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Histamine H3 receptor antagonists and inverse agonists have been extensively developed to treat sleep–wake, neurocognitive, and allied disorders. However, potential adverse effects, including insomnia, hampered the clinical use of these drugs, possibly due to their persistent interaction with the target molecules. The purpose of the present study was to estimate the pharmacokinetics and pharmacodynamics of enerisant, a novel antagonist and inverse agonist for histamine H3 receptors. To measure the histamine H3 receptor occupancy by enerisant, positron emission tomography studies using [11C]TASP457, a specific radioligand for histamine H3 receptors, were performed in 12 healthy men at baseline and at 2 h after oral administration of enerisant hydrochloride. For three of these subjects, two additional scans were performed at 6 and 26 h after the administration. Relationships between the receptor occupancy by enerisant and its dose and plasma concentrations were then analyzed. Administration of enerisant hydrochloride decreased the radioligand binding in a dose-dependent manner. The estimated receptor occupancy values at 2 h varied as a function of its dose or plasma concentration. The time course of the occupancy showed persistently high levels (> 85%) in the two subjects with higher doses (25 and 12.5 mg). The occupancy was also initially high at 2 h and 6 h with the lower dose of 5 mg, but it decreased to 69.7% at 26 h. The target engagement of enerisant was demonstrated in the brains of living human subjects. The occupancy of histamine H3 receptors by enerisant at 2 h can be predicted by applying the plasma concentration of enerisant to Hill’s plot. The preliminary time-course investigation showed persistently high brain occupancy with high doses of enerisant despite the decreasing plasma concentration of the drug. Five milligrams or less dose would be appropriate for the treatment for narcolepsy with initially high occupancy allowing for effective treatment of narcolepsy, and then the occupancy level would be expected to decrease to a level to avoid this drug’s unwanted side effect of insomnia at night, although further research is warranted to confirm the statement since the expected decrease is based on the finding in one subject. This study was retrospectively registered with ClinicalTrials.gov (NCT04631276) on November 17, 2020.

Positron emission tomography (PET) has been used to investigate changes in the concentration of endogenous neurotransmitters. Recently, this technique has been applied to the imaging of serotonin2A receptors using [18F]altanserin. In these measurements, a reduction in binding potential (BP) suggests an increase in endogenous serotonin levels caused by pharmacological or cognitive stimulations, and the sensitivity of BP reduction depends on the characteristics of [18F]altanserin. In this study, we evaluated an analytical method for estimating the changes in endogenous serotonin levels based on PET scans with [18F]altanserin at baseline and stimulated states and validated it using simulations and small animal PET studies. First, in the simulations, the time-activity curves at baseline and the stimulated states were generated using an extended compartment model including the competition for the receptors between the administered [18F]altanserin and endogenous serotonin. In the stimulated state, the magnitude and onset of the endogenous serotonin elevation were altered to varying degrees. In these time-activity curves, BP was estimated using the simplified reference tissue model (SRTM), and the reduction in BP was evaluated by comparison with that of the baseline state. Next, the proposed method was applied to mouse PET studies. Endogenous serotonin levels were elevated by treatment with selective serotonin reuptake inhibitors (SSRIs), and PET studies were performed twice, once with and once without treatment. In both scans, BP was estimated using the SRTM with the cerebellum as a reference region, and the reduction in BP after SSRI treatment was evaluated. In the simulations, the BP estimate of the stimulated state was smaller than that of the baseline state, and their reduction was related to the amount of change in the serotonin concentration. BP reduction was also affected by the onset of serotonin elevation. In the mouse studies, the BP of the cerebral cortex decreased in the scans with SSRI treatment. The reduction in BP estimated using the SRTM from [18F]altanserin-PET studies at baseline and in stimulated states can detect changes in the binding conditions of serotonin2A receptors. This may be useful for investigating the elevation of endogenous serotonin levels caused by stimulations.

[11C]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 [11C]K-2 in various organs and calculate the effective dose after injection of [11C]K-2 in healthy human subjects. Twelve healthy male subjects were registered and divided into two groups (370 or 555 MBq of [11C]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 [11C]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 [11C]K-2 injections. The effective dose of [11C]K-2 ranged from 5.0 to 5.2 μSv/MBq. Our findings suggest that [11C]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.

Depression is one of the common psychiatric disorders in old age. Major depressive disorder (MDD) has been identified as a risk factor or prodrome for neurodegenerative dementias, suggesting neuropathological overlaps and a continuum between MDD and neurodegenerative disorders. In this study, we examined tau and amyloid-β (Aβ) accumulations in the brains of MDD and healthy controls using positron emission tomography (PET) to explore pathological substrates of this illness. Twenty MDD and twenty age-matched, healthy controls were examined by PET with a tau radioligand, [11C]PBB3, and an Aβ radioligand, [11C]PiB. Radioligand retentions were quantified as a standardized uptake value ratio (SUVR). We also assessed clinical manifestations of the patients using the 17-item Hamilton Depression Scale, the Geriatric Depression Scale, and psychotic symptoms. Mean cortical [11C]PBB3 SUVRs in MDD patients were significantly higher than those of healthy controls. These values were higher in MDD patients with psychotic symptoms than in those without any. The present findings indicate that tau depositions may underlie MDD, and especially in patients with psychotic symptoms. PET detection of tau accumulations may provide mechanistic insights into neuronal dysfunctions in these cases and could serve as predictions of their clinical consequences.

Tau deposits is a core feature of neurodegenerative disorder following traumatic brain injury (TBI). Despite ample evidence from post-mortem studies demonstrating exposure to both mild-repetitive and severe TBIs are linked to tau depositions, associations of topology of tau lesions with late-onset psychiatric symptoms due to TBI have not been explored. To address this issue, we assessed tau deposits in long-term survivors of TBI by PET with 11C-PBB3, and evaluated those associations with late-life neuropsychiatric outcomes. PET data were acquired from 27 subjects in the chronic stage following mild-repetitive or severe TBI and 15 healthy control subjects. Among the TBI patients, 14 were diagnosed as having late-onset symptoms based on the criteria of traumatic encephalopathy syndrome. For quantification of tau burden in TBI brains, we calculated 11C-PBB3 binding capacity (cm3), which is a summed voxel value of binding potentials (BP*ND) multiplied by voxel volume. Main outcomes of the present study were differences in 11C-PBB3 binding capacity between groups, and the association of regional 11C-PBB3 binding capacity with neuropsychiatric symptoms. To confirm 11C-PBB3 binding to tau deposits in TBI brains, we conducted in vitro PBB3 fluorescence and phospho-tau antibody immunofluorescence labelling of brain sections of chronic traumatic encephalopathy obtained from the Brain Bank. Our results showed that patients with TBI had higher 11C-PBB3 binding capacities in the neocortical grey and white matter segments than healthy control subjects. Furthermore, TBI patients with traumatic encephalopathy syndrome showed higher 11C-PBB3 binding capacity in the white matter segment than those without traumatic encephalopathy syndrome, and regional assessments revealed that subgroup difference was also significant in the frontal white matter. 11C-PBB3 binding capacity in the white matter segment correlated with the severity of psychosis. In vitro assays demonstrated PBB3-positive tau inclusions at the depth of neocortical sulci, confirming 11C-PBB3 binding to tau lesions. In conclusion, increased 11C-PBB3 binding capacity is associated with late-onset neuropsychiatric symptoms following TBI, and a close correlation was found between psychosis and 11C-PBB3 binding capacity in the white matter.

Hypoxia plays important roles in the prognosis of malignant brain tumors such as glioblastoma because it causes drug delivery deficiencies and the induction of hypoxia-inducible factor-1α in tumor cells. Extensive hypoxic areas are associated with poor prognosis of these fatal diseases. We previously reported that multiple administrations of the hypoxia-targeted internal radiotherapy agent 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), four times at intervals of 1 or 2 weeks, show antitumor effects in glioblastoma without treatment-related adverse events. Before initiating clinical trials, preclinical safety studies using Cu-ATSM composed of stable isotopes and its precursor ATSM were required to understand the potential risks of systemic and repeated chemical exposure of our investigational drug. In this study, the concentrations of Cu-ATSM and ATSM in mouse plasma after intravenous administration were determined by liquid chromatography–tandem mass spectrometry, and the half-lives were estimated to be 21.5 and 22.4 minutes for Cu-ATSM and ATSM, respectively. Based on this result, approach 2 of the current ICH M3 [R2] guideline was adopted, and a 7-day intravenous toxicity study was conducted in mice. Cu-ATSM and ATSM in a ratio of 2:25 mimicking our current investigational drug was used, and no adverse effects were observed when Cu-ATSM and ATSM were administered at 81 μg/kg. These results and those of previous studies suggest that our current investigational drug formulation containing Cu-ATSM and ATSM at a dose of 15 μg can be safely administered to patients once per week for 4 weeks for treatment with 64Cu-ATSM.

Summary A panel of radiochemicals has enabled in vivo positron emission tomography (PET) of tau pathologies in Alzheimer’s disease (AD), although sensitive detection of frontotemporal lobar degeneration (FTLD) tau inclusions has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing diverse tau deposits. In vitro assays demonstrated the reactivity of this compound with tau pathologies in AD and FTLD. We could also utilize PM-PBB3 for optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of 18F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant progressive supranuclear palsy (PSP) tau topologies. Notably, the in vivo reactivity of 18F-PM-PBB3 with FTLD tau inclusion was strongly supported by neuropathological examinations of brains derived from Pick’s disease, PSP, and corticobasal degeneration patients who underwent PET scans. Finally, visual inspection of 18F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on a neuropathological basis.

Depositions of fibrillary tau protein aggregates are implicated in diverse tauopathies, including Alzheimers disease (AD) and frontotemporal lobar degeneration (FTLD). A panel of radiochemicals has enabled in-vivo positron emission tomography (PET) of AD tau pathologies composed of all six tau isoforms, while sensitive detection of FTLD tau inclusions, mostly consisting of tau isoforms with three or four repeat domains only, has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing tau deposits with all isoform composites. In-vitro assays demonstrated the reactivity of this compound with tau pathologies in AD, four-repeat tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and three-repeat tauopathies represented by Picks disease (PiD). We could also utilize PM-PBB3 for bimodal, multiscale optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of radiolabeled 18 F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant PSP tau topologies. Notably, the in-vivo reactivity of 18 F-PM-PBB3 with three- and four-repeat tau lesions was strongly supported by neuropathological examinations of autopsied and biopsied brains derived from PiD, PSP and CBD patients who underwent PET scans. Finally, visual inspection of 18 F-PM-PBB3-PET images was indicated to facilitate individually based identification of the neuropathological basis, composed of PSP, CBD and PiD, underlying the diverse clinical phenotypes of FTLD. Taking these findings together, we propose the new tau probe as a powerful tool for etiological, diagnostic and therapeutic PET assessments of the tau pathogenesis in AD and FTLD spectra at nonclinical and clinical levels.

Background The histamine H3 receptor is regarded as a drug target for cognitive impairments in psychiatric disorders. H3 receptors are expressed in neocortical areas, including the prefrontal cortex, the key region of cognitive functions such as working memory. However, the role of prefrontal H3 receptors in working memory has not yet been clarified. Therefore, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) techniques, we aimed to investigate the association between the neural activity of working memory and the density of H3 receptors in the prefrontal cortex. Findings Ten healthy volunteers underwent both fMRI and PET scans. The N-back task was used to assess the neural activities related to working memory. H3 receptor density was measured with the selective PET radioligand [11C] TASP457. The neural activity of the right dorsolateral prefrontal cortex during the performance of the N-back task was negatively correlated with the density of H3 receptors in this region. Conclusions Higher neural activity of working memory was associated with lower H3 receptor density in the right dorsolateral prefrontal cortex. This finding elucidates the role of H3 receptors in working memory and indicates the potential of H3 receptors as a therapeutic target for the cognitive impairments associated with neuropsychiatric disorders.

Background α-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor is a primary mediator of fast glutamatergic excitatory signaling in the brain and has been implicated in diverse neuropsychiatric diseases. We recently developed a novel positron emission tomography (PET) ligand, 2-(1-(3-([11C]methylamino)phenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitrile ([11C]HMS011). This compound is a radiolabelled derivative of perampanel, an antiepileptic drug acting on AMPA receptors, and was demonstrated to have promising in vivo properties in the rat and monkey brains. In the current study, we performed a human PET study using [11C]HMS011 to evaluate its safety and kinetics. Four healthy male subjects underwent a 120-min PET scan after injection of [11C]HMS011. Arterial blood sampling and metabolite analysis were performed to obtain parent input functions for three of the subjects using high-performance liquid chromatography. Regional distribution volumes (V Ts) were calculated based on kinetic models with and without considering radiometabolite in the brain. The binding was also quantified using a reference tissue model with white matter as reference. Results Brain uptake of [11C]HMS011 was observed quickly after the injection, followed by a rapid clearance. Three hydrophilic and one lipophilic radiometabolites appeared in the plasma, with notable individual variability. The kinetics in the brain with apparent radioactivity retention suggested that the lipophilic radiometabolite could enter the brain. A dual-input graphical model, an analytical model designed in consideration of a radiometabolite entering the brain, well described the kinetics of [11C]HMS011. A reference tissue model showed small radioligand binding potential (BP*ND) values in the cortical regions (BP*ND = 0–0.15). These data suggested specific binding component of [11C]HMS011 in the brain. Conclusions Kinetic analyses support some specific binding of [11C]HMS011 in the human cortex. However, this ligand may not be suitable for practical AMPA receptor PET imaging due to the small dynamic range and metabolite in the brain.

Introduction Recently, 6-[(1-cyclobutylpiperidin-4-yl)oxy]-1-(6-[ 11 C]methoxypyridin-3-yl)-3,4-dihydroquinolin-2(1 H )-one ([ 11 C]TASP457, [ 11 C] 2 ) has been developed as a novel PET ligand for histamine H 3 receptors in brain. [ 11 C] 2 is potentially suitable for imaging H 3 receptors in rat and monkey brains, which has motivated us to perform first-in-human study of [ 11 C] 2 for qualifying H 3 receptors in human brain. In this paper, we report an efficient radiosynthesis of [ 11 C] 2 to obtain sufficient radioactivity and high quality for clinical application. Methods In manual synthesis, we optimized the reaction conditions of desmethyl precursor 1 , which contains a 2-hydroxypyridine moiety, with [ 11 C]MeI or [ 11 C]MeOTf. After optimization, we performed automated synthesis and quality control of [ 11 C] 2 . Results Bubbling [ 11 C]MeOTf into a heated mixture of precursor 1 and cesium carbonate in DMF at 100°C for 90s produced [ 11 C] 2 with decay-corrected radiochemical yields of (based on [ 11 C]CO 2 ) 7.9±1.8% ( n =78). The specific activity of [ 11 C] 2 was 156±52GBq/μmol ( n =78) at the end of synthesis. The total synthesis time was approximately 35min from the end of bombardment. All the quality control results of [ 11 C] 2 were in compliance with our in-house quality control/assurance specifications. Conclusion We radiosynthesized [ 11 C]TASP457 ([ 11 C] 2 ) with sufficient amounts of radioactivity and high quality for clinical usefulness. This radioligand is being used for PET assessment of H 3 receptors in human brain in our facility.

Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide radiolabeled with 11C ([11C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [11C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [11C]K-2 in the brain; secondary outcome: adverse events of [11C]K-2 during the 4–10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased [11C]K-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between [11C]K-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus, [11C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders. A newly developed PET tracer allows visualization of AMPA receptors in the living human brain, providing a new tool to study their potential involvement in neurological or psychiatric disorders.

The effective utilization and assessment of medical resources have become a common concern for scholars in various countries due to the impact of the COVID-19 pandemic. This study deals with a method to monitor medical resource allocation in real-time and verify the effectiveness of the proposed method with actual data. In this work, we selected Iwate Prefecture in northeastern Japan based on the geographical characteristics and social environment. By collecting data from the Japanese Ministry of Land, Infrastructure, Transport, and Tourism and Welfare (MLIT), we clustered population centers in Iwate Prefecture, and found the clustering centers in densely populated areas from the k-means algorithm. Subsequently, to compare the distribution of county-level medical resources across different secondary care areas, we selected the indicators of Iwate Prefectural Hospitals from the Hospital Intelligence Agency. We classified 19 prefectural hospitals in Iwate Prefecture into four different clusters using the spectral clustering algorithm. The clustering results revealed that all hospitals close to the " clustering centers in densely populated areas" were Iwate prefectural disaster stronghold hospitals. Moreover, we found that these hospitals performed well in operational indicators. Only the Ninohe prefectural hospital in the Ninohe medical area was found not located in a population center. However, it still performs well in terms of business indicators since the Ninohe medical area has a high proportion of public hospitals and the Ninohe prefectural hospital plays an important role. Hence, the government should fully consider geographical characteristics when considering hospital restructuring. We used a real data set to demonstrate the validity of the proposed technique, providing a theoretical basis for the government's healthcare policy.

Introduction A positron emission tomography (PET) probe with ultra-high specific radioactivity (SA) enables measuring high receptor specific binding in brain regions by avoiding mass effect of the PET probe itself. It has been reported that PET probe with ultra-high SA can detect small change caused by endogenous or exogenous ligand. Recently, Kealey et al. developed [ 11 C]BU99008, a more potent PET probe for I 2 -imidazoline receptors (I 2 Rs) imaging, with a conventional SA (mean 76GBq/μmol) showed higher specific binding in the brain. Here, to detect small change of specific binding for I 2 Rs caused by endogenous or exogenous ligand in an extremely small region, such as hypothalamus in the brain, we synthesized and evaluated [ 11 C]BU99008 with ultra-high SA as a useful PET probe for small-animal PET imaging of I 2 Rs. Methods [ 11 C]BU99008 was prepared by [ 11 C]methylation of N -desmethyl precursor with [ 11 C]methyl iodide. Biodistribution, metabolite analysis, and brain PET studies were conducted in rats. Results [ 11 C]BU99008 with ultra-high SA in the range of 5400–16,600GBq/μmol were successfully synthesized ( n =7), and had appropriate radioactivity for in vivo study. In the biodistribution study, the mean radioactivity levels in all investigated tissues except for the kidney did not show significant difference between [ 11 C]BU99008 with ultra-high SA and that with conventional SA. In the metabolite analysis, the percentage of unchanged [ 11 C]BU99008 at 30min after the injection of probes with ultra-high and conventional SA was similar in rat brain and plasma. In the PET study of rats' brain, radioactivity level (AUC 30–60 min ) in the hypothalamus of rats injected with [ 11 C]BU99008 with ultra-high SA (64 [SUV ∙ min]) was significantly higher than that observed for that with conventional SA (50 [SUV ∙ min]). The specific binding of [ 11 C]BU99008 with ultra-high SA (86% of total binding) for I 2 R was higher than that of conventional SA (76% of total binding). Conclusion A PET study using [ 11 C]BU99008 with ultra-high SA would thus contribute to the detection of small changes in or small regions with I 2 R expression and hence may be useful in elucidating new functions of I 2 R.

Tau accumulation in the brain is a pathologic hallmark of Alzheimer disease and other tauopathies. Quantitative visualization of tau pathology in humans can be a powerful method as a diagnostic aid and for monitoring potential therapeutic interventions. We established methods of PET quantification of tau pathology with 11C-PBB3 (2-((1E,3E)-4-(6-(11C-methylamino)pyridin-3-yl)buta-1,3-dienyl) benzo[d]thiazol-6-ol), considering its radiometabolite entering the brain. Methods: Seven Alzheimer disease patients and 7 healthy subjects underwent dynamic 11C-PBB3 PET scanning. Arterial blood was sampled to obtain the parent and metabolite input functions. Quantification of 11C-PBB3 binding was performed using dual-input models that take the brain metabolite activity into consideration, traditional single-input models without such considerations, and the reference tissue model (MRTMO) and standardized uptake value ratio (SUVR). The cerebellar cortex was used as the reference tissue for all methods. Results: The dual-input graphical models estimated binding parameter ( B P ND * ) stably (∼0.36 in high-binding regions). The MRTMO B P ND * matched the corresponding B P ND * by the dual-input graphical model (r2 = 1.00). SUVR minus 1 correlated well with MRTMO B P ND * (r2 > 0.97). However, BPND by the single-input models did not correlate with B P ND * by the dual-input graphical model (r2 = 0.04). Conclusion: The dual-input graphical model B P ND * is consistent with the reference tissue B P ND * and SUVR-1, suggesting that these parameters can accurately quantify binding of 11C-PBB3 despite the entry of its radiometabolites into the brain.

Introduction The functions of I 2 -imidazoline receptors (I 2 Rs) are unknown, but evidence exists for their involvement in various neuropsychiatric disorders. Although a few positron emission tomography (PET) I 2 R ligands have been developed, of which [ 11 C]FTIMD and [ 11 C]BU99008 were evaluated as PET I 2 R imaging ligands in monkeys, no human PET imaging study using an I 2 R-selective PET ligand has been conducted yet. Thus, we synthesized an 18 F-labeled I 2 R-selective ligand (BU99018 or FEBU, K i for I 2 Rs=2.6nM), and evaluated its application using rodents in PET imaging in vivo toward the development of a clinically-useful I 2 R PET imaging ligand. Methods [ 18 F]FEBU was synthesized by the reaction of its precursor and [ 18 F]fluoroethyl bromide. A biodistribution and brain PET study were conducted in mice and rats respectively. Results [ 18 F]FEBU was successfully synthesized yielding a radioactivity suitable for injection (10.1±5.3% at the end of the irradiation ( n =10) based on 18 F − ). The specific activity at end of synthesis (EOS) was 40–147TBq/mmol ( n =10). The radiochemical purity was >99% at EOS and remained >99% for 90min after EOS. In mice brain uptake was relatively high. In the blocking study with the co-injection of the high-affinity I 2 R ligand BU224 (1mg/kg b.w.) brain uptake was significantly decreased 30min post-injection. In the PET studies the radioactivity was highly accumulated in the I 2 R-rich hypothalamus. Pretreatment with BU224 (1mg/kg b.w.) significantly decreased the radioactivity in the hypothalamus to 23% of that of the control from 60 to 90min post-injection. Conclusion [ 18 F]FEBU was sufficiently stable as a PET ligand and had a relatively high specific binding affinity for I 2 Rs in rats and mice.

Cu(In,Ga)Se2 (CIGS) absorbers with several Ga/III, Ga/(In + Ga), profiles were fabricated by the so-called “multi layer precursor method” under the control of Ga flux rate during film's deposition. Open-circuit voltage (VOC) of CIGS solar cell is principally dependent on average band-gap energy (Eg) in space-change region (SCR) of below 1.3 eV. This average Eg in SCR, principally controlled by average Ga/III ratio in SCR, is estimated by the peak position of (220/204)-oriented CIGS films on soda-lime grass (SLG) substrates investigated by grazing incidence X-ray diffraction (GIXRD) with 0.1° incident angle, whereas the average Eg in SCR is predicted by Raman or photoluminescence (PL) peak positions of CIGS absorbers on both SLG and stainless steel (SUS) substrates. Ultimately, with the average Eg in SCR of below 1.3 eV, the (220/204) peak position (GIXRD) can be well used as a predictor of the VOC on rigid SLG substrates. On the other hand, Raman peak and PL peak positions can be well utilized as indicators of the VOC on not only rigid SLG but also flexible SUS substrates before solar cell fabrication. These are fast and non-destructive methods to evaluate the Ga content, Eg near CIGS surface, and corresponding VOC for high cell performance.

Cu(In,Ga)Se2 (CIGS) absorbers with several Ga/III, Ga/(In+Ga) ratio, profiles were deposited by the so-called “multi layer precursor method” consisting of Ga-Se/In-Se/Cu-Se stacks. The effects of average Ga/III ratios and back slopes of the Ga/III profiles on the photovoltaic performance were investigated. The optimum average Ga/III ratio of approximately 0.36 leads to the appropriate average band-gap energy as well as sufficiently long carrier lifetime in CIGS absorber, thus enhancing open-circuit voltage. In addition, the back slope of 0.50 μm−1, defined as the ratio of the change in Ga/III ratio to the change in the depth range from 1 to 2 μm from CIGS surface, induces back surface field of 0.34 V/μm, thereby increasing short-circuit current density. Ultimately, the CIGS absorber on flexible stainless steel substrate with the double graded Ga/III profile (the average Ga/III of 0.36 and the back slope of 0.50 μm−1) was fabricated by the multi layer precursor method. This results in the 14.36%-efficient CIGS solar cell on the flexible substrate without an anti-reflective layer.

We developed 2-methylpyridin-3-yl-4-(5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)piperidine-1-[(11)C]carboxylate ([(11)C]MFTC) as a promising PET tracer for in vivo imaging of fatty acid amide hydrolase (FAAH) in rat and monkey brains. [(11)C]MFTC was synthesized by reacting 3-hydroxy-2-methylpyridine (2) with [(11)C]phosgene ([(11)C]COCl2), followed by reacting with 4-(5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)piperidine (3), with a 20 ± 4.6% radiochemical yield (decay-corrected, n = 30) based on [(11)C]CO2 and 40 min synthesis time from the end of bombardment. A biodistribution study in mice showed high uptake of radioactivity in FAAH-rich organs, including the lung, liver, and kidneys. Positron emission tomography (PET) summation images of rat brains showed high radioactivity in the frontal cortex, cerebellum, and hippocampus, which was consistent with the regional distribution pattern of FAAH in rodent brain. Pretreatment with MFTC or FAAH-selective URB597 significantly reduced the uptake in the brain. PET imaging of monkey brain showed relatively high uptake in the whole brain, particularly in the occipital cortex, which was also inhibited by treatment with MFTC or URB597. More than 96% of the total radioactivity was irreversible in the brain homogenate of rats 5 min after the radiotracer injection. The specific in vivo FAAH binding indicates that [(11)C]MFTC is a promising PET tracer for visualizing FAAH in the brain.

Time-resolved photoluminescence (TRPL) measurement has been performed on Cu(In,Ga)Se 2 (CIGS) absorbers. In this contribution, CIGS films on both rigid soda-lime glass and flexible stainless steel (SUS) substrates are fabricated by the so-called “multi-layer precursor method” consisting of Ga–Se/In–Se/Cu–Se stacks. The TRPL lifetime, demonstrating a positive relationship with PL intensity, exhibits a close correlation with all photovoltaic parameters. According to TRPL and sensitive capacitance measurements, the average band-gap energy ( E g ) should be in a range of 1.25–1.30 eV, giving rise to sufficiently long TRPL lifetimes. Ultimately, CIGS absorber is fabricated with double graded E g profile with a proper average E g of 1.27 eV and back-surface field of 0.22 V/μm, defined as a ratio of the change in E g divided by the change in a depth range from 1 to 2 μm from CIGS surface. This graded E g profile results in the improvement of the efficiency of the CIGS solar cell on a flexible SUS substrate up to 16.22% without an anti-reflective layer.

2-((1E,3E)-4-(6-((11)C-methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol ((11)C-PBB3) is a clinically useful PET probe that we developed for in vivo imaging of tau pathology in the human brain. To ensure the availability of this probe among multiple PET facilities, in the present study we established protocols for the radiosynthesis and quality control of (11)C-PBB3 and for the characterization of its photoisomerization, biodistribution, and metabolism.(11)C-PBB3 was synthesized by reaction of the tert-butyldimethylsilyl desmethyl precursor ( 1: ) with (11)C-methyl iodide using potassium hydroxide as a base, followed by deprotection. Photoisomerization of (11)C-PBB3 under fluorescent light was determined. The biodistribution and metabolite analysis of (11)C-PBB3 was determined in mice using the dissection method.(11)C-PBB3 was synthesized with 15.4% ± 2.8% radiochemical yield (decay-corrected, n = 50) based on the cyclotron-produced (11)C-CO2 and showed an averaged synthesis time of 35 min from the end of bombardment. The radiochemical purity and specific activity of (11)C-PBB3 were 98.0% ± 2.3% and 180.2 ± 44.3 GBq/μmol, respectively, at the end of synthesis (n = 50). (11)C-PBB3 showed rapid photoisomerization, and its radiochemical purity decreased to approximately 50% at 10 min after exposure to fluorescent light. After the fluorescent light was switched off, (11)C-PBB3 retained more than 95% radiochemical purity over 60 min. A suitable brain uptake (1.92% injected dose/g tissue) of radioactivity was observed at 1 min after the probe injection, which was followed by rapid washout from the brain tissue. More than 70% of total radioactivity in the mouse brain homogenate at 5 min after injection represented the unchanged (11)C-PBB3, despite its rapid metabolism in the plasma.(11)C-PBB3 was produced with sufficient radioactivity and high quality, demonstrating its clinical utility. The present results of radiosynthesis, photoisomerization, biodistribution, and metabolite analysis could be helpful for the reliable production and application of (11)C-PBB3 in diverse PET facilities.

Oncoimaging using positron emission tomography (PET) with a specific radioprobe would facilitate individualized cancer management. Evidence indicates that ectopically expressed metabotropic glutamate 1 (mGlu1) receptor independently induces melanocyte carcinogenesis, and it is therefore becoming an important target for personalized diagnosis and treatment strategies for melanomas. Here, we report the development of an oncoprotein-based PET imaging platform in melanomas for noninvasive visualization and quantification of mGlu1 with a novel mGlu1-specific radioprobe, 4-(18)F-fluoro-N-[4-[6-(isopropyl amino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ((18)F-FITM). (18)F-FITM shows excellent pharmacokinetics, namely the dense and specific accumulation in mGlu1-positive melanomas versus mGlu1-negative hepatoma and normal tissues. Furthermore, the accumulation levels of radioactivity corresponded to the extent of tumor and to levels of mGlu1 protein expression in melanomas and melanoma metastasis. The (18)F-FITM PET imaging platform, as a noninvasive personalized diagnostic tool, is expected to open a new avenue for defining individualized therapeutic strategies, clinical trials, patient management and understanding mGlu1-triggered oncologic events in melanomas.

Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is a NET-selective tricyclic antidepressant (TCAs) that has been widely used for the treatment of depression. Previous positron emission tomography (PET) studies have reported over 80% serotonin transporter occupancy with clinical doses of selective serotonin reuptake inhibitors (SSRIs), but there has been no report of NET occupancy in patients treated with relatively NET-selective antidepressants. In the present study, we used PET and (S,S)-[18¹⁸F]FMeNER-D₂ to investigate NET occupancies in the thalamus in 10 patients with major depressive disorder taking various doses of nortriptyline, who were considered to be responders to the treatment. Reference data for the calculation of occupancy were derived from age-matched healthy controls. The result showed approximately 50-70% NET occupancies in the brain as a result of the administration of 75-200 mg/d of nortriptyline. The estimated effective dose (ED₅₀) and concentration (EC₅₀) required to induce 50% occupancy was 65.9 mg/d and 79.8 ng/ml, respectively. Furthermore, as the minimum therapeutic level of plasma nortriptyline for the treatment of depression has been reported to be 70 ng/ml, our data indicate that this plasma nortriptyline concentration corresponds to approximately 50% NET occupancy measured with PET, suggesting that more than 50% of central NET occupancy would be appropriate for the nortriptyline treatment of patients with depression.

Background Histamine H3 receptor (H3R) is a potential therapeutic target of sleep- and cognition-related disorders. The purpose of the present study is to develop a novel positron emission tomography (PET) ligand for H3Rs from dihydroquinolinone derivatives, which we previously found to have high affinity with these receptors. Methods Six compounds were selected from a dihydroquinolinone compound library based on structural capability for 11C labeling and binding affinity for H3Rs. Their in vivo kinetics in the rat brain were examined in a comparative manner by liquid chromatography and tandem mass spectrometry (LC-MS/MS). Chemicals with appropriate kinetic properties were then labeled with 11C and evaluated in rats and monkeys using PET. Results Of the six compounds, TASP0410457 (also diminutively called TASP457) and TASP0434988 exhibited fast kinetics and relatively high brain uptakes in ex vivo LC-MS/MS and were selected as candidate PET imaging agents. PET data in rat brains were mostly consistent with LC-MS/MS findings, and rat and monkey PET scans demonstrated that [11C]TASP0410457 was superior to [11C]TASP0434988 for high-contrast H3R PET imaging. In the monkey brain PET, distribution volume for [11C]TASP0410457 could be quantified, and receptor occupancy by a nonradioactive compound was measurable using this radioligand. The specific binding of [11C]TASP0410457 to H3Rs was confirmed by autoradiography using rat and monkey brain sections. Conclusions We developed [11C]TASP0410457 as a radioligand enabling a robust quantification of H3Rs in all brain regions and demonstrated the utility of ex vivo LC-MS/MS and in vivo PET assays for selecting appropriate imaging tracers. [11C]TASP0410457 will help to examine the implication of H3Rs in neuropsychiatric disorders and to characterize emerging therapeutic agents targeting H3Rs. Electronic supplementary material The online version of this article (doi:10.1186/s13550-016-0170-2) contains supplementary material, which is available to authorized users.

Hepatic fibrosis is the wound healing response to chronic hepatic injury caused by various factors. In this study, we aimed to evaluate the utility of translocator protein (18 kDa) (TSPO) as a molecular imaging biomarker for monitoring the progression of hepatic fibrosis to cirrhosis. Model rats were induced by carbon tetrachloride (CCl4) and liver fibrosis was assessed. Positron emission tomography (PET) with N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[18F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]-acetamide ([18F]FEDAC), a radioprobe specific for TSPO, was used for noninvasive visualisation in vivo. PET scanning, immunohistochemical staining, ex vivo autoradiography and quantitative reverse-transcription polymerase chain reaction were performed to elucidate the relationships among radioactivity uptake, TSPO levels and cellular sources enriching TSPO expression in damaged livers. PET showed that uptake of radioactivity in livers increased significantly after 2, 4, 6 and 8 weeks of CCl4 treatment. Immunohistochemistry demonstrated that TSPO was mainly expressed in macrophages and hepatic stellate cells (HSCs). TSPO-expressing macrophages and HSCs increased with the progression of liver fibrosis. Interestingly, the distribution of radioactivity from [18F]FEDAC was well correlated with TSPO expression and TSPO mRNA levels increased with the severity of liver damage. TSPO was a useful molecular imaging biomarker and could be used to track the progression of hepatic fibrosis to cirrhosis with PET.

Oseltamivir phosphate (Tamiflu(®)) is an orally active anti-influenza drug, which is hydrolyzed to its metabolite Ro 64-0802 inhibiting the influenza virus with potent activity. The abnormal behavior of young influenza patients associated with the use of oseltamivir has developed to a social problem in countries where Tamiflu is often prescribed. It is important to determine the amount of oseltamivir in the brain and to elucidate the relationship between its presence and neuropsychiatric side effects. The aim of this study was to determine the radioactivity in the infant, juvenile and adult rat brains after injection of [(11)C]oseltamivir into the rats using PET and autoradiography. After injection of this radioligand, the highest radioactivity was found in the infant brain and the radioactivity level decreased with age. Ex vivo autoradiography on the infant brain displayed a relatively higher radioactivity in the cerebellum than that in the cerebrum. Pretreatment with cyclosporin A (an inhibitor for P-glycoprotein) increased the brain radioactivity. These results give helpful insights into elucidating why the neuropsychiatric side effects of oseltamivir occur in young patients.

The aim of this study was to visualize early infarction in the rat brain after ischemia using a translocator protein (TSPO) (18 kDa) PET ligand [ 11 C]DAC with ultra-high specific activity (SA) of 3670–4450 GBq/μmol. An infarction model of rat brain was prepared by ischemic surgery and evaluated 2 days after ischemia using small-animal PET and in vitro autoradiography. Early infarction with a small increase of TSPO expression in the brain was visualized using PET with high SA [ 11 C]DAC (average 4060 GBq/μmol), but was not distinguished clearly with usually reported SA [ 11 C]DAC (37 GBq/μmol). Infarction in the rat brain 4 days after ischemia was visualized using high and usually reported SAs [ 11 C]DAC. Displacement experiments with unlabeled TSPO-selective AC-5216 or PK11195 diminished the difference in radioactivity between ipsilateral and contralateral sides, confirming that the increased uptake on the infracted brain was specific to TSPO. In vitro autoradiography with high SA [ 11 C]DAC showed that the TSPO expression increased on early infarction in the rat brain. High SA [ 11 C]DAC is a useful and sensitive biomarker for the visualization of early infarction and the characterization of TSPO expression which was slightly elevated in the infarcted brain using PET.

This study presents a combined small animal holding fixture system, termed a 'bridge capsule', which provides for small animal re-fixation with positional reproducibility. This system comprises separate holding fixtures for the head and lower body and a connecting part to a gas anesthesia system. A mouse is fixed in place by the combination of a head fixture with a movable part made from polyacetal resin, a lower body fixture made from vinyl-silicone and a holder for the legs and tail. For re-fixation, a similar posture could be maintained by the same holding fixtures and a constant distance between the head and lower body fixtures is maintained. Artifacts caused by the bridge capsule system were not observed on magnetic resonance (MRI) and positron emission tomography (PET) images. The average position differences of the spinal column and the iliac body before and after re-fixation for the same modality were approximately 1.1 mm. The difference between the MRI and PET images was approximately 1.8 mm for the lower body fixture after image registration using fiducial markers. This system would be useful for longitudinal, repeated and multimodal imaging experiments requiring similar animal postures.

Objective XR9576 (tariquidar) is an anthranilic acid derivative and potent P-glycoprotein (P-gp) inhibitor. XR9576 has undergone phase I and II studies as combined chemotherapy against cancer. XR9576 has been developed as a useful therapeutic agent but not as a PET probe. We therefore developed [11C]XR9576 as a PET probe and assessed whether PET studies using [11C]XR9576 are a promising approach to assess P-gp function primarily. Methods We synthesized [11C]XR9576 by methylation of 7-O-desmethyl XR9576 with [11C]methyl iodide. In in vivo tissue distribution, the effects of co-injection with XR9576 on the uptake of [11C]XR9576 in mice were investigated. PET studies using [11C]XR9576 were performed in P-gp and/or Bcrp knockout mice as well as in wild-type mice. Metabolites of [11C]XR9576 were measured in the brain and plasma of mice. Results [11C]XR9576 was successfully synthesized with suitable radioactivity for injection as well as appropriate radiochemical purity and stability. In in vivo tissue distribution, the brain uptake of [11C]XR9576 significantly increased about tenfold of control on co-injection with >10 mg/kg of XR9576. In PET studies, the AUCbrain [0–60 min] in P-gp and P-gp/Bcrp knockout mice was 2- and 11-fold higher than that in wild-type mice. [11C]XR9576 showed a high metabolic stability (>90% unchanged form) in the brain and plasma of mice 30 min after injection. These results suggest that a tracer amount of [11C]XR9576 behave as the P-gp and Bcrp substrate, and the increased brain uptake or AUCbrain of [11C]XR9576 correlates with P-gp and Bcrp functions. Conclusions PET studies using [11C]XR9576 may be a promising approach for evaluating deficiency of the function of drug efflux transporters targeting intracranial diseases and tumors.

[(18)F] fluorodeoxyglucose-positron emission tomography (FDG-PET) is regarded as a unique imaging modality, because the images reflect tumor activity. This characteristic of PET encouraged us to use it to develop a novel method of quantitatively measuring liver metastasis viability.F344 rats were injected with rat colon adenocarcinoma cells (RCN-9 cell line) via the portal vein, and some of them were treated with 5-fluorouracil (5-FU). Tumor growth and tumor activity were measured by PET. We used a tumor viability index (TVI) to evaluate changes in tumor activity and to quantitatively evaluate tumor proliferation activity, instead of using the standardized uptake value (SUV) of the tumor tissue. The TVI was compared with the number of tumor nodules and the proliferating cell nuclear antigen (PCNA) index 28 days after RCN-9 cell inoculation.[(18)F] FDG uptake by the liver tumors was measured by PET, and the TVI was found to increase as the tumor nodules increased in number and size. The TVI values in the experimental model represented the viability of tumors suppressed by chemotherapy, and the values were significantly correlated with the number of nodules and the PCNA index.The TVI was concluded to be superior to the SUV, the commonly used indicator, for evaluating tumor growth, especially that of multiple, small tumors.

We investigated feasibility of positron emission tomography (PET) with [11C]SA4503 for evaluating the sigma1 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 sigma1 receptor (sigma1R), 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 sigma1R 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 sigma1R occupancy rates were approximately 80% in all seven regions investigated including the caudate, putamen and cerebellum 18 h after the administration, suggesting that the sigma1R 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 sigma1R occupancy rates by neuroleptics or other drugs.

Sigma receptors are expressed in a wide variety of tumor cell lines, and are expressed in proliferating cells. A radioligand for the visualization of sigma receptors could be useful for selective detection of primary tumors and their metastases, and for non-invasive assessment of tumor proliferative status. To this end we evaluated two sigma receptor ligands, [11C]SA5845 and [11C]SA4503. In an in vitro study, AH109A hepatoma showed moderate densities of sigma1 and sigma2 receptors, and VX-2 carcinoma showed a high density of sigma2 receptors: Bmax (fmol/mg protein) for sigma1 vs. sigma2, 1,700 vs. 1,200 for AH109A hepatoma and 800 vs. 10,000 for VX-2 carcinoma. In a cell growth assay in vitro, neither SA5845 nor SA4503 (

Fully quantitative analysis of the adenosine A 1 receptor (A1R) in the brain with 11 C-MPDX and positron emission tomography is reported. The kinetics is described using a two-tissue three-compartment model, and estimated binding potentials correspond well with the estimates made by Logan plot. The image of the binding potential of the MPDX is physiologically reasonable. We conclude that MPDX is applicable to the visualization of the A1Rs in the brain with Logan plot.

Recently we have clinically used three new radioligands, [11C]SA4503, [11C]MPDX, and [11C]TMSX, for mapping sigma1, adenosine A1, and adenosine A2A receptors, respectively, in the human brain by positron emission tomography. These radioligands are synthesized by methylation of the respective demethyl precursor with [11C]methyl iodide. Here we demonstrate the improved syntheses of these compounds by use of [11C]methyl triflate, a highly reactive alternative to [11C]methyl iodide.

To determine whether positron emission tomography (PET) can be used for imaging of neuroreceptors in eyes of rabbits. PET imaging of dopamine D2 receptor, dopamine transporter, serotonin1A receptor and sigma1 receptor in the eyes and brain was performed using corresponding positron-emitting ligands in baseline, pretreatment and displacement conditions. The 4 radioligands outlined the eyes and brain in the baseline. Pretreatment resulted in a slight reduction (26–28%) in the uptake in the anterior segments of eyes. The binding of each radioligand in the iris-ciliary body and retina was confirmed by ex vivo autoradiography. However, the PET signal in the eyes was unexpectedly higher than the autoradiography signal. The identification of radioligand-neuroreceptor binding by PET in the rabbit eyes is not specific enough.

In previous in vivo studies with mice, rats and monkeys, we have demonstrated that [11C]TMSX ([7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine) is a potential radioligand for mapping adenosine A2A receptors of the brain by positron emission tomography (PET). In the present study, we performed a preclinical study. A suitable preparation method for [11C]TMSX injection was established. The radiation absorbed-dose by [11C]TMSX in humans estimated from the tissue distribution in mice was low enough for clinical use, and the acute toxicity and mutagenicity of TMSX were not found. The striatal uptake of [11C]TMSX in mice was reduced by pretreatment with theophylline at the dose of 10 and 100 mg/kg, suggesting that the [11C]TMSX PET should be carefully performed in the patients received with theophylline. We have concluded that [11C]TMSX is suitable for mapping adenosine A2A receptors in the human brain by PET.

The potential of a 11C-labeled selective sigma1 receptor ligand, 1-(3,4-dimethoxyphenethyl)-4-[3-(3,4-dichlorophenyl)propyl]piperazine ([11C]SA6298), was evaluated as a positron emission tomography (PET) ligand for mapping sigma, receptors in the central nervous system and peripheral organs. [11C]SA6298 was synthesized by methylation of the desmethyl SA6298 with [11C]CH3I, with the decay-corrected radiochemical yield of 39 +/- 5% based on [11C]CH3I and with the specific activity of 53 +/- 17 TBq/mmol within 20 min from end of bombardment (EOB). In mice, the uptake of [11C]SA6298 was significantly decreased by carrier loading in the brain, liver, spleen, heart, lung, small intestine, and kidney in which sigma receptors are present as well as in the skeletal muscle. Pretreatment with SA6298 also blocked the uptake of [11C]SA6298 by these organs except for the small intestine, but significant displacement of [11C]SA6298 by posttreatment with SA6298 was observed only in the heart, lung, and muscle. In the blocking study with one of the eight sigma receptor ligands, including haloperidol, SA6298, NE-100, (+)-pentazocine, SA4503, (-)-pentazocine, (+)-3-PPP, and (+)-SKF 10,047 (in the order of the affinity for sigma1 receptor subtype), only SA6298 and an analog SA4503 significantly reduced the brain uptake of [11C]SA6298 to approximately 80% of the control, but the other six ligands did not. Peripherally, the uptake of [11C]SA6298 by the organs described above was decreased predominantly by SA6298 or SA4503, but the blocking effects of the other five ligands except for NE-100 depended on their affinity for sigma1 receptors. The saturable brain uptake of [11C]SA6298, approximately 20%, was also observed by tissue dissection method in rats and by PET in a cat. Ex vivo autoradiography of the rat brain showed a high uptake in the cortex and thalamus. In the cat brain a relatively high uptake was found in the cortex, thalamus, striatum, and cerebellum. These results have indicated a receptor-mediated uptake of the tracer to some extent in the brain and peripheral organs. However, the tracer has a limited potential for the PET study of the brain receptors because of a relatively high nonspecific binding.

Background Metabotropic glutamate 7 (mGlu7) receptor is a crucial target protein for the development of pharmaceuticals against central nervous system disorders. In the present study, we synthesized [11C]MMPIP, a putative radioligand for mGlu7 (binding constant K B = 30 nM), and evaluated its potential for imaging of mGlu7 via in vitro and in vivo techniques. Methods [11C]MMPIP was synthesized by the reaction of phenol precursor 3 with [11C]CH3I. In vitro autoradiography using [11C]MMPIP was performed on rat brain sections. To determine in vitro specific binding of [11C]MMPIP with mGlu7, a blocking study was conducted by co-incubation with excess AMN082, a selective antagonist for mGlu7, or unlabeled MMPIP. Positron emission tomography (PET) studies and ex vivo metabolite analysis were carried out on rat brains. Results [11C]MMPIP was obtained with two specific activity (SA) levels of average 58 (conventional) and 3,800 (high SA) GBq/μmol, respectively. High radioactive signals derived from conventional [11C]MMPIP in the in vitro autoradiography were seen in the thalamus, medulla oblongata, and striatum, corresponding with comprehensive brain distributions of mGlu7. Co-incubation with ANM082 or unlabeled MMPIP reduced the radioactive signals in the brain sections, respectively. In the PET studies with [11C]MMPIP, no specific uptake relative to mGlu7 was found in the examined brain regions. Conclusion Despite in vitro specific binding of [11C]MMPIP with mGlu7, visualization of mGlu7 in the living brain using PET was not successful. Development of new ligand candidates with higher affinity for mGlu7 is necessary.

Neuroimaging measures have potential for monitoring neuroinflammation to guide treatment before the occurrence of significant functional impairment or irreversible neuronal damage in multiple sclerosis (MS). N-Benzyl-N-methyl-2-(7-[(11)C]methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl) acetamide ([(11)C]DAC), a new developed positron emission tomography (PET) probe for translocator protein 18 kDa (TSPO), has been adopted to evaluate the neuroinflammation and treatment effects of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. [(11)C]DAC-PET enabled visualization of neuroinflammation lesion of EAE by tracing TSPO expression in the spinal cords; the maximal uptake value reached in day 11 and 20 EAE rats with profound inflammatory cell infiltration compared with control, day 0 and 60 EAE rats. Biodistribution studies and in vitro autoradiography confirmed these in vivo imaging results. Doubling immunohistochemical studies showed the infiltration and expansion of CD4+ T cells and CD11b+ microglia; CD68+ macrophages were responsible for the increased TSPO levels visualized by [(11)C]DAC-PET. Furthermore, mRNA level analysis of the cytokines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) revealed that TSPO+/CD4 T cells, TSPO+ microglia and TSPO+ macrophages in EAE spinal cords were activated and secreted multiple proinflammation cytokines to mediate inflammation lesions of EAE. EAE rats treated with an immunosuppressive agent: 2-amino-2-[2-(4-octylphenyl)ethyl] propane-1,3-diolhydrochloride (FTY720), which exhibited an absence of inflammatory cell infiltrates, displaying a faint radioactive signal compared with the high accumulation of untreated EAE rats. These results indicated that [(11)C] DAC-PET imaging is a sensitive tool for noninvasively monitoring the neuroinflammation response and evaluating therapeutic interventions in EAE.

Gefitinib (Iressa) is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. Recent studies confirmed that gefitinib interacted with the breast cancer resistance protein (BCRP) at submicromolar concentrations, whereas other multidrug transporters, including P-glycoprotein (P-gp), showed much lower reactivity toward gefitinib. Recently, many tracers for positron emission tomography (PET) have been prepared to study P-gp function in vivo; however, PET tracers had not been evaluated for both P-gp and BCRP modulation in the brain. Therefore, we evaluated in vivo brain penetration-mediated P-gp and BCRP in mice using [(11)C]gefitinib. Co-injection with gefitinib (over 50 mg/kg), a nonspecific P-gp modulator cyclosporin A (50 mg/kg), and the dual P-gp and BCRP modulator GF120918 (over 5 mg/kg) induced an increase in the brain uptake of [(11)C]gefitinib in mice 30 min after injection. In the PET study of mice, the radioactivity level in the brain with co-injection of GF120918 (5 mg/kg) was three- to fourfold higher than that in control after initial uptake. The radioactivity level in the brain in P-gp and Bcrp knockout mice was approximately eightfold higher than that in wild-type mice 60 min after injection. In conclusion, [(11)C]gefitinib is a promising PET tracer to evaluate the penetration of gefitinib into the brain by combined therapy with P-gp or BCRP modulators, and into brain tumors. Furthermore, PET study with GF120918 is a promising approach for evaluating brain penetration-mediated P-gp and BCRP.

For evaluating a newly developed radioligand for positron emission tomography (PET), successive measurements of regional cerebral blood flow (rCBF) and the kinetics of the radioligand in the same subject are preferable in the first clinical trial. In this study, we demonstrate an example for the study of (11)C-labeled 1-(3,4-dimethoxyphenethyl)-4-(3-phenylprophyl) piperazine ((11)C-SA4503) for mapping sigma(1) receptors in the human brain. Five healthy male subjects underwent two successive PET scans with (15)O-H(2)O to measure the rCBF and with (11)C-SA4503 (dynamic 60-min scan). The brain kinetics of (11)C-SA4503 was evaluated using the time-activity curve (TAC) of tissue in each of the 11 regions of the brain and the metabolite-corrected TAC of plasma on the basis of a two-tissue compartment fourparameter model. The estimated parameters were four rate constants: K (1), influx from plasma to brain tissue; k (2), efflux from tissue to plasma; k (3), association between tracer and receptors; and k (4), dissociation of tracer-receptor complex, and the binding potential (BP), k (3)/k (4). (11)CSA4503 was distributed all over the brain, and the TACs exhibited an accumulation pattern in all the 11 regions. K (1) of (11)C-SA4503 correlated with rCBF, but the other three rate constant parameters and BP did not. The regional difference in the BP of (11)C-SA4503 is compatible with those of sigma(1) receptors. In conclusion, successive PET measurements of rCBF and the brain kinetics of radioligand-neuroreceptor binding are useful for the first clinical trial of a newly developed radioligand for mapping neuroreceptors, and the protocol is applicable to pathophysiological studies of brain disorders.

The sigma1 receptor is considered to be involved in cognitive function. A postmortem study reported that the sigma1 receptors were reduced in the hippocampus in Alzheimer’s disease (AD). However, in vivo imaging of sigma1 receptors in the brain of AD patients has not been reported. The aim of this study is to investigate the mapping of sigma1 receptors in AD using [11C]SA4503 positron emission tomography (PET). We studied five AD patients and seven elderly volunteers. A dynamic series of decay-corrected PET data acquisition was performed for 90 min starting at the time of the injection of 500 MBq of [11C]SA4503. A two-tissue three-compartment model was used to estimate K 1, k 2, k 3, k 4, and the delay between metabolite-corrected plasma and tissue time activity using a Gauss-Newton algorithm. The ratio of k 3 to k 4 was computed as the binding potential (BP), which is linearly related to the density of sigma1 receptors. Unpaired t tests were used to compare K 1 and BP in patients with AD and normal subjects. As compared with normals, BP in the AD was significantly lower in the frontal, temporal, and occipital lobe, cerebellum and thalamus, whereas K 1 was significantly lower in the parietal lobe. [11C]SA4503 PET can demonstrate that the density of cerebral and cerebellar sigma1 receptors is reduced in early AD.

The distribution characteristics of18F-fluoromethylcholine (18F-choline) in tumor and inflammatory tissue were compared with those of14C or3H-2-deoxyglucose (2DG) as a substitute for fluorodeoxyglucose (FDG). A solid tumor model of AH109A in the back of Donryu rats and an aseptic inflammation model of turpentine oil injection subcutaneously in rats were used for experiments. Tissue distribution was examined at 5, 30 and 60 min after injection of a mixture of18F-choline and3H-2DG. Double-tracer high-resolution autoradiographs (ARGs) of tumor and inflammation were obtained using18F-choline and14C-2DG. Whole body (WB) ARG was performed with18F-choline. Tumor uptake of18F-choline reached a peak at 30 min, when the tumor to blood ratio was 5.1. Both tumor and inflammation uptake of 2DG were higher than those of18F-choline.18F-choline uptake by inflammation was lower than that by tumor. The tumor to brain uptake ratio was 5.7 with18F-choline and 1.2 with 2DG. In the ARG of inflammation, linear or ring-like structures of 2DG uptake were observed in the wall of the abscess, but were not identified with18F-choline. Photomicrography showed that the uptake was limited to granulocytes, macrophages and fibroblasts, consistent with sub-acute or chronic inflammation. 18F-choline uptake by inflammation was lower than that of 2DG in the tissue distribution study, and18F-choline uptake by abscess wall was significantly lower than that of 2DG in the autoradiography study. Our results may suggest the feasibility of18F-choline-PET imaging for the differential diagnosis of cancer and chronic inflammation in lung and brain.

We prepared a liver metastatic tumor model by injection of rat colon adenocarcinoma cells to Fischer F344 rats through portal vein, and applied positron emission tomography (PET) using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) ([18F]FDG-PET) to this model. At an early stage of the model, multiple small tumor nodules appeared in the inferior lobes of the livers, and extended later into the superior lobes. To evaluate the tumor growth and tumor viability at the early stage, we proposed a new concept, tumor viability index (TVI), instead of the standardized uptake value (SUV) of the [18F]FDG uptake. The TVI was defined by subtracting the signal based on the normal liver from the total signal in the whole liver including tumor nodules: (whole liver SUV — normal liver SUV) × ml of whole liver region of interest (ROI). For the signal of the whole liver, ROIs were placed on six slices covering the whole liver, and the ROI of normal liver region was located in the superior lobe of the liver. The average TVI values increased with tumor growth and significantly correlated with the numbers of tumor nodules. The new concept may be useful for evaluating the tumor viability non-invasively and quantitatively by [18F]FDG-PET.

(-)-O-Methylvesamicol ((-)-OMV) exhibited in vitro a high affinity for vesicular acetylcholine transporter (VAChT) (Ki, 6.7 nM) and a relatively low affinity for sigmal receptor (Ki, 33.7 nM). We prepared (-)-[11C]OMV by a palladium-promoted cross-coupling reaction using [11C]methyl iodide, in a radiochemical yield of 38 +/- 6.9% (n=3), a radiochemical purity of 98 +/- 2.3% (n = 5), and a specific activity of 11 +/- 7.0 TBq/mmol at 30 minutes after EOB (n=5). Then, we evaluated in vivo whether (-)-[11C]OMV has properties as a PET radioligand for mapping VAChT. In rats, the brain uptake of (-)-[11C]OMV was 1.1%ID/g at 5 minutes postinjection, and was retained of a high level for 60 minutes. The brain uptake was significantly inhibited by the co-injection (500 nmol/kg) of cold (-)-OMV (58-66%), (-)-vesamicol (57-65%), and two sigma receptor ligands with modulate affinities for VAChTs: SA4503 (56-71%) and haloperidol (39-64%) in all of the brain regions, including the cerebellum with a low density of VAChTs, but not of sigmal-selective ligand (+)-pentazocine. However, the pretreatment with a large excess amount of (+/-)-pentazocine (50 micromol/kg) reduced the uptake in a different manner in the brain regions: 25% reduction in the striatum with a high density of VAChTs, and a 50-55% reduction in the other regions with a lower density of VAChTs. Ex vivo autoradiography using (-)-[11C]OMV showed a similar regional brain distribution of [3H](-)-vesamicol. In the PET study of the monkey brain, the regional brain distribution pattern of (-)-[11C]OMV was different from that of [11C]SA4503. The uptake of (-)-[11C]OMV was relatively higher in the striatum, was reversible, and an apparent equilibrium state was found at 20-40 minutes. In conclusion, (-)-[11C]OMV exhibited appropriate brain kinetics during the time frame of 11C-labeled tracers and bound mainly to VAChTs; however, the binding to sigmal receptors was not disregarded. Therefore, (-)-[11C]OMV-PET together with help of [11C]SA4503-PET may evaluate VAChTs.