registered and divided into two groups (370 or 555 MBq of [ 11 C]K-2), followed by 2 h whole-body scans. We estimated the radiation dose of each organ and then calculated the effective dose for each subject. The highest uptake of [ 11 C]K-2 was observed in the liver, while the brain also showed relatively high uptake. The urinary bladder exhibited the highest radiation dose. The kidneys and liver also showed high radiation doses after [ 11 C]K-2 injections. The effective dose of [ 11 C]K-2 ranged from 5.0 to 5.2 μSv/MBq. Our findings suggest that [ 11 C]K-2 is safe in terms of the radiation dose and adverse effects. The injection of 370–555 MBq (10 to 15 mCi) for PET studies using this radiotracer is applicable in healthy human subjects and enables serial PET scans in a single subject.

Changes in the number of postsynaptic AMPA receptors are believed to underlie long-term potentiation and long-term depression in cellular models of learning and memory. Furthermore, dysfunctions in AMPA receptors leading to imbalances between excitatory and inhibitory synapses are thought to underlie certain neuronal disorders such as epilepsy, Alzheimer's disease, depression and schizophrenia. Despite an accumulation of basic research on AMPA receptors suggesting substantial potential of these receptors as a therapeutic target, clinical translation has been limited. This could be attributed to the lack of technology to visualize AMPA receptors in the living human brain. Thus, there is a need for a technology to visualize AMPA receptors in the living human brain to further elucidate the molecular and circuit bases of neuronal diseases and to develop novel diagnostic and therapeutic options. PET is widely used in clinical diagnosis. Although several compounds have been developed as potential PET tracers for AMPA receptors, there is currently no radiotracer suitable for in vivo PET imaging of AMPA receptors. Here we developed a new AMPA receptor PET tracer named [11C]K-2, which is suitable for visualizing AMPA receptors in the human brain.

Depression is the major mental disorder and over one million patients are suffering from this disease. It was also reported that the number of patients showing resistance toward anti-depressant, i.g. SSRI and SNRI, got increase. We have already known that molecular mechanism underlying depression is heterogeneous so that it is hard to estimate the efficacy of anti-depressant without molecular rationale. Postmortem human brain analysis indicated that the number of AMPA receptors (AMPARs), major molecule controlling synaptic functions, varied among depression patients and the results of these analysis were not consistent. To clarify the dynamics of AMPARs in depression patients, we developed the novel PET imaging method to measure the density of AMPARs in depression patients. This result showed that depression patients decreased AMPARs broadly throughout the brain. This fact motivated us to develop novel AMPARs potentiator in order to cure the depression. To find the compound showing high affinity to AMPARs and high BBB penetratability, we modified the compound named PEPA, already known to bind specifically to AMPARs, and finally succeeded in synthesizing the seed compound. This compound could exert the anti-depressant effect quickly and sustained for a week after the cessation of drug administration. Furthermore, this anti-depressant effect was significantly stronger that another AMPARs potentiators.

Standardized uptake values (SUVs) are the most widely used quantitative imaging biomarkers in PET. It is important to evaluate the variability and repeatability of measured SUVs. Phantom studies seem to be essential for this purpose; however, repetitive phantom scanning is not recommended due to the decay of radioactivity. In this study, we performed count-based image reconstruction to avoid the influence of decay using two different PET/CT scanners. By adjusting the ratio of 18F-fluorodeoxyglucose solution to tap water, a NEMA IEC body phantom was set for SUVs of 4.0 inside six hot spheres. The PET data were obtained using two scanners (Aquiduo and Celesteion; Toshiba Medical Systems, Tochigi, Japan). We set the start time for image reconstruction when the total radioactivity in the phantom was 2.53 kBq/cc, and employed the counts of the first 2-min acquisition as the standard. To maintain the number of counts for each image, we set the acquisition time for image reconstruction depending on the decay of radioactivity. We obtained 50 images, and calculated the SUVmax and SUVpeak of all six spheres in each image. The average values of the SUVmax were used to calculate the recovery coefficients to compare those measured by the two different scanners. Bland-Altman analyses of the SUVs measured by the two scanners were also performed. The measured SUVs using the two scanners exhibited a 10-30% difference, and the standard deviation (SD) of the measured SUVs was between 0.1-0.2. The Celesteion always exhibited higher values than the Aquiduo. The smaller sphere exhibited a larger SD, and the SUVpeak had a smaller SD than the SUVmax. The Bland-Altman analyses showed poor agreement between the SUVs measured by the two scanners. The recovery coefficient curves obtained from the two scanners were considerably different. The Celesteion exhibited higher recovery coefficients than the Aquiduo, especially at approximately 20-mm-diameter. Additionally, the curves were lower than those calculated from the standard 30-min acquisition images. We propound count-based image reconstruction to evaluate the variability and repeatability of measured SUVs. These results are also applicable for the standardization and harmonization of SUVs in multi-institutional studies.

AMPA receptor is one of the most important molecules controlling the neuronal activities. Dysfunction of AMPA receptors is believed to underlie some of psychiatric disorders. Recent studies have clarified that AMPA receptors expression is decreased in post-mortem brain of patients with major depressive disorder (Gibbons et al., 2012, Duric et al., 2013). Positive allosteric modulators (PAMs) enhancing AMPA receptors function have been developed toward patients with depression but the effects of PAMs on depression seem to be limited. Here we show that we success in developing a new type of PAMs targeting AMPA receptors improving the depressive phenotype of rodent depression model.

Post-filtering with a Gaussian filter is commonly used to reduce noise in positron emission tomography (PET) images. However, its non-selective smoothing obscures the edges of lesions or organs. We compared the performance of a newly developed anisotropic diffusion filter called “Statistical Transfer with Optimizing Noise and Edge Sensing” (STONES) with that of the Gaussian filter for small lesions on PET images. We selected seven PET/computed tomography (CT) image slices of the lungs from three patients with multiple lung metastases. For each slice, the lesion detection rates by two physicians (A and B) were compared for Gaussian- and STONES-filtered PET images. The maximum standardized uptake (SUVmax) values of the detected lesions were also compared for non-, Gaussian-, and STONES-filtered images. Physician A detected 19 lesions in the Gaussian-filtered images and 23 lesions in the STONES-filtered images, while Physician B detected 14 lesions in the Gaussian-filtered images and 19 lesions in the STONES-filtered images. SUVmax for the STONES-filtered images was significantly higher and closer to that of the non-filtered images compared to those for the Gaussian-filtered images. STONES improved the detection rate and increased SUVmax in comparison with Gaussian filter. Thus, it should be more advantageous for the detection of small lesions with PET.

The goal of this study was to evaluate the performance of the Celesteion positron emission tomography/computed tomography (PET/CT) scanner, which is characterized by a large-bore and time-of-flight (TOF) function, in accordance with the NEMA NU-2 2012 standard and version 2.0 of the Japanese guideline for oncology fluorodeoxyglucose PET/CT data acquisition protocol. Spatial resolution, sensitivity, count rate characteristic, scatter fraction, energy resolution, TOF timing resolution, and image quality were evaluated according to the NEMA NU-2 2012 standard. Phantom experiments were performed using 18F-solution and an IEC body phantom of the type described in the NEMA NU-2 2012 standard. The minimum scanning time required for the detection of a 10-mm hot sphere with a 4:1 target-to-background ratio, the phantom noise equivalent count (NECphantom), % background variability (N 10mm), % contrast (Q H,10mm), and recovery coefficient (RC) were calculated according to the Japanese guideline.

Standardized uptake values (SUVs) are the most widely used quantitative imaging biomarkers in positron emission tomography (PET); however, little is known about the changes in variation and repeatability of SUVs depending on the magnitude of the values. We hypothesized that low SUVs have larger variations than high SUVs, and attempted various kinds of experimental PET scans using a phantom. By adjusting the ratio of F-18 solution to tap water, a NEMA IEC body phantom was set for SUVs of 2.0, 4.0, and 8.0 inside six hot spheres. PET data were obtained for 4 hours, and the data reconstructed every 2 min. The SUVmax and SUVpeak of the spheres in all images were recorded. The relative SUVs were calculated by dividing the measured SUV by actual SUV, and used for the Bland-Altman plots. Some variation was observed for the measured SUVs. The measured SUVs for the actual SUV of 2.0 showed the largest variation among those of 2.0, 4.0, and 8.0, and those of 8.0 showed the smallest. Similarly, the relative SUVs showed significantly larger variations for lower values. In addition, the relative SUVmax showed larger variation and value than the relative SUVpeak. The Bland-Altman plots showed considerable variation and little agreement, but the degree of variation decreased as the measured value increased. We demonstrated some variation of the measured SUVs, which decreased for larger measured values. Clinicians should consider the inaccuracy of low SUVs not only in daily practice, but also for multi-institutional studies.

An efficient, flexible route to highly functionalized linearly fused dicyclobutabenzenes is described based on the dual, regioselective cycloaddition of benzyne and ketene silyl acetals.

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