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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.

The histamine H3 receptors are presynaptic neuroreceptors that inhibit the release of histamine and other neurotransmitters. The receptors are considered a drug target for sleep disorders and neuropsychiatric disorders with cognitive decline. We developed a novel PET ligand for the H3 receptors, [11C]TASP0410457 ([11C]TASP457), with high affinity, selectivity and favorable kinetic properties in the monkey, and evaluated its kinetics and radiation safety profile for quantifying the H3 receptors in human brain. Ten healthy men were scanned for 120 min with a PET scanner for brain quantification and three healthy men were scanned for radiation dosimetry after injection of 386 ± 6.2 MBq and 190 ± 7.5 MBq of [11C]TASP457, respectively. For brain quantification, arterial blood sampling and metabolite analysis were performed using high-performance liquid chromatography. Distribution volumes (V T) in brain regions were determined by compartment and graphical analyses using the Logan plot and Ichise multilinear analysis (MA1). For dosimetry, radiation absorbed doses were estimated using the Medical Internal Radiation Dose scheme. [11C]TASP457 PET showed high uptake (standardized uptake values in the range of about 3 – 6) in the brain and fast washout in cortical regions and slow washout in the pallidum. The two-tissue compartment model and graphical analyses estimated V T with excellent identification using 60-min scan data (about 16 mL/cm3 in the pallidum, 9 – 14 in the basal ganglia, 6 – 9 in cortical regions, and 5 in the pons), which represents the known distribution of histamine H3 receptors. For parametric imaging, MA1 is recommended because of minimal underestimation with small intersubject variability. The organs with the highest radiation doses were the pancreas, kidneys, and liver. The effective dose delivered by [11C]TASP457 was 6.9 μSv/MBq. [11C]TASP457 is a useful novel PET ligand for the investigation of the density of histamine H3 receptors in human brain.

Parkinson's disease (PD) is a prevalent degenerative disorder affecting the CNS that is primarily characterized by resting tremor and movement deficits. Group I metabotropic glutamate receptor subtypes 1 and 5 (mGluR1 and mGluR5, respectively) are important targets for investigation in several CNS disorders. In the present study, we investigated thein vivoroles of mGluR1 and mGluR5 in chronic PD pathology by performing longitudinal positron emission tomography (PET) imaging inA53Ttransgenic (A53T-Tg) rats expressing an abnormal human α-synuclein (ASN) gene.A53T-Tgrats showed a dramatic decline in general motor activities with age, along with abnormal ASN aggregation and striatal neuron degeneration. In longitudinal PET imaging, striatal nondisplaceable binding potential (BPND) values for [11C]ITDM (N-[4-[6-(isopropylamino) pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[11C]methylbenzamide), a selective PET ligand for mGluR1, temporarily increased before PD symptom onset and dramatically decreased afterward with age. However, striatal BPNDvalues for (E)-[11C]ABP688 [3-(6-methylpyridin-2-ylethynyl)-cyclohex-2-enone-(E)-O-[11C]methyloxime], a specific PET ligand for mGluR5, remained constant during experimental terms. The dynamic changes in striatal mGluR1 BPNDvalues also showed a high correlation in pathological decreases in general motor activities. Furthermore, declines in mGluR1 BPNDvalues were correlated with decreases in BPNDvalues for [18F]FE-PE2I [(E)-N-(3-iodoprop-2E-enyl)-2β-carbo-[18F]fluoroethoxy-3β-(4-methylphenyl) nortropane], a specific PET ligand for the dopamine transporter, a biomarker for dopaminergic neurons. In conclusion, our results have demonstrated for the first time that dynamic changes occur in mGluR1, but not mGluR5, that accompany pathological progression in a PD animal model.SIGNIFICANCE STATEMENTSynaptic signaling by glutamate, the principal excitatory neurotransmitter in the brain, is modulated by group I metabotropic glutamate receptors, including the mGluR1 and mGluR5 subtypes. In the brain, mGluR1 and mGluR5 have distinct functional roles and regional distributions. Their roles in brain pathology, however, are not well characterized. Using longitudinal PET imaging in a chronic rat model of PD, we demonstrated that expression of mGluR1, but not mGluR5, dynamically changed in the striatum accompanying pathological PD progression. These findings imply that monitoring mGluR1in vivomay provide beneficial information to further understand central nervous system disorders.

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.

[11C]choline has a weak UV absorption chromophore, and it is challenging to detect less than 1 μg/mL choline using radio-HPLC-UV. In this study, we established an analytical procedure of [11C]choline using the radio-HPLC coupled with the corona-charged aerosol detector. As a result, we achieved more than 100 GBq/μmol (over 0.1 μg/mL of choline) of molar radioactivity at the end of synthesis, over 95% of radiochemical purity, and more than 0.1 μg/mL of 2-dimethyoaminoethanol as a chemical impurity.

The imdazoline IPET scans were acquired in the Zucker (ZUC) lean and fatty rats, radioactivity and metabolites of plasma were measured, and the kinetic parameters were estimated.Radioactivity levels after the injection of [By PET imaging using [

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.

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.

Bismuth (Bi)-doped Cu(In,Ga)Se2 (CIGS) films were prepared by the so-called “multi-layer precursor method”, obtained by depositing them onto Bi layers with various thicknesses on Mo-coated soda-lime glass (SLG) substrates. Material composition (Cu, In, Ga, and Se) profiles of the CIGS films are almost identical, whereas sodium (Na) is reduced, when Bi thickness is increased. Moreover, the incorporation of Bi into the CIGS film is enhanced with thicker Bi layer. With Bi thickness from 0 to 70 nm, the 2.4-μm-thick CIGS absorbers demonstrate the increase in CIGS grain size, carrier lifetime, and carrier concentration, thus improving their cell performances, especially open-circuit voltage (VOC). With further increase in Bi thickness of above 70 nm, the CIGS films show the deterioration of CIGS film quality owing to the formation of Bi compounds such as Bi, BiSe, and Bi4Se3. Consequently, Bi-doped CIGS absorber with thickness of 2.4 μm, prepared with the 70-nm-thick Bi layer on Mo-coated SLG substrate, gives rise to the improvement of photovoltaic performances, especially VOC. (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Cu(In,Ga)Se 2 (CIGS) solar cells were fabricated on both rigid soda-lime glass (SLG) and flexible stainless steel (SUS) substrates. Their absorbers, with several [Ga] / ([Ga] + [In]) profiles, were deposited using the so-called “multi-layer precursor method”, consisting of Ga–Se/In–Se/Cu–Se stacked precursors. It was revealed that the open-circuit voltage ( V OC ) of the CIGS solar cell is well correlated with the near-surface GGI, defined as the average [Ga] / ([Ga] + [In]) ratio within 200 nm of the CIGS surface. The near-surface GGI could be predicted when the Raman scattering peak position of the CIGS film was known. The estimated penetration depth of Raman scattering light into the CIGS layer was approximately 100–140 nm from its surface. Moreover, a relationship between V OC and the Raman scattering peak position was observed. Ultimately, the Raman scattering peak position, corresponding to the near-surface GGI of below 0.45, could be utilized as an indicator of V OC of CIGS solar cells on both rigid SLG and flexible SUS substrates without cell fabrication, which is measured by the rapid and non-destructive method.

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.

Perceptual changes in shape, size, or color are observed in patients with derealization symptoms; however, the underlying neural and molecular mechanisms are not well understood. The current study explored the relationship between neural activity associated with altered colorfulness perception assessed by fMRI and striatal dopamine D2 receptor availability measured by [11C]raclopride PET in healthy participants. Inside an fMRI scanner, participants performed the saturation adaptation task, where they rated how much vivid/faded visual objects looked like real/unreal ones using a visual analog scale. We found that participants experienced greater unreality when they perceived fadedness than vividness despite physically identical saturation. The combined fMRI and PET analyses revealed that the faded perception-related activities of the dorsolateral prefrontal and parietal cortex were positively correlated with striatal D2 receptor availability. This finding may help to understand the neuromolecular mechanisms of faded perception associated with feeling unreal in derealization symptoms.

2-(2-(3-(4-(2-[We performed the automated synthesis of [The efficiency of the [[

Introduction `The growth hormone secretagogue receptor 1a (GHS-R1a) is the orphan G-protein-coupled receptor, and its endogenous ligand is ghrelin. GHS-R1a contributes to regulation of glucose homeostasis, memory and learning, food addiction, and neuroprotection. Several PET tracers for GHS-R1a have been developed, but none have been reported to be clinically applicable to GHS-R1a imaging. In this study, we developed three new PET tracers for GHS-R1a: 18 F-labeled 6-(4-chlorophenyl)-3-((1-(2-fluoroethyl)piperidin-3-yl)methyl)-2-(o-tolyl)quinazolin-4(3 H )-one ( 1 ), 11 C-labeled 6-(4-chlorophenyl)-3-((1-(2-methoxyethyl)piperidin-3-yl)methyl)-2-(o-tolyl)quinazolin-4(3 H )-one ( 2 ), and 11 C-labeled ( S )-(4-(1 H -indole-6-carbonyl)-3-methylpiperazin-1-yl)(4′-methoxy-[1,1′-biphenyl]-4-yl)methanone ( 3 ). Methods [ 18 F] 1 was synthesized by the 18 F-fluoroethylation; [ 11 C] 2 or [ 11 C] 3 was synthesized by the 11 C-methylation. Biodistribution studies and PET studies were conducted in mice. Results We successfully radiosynthesized [ 18 F] 1, [ 11 C] 2 , and [ 11 C] 3 with appropriate radioactivity for the animal study. In the ex vivo biodistribution study, 60min following injection, the radioactivity level of [ 18 F] 1 was relatively high in the small intestine, that of [ 11 C] 2 was high in the liver, and that of [ 11 C] 3 was high in the pancreas. The radioactivity levels of the three PET tracers were relatively low in the brain. Under pretreatment with YIL781 (a selective and high affinity antagonist for GHS-R1a), the pancreas radioactivity level at 30min following [ 11 C] 3 injection was significantly reduced to 55% of control, but the radioactivity in the brain was not changed. In the PET study under control conditions, high radioactivity levels in the liver and pancreas were observed following [ 11 C] 3 injection. With YIL781 pretreatment, the accumulated radioactivity in the pancreas 15–60min after [ 11 C] 3 injection was significantly decreased to 78% of control. Conclusion [ 11 C] 3 exhibited relatively high uptake and in vivo specific binding to GHS-R1a in the mouse pancreas. [ 11 C] 3 may be a useful PET tracers for in vivo imaging of GHS-R1a in the pancreas.

Cu(In,Ga)Se2 (CIGS) films with different crystal orientations and Ga/(In + Ga), Ga/III, profiles are fabricated by the so-called “multi-layer precursor method”, utilizing multi-layer co-evaporation of material sources. In this literature, the crystal orientation and averaged Ga/III near the CIGS surface, estimated from the Ga/III profile, are investigated to improve the cell performance, especially open-circuit voltage (VOC). It is revealed that the VOC increases and more enhances with (220/204)-oriented CIGS absorbers, when the averaged Ga/III near the CIGS surface increases. The conversion efficiency of the solar cell on flexible stainless steel substrate is ultimately improved by the manipulations of the crystal orientation, namely, I(220/204)/I(112) of approximately 1.7, and the averaged Ga/III near the CIGS surface of 0.38 under the multi-layer precursor method.

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.

Cu(In,Ga)Se 2 (CIGS) is one of the most promising materials to fabricate low-cost and high-efficiency thin film solar cells. In this work, CIGS films were deposited by the so-called “multi-layer precursor method” using multi-layer co-evaporation of material sources. Based on the simulated and experimental results, the optimum averaged Ga/III, Ga/(In + Ga), in space charge region (SCR) controlling the carrier recombination near the junction and back surface Ga/III grading forming back surface field have drastic influence on cell performance. The CIGS absorber layer with double Ga/III grading profile (averaged Ga/III in SCR; 0.38 and the height of the back surface Ga/III grading; 0.33) is readily achieved by multi-layer precursor method. This leads to the improvement of efficiency of the CIGS solar cell up to 15.30% without anti-reflective layer.

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.

Because of its role in multiple central nervous system (CNS) pathways, metabotropic glutamate receptor type 1 (mGluR1) is a crucial target in the development of pharmaceuticals for CNS disorders. N-[4-[6-(isopropylamino)-pyrimidin-4-yl]-1,3-thiazol-2-yl]- N-methyl-4-[11C]-methylbenzamide ([11C]ITDM) was recently developed as a positron emission tomography (PET) ligand for mGluR1. To devise a method for measurement of the binding potential ( BP ND) of [11C]ITDM to mGluR1, reference tissue methods aimed at replacing measurement of the arterial input function are desirable. In this study, we evaluated a noninvasive quantification method of mGluR1 with [11C]ITDM, demonstrating its accuracy using Huntington disease model R6/2 mice. The BP ND measurements based on the Logan reference (Logan Ref) method have closely approximated that based on the arterial input method. We performed PET analysis with Logan Ref to assess its accuracy in quantifying the decline of mGluR1 expression in R6/2 mice. Significant decreases in BP ND values in R6/2 mice were detected in cerebellum, thalamus, striatum, and cingulate cortex. We compared autoradiographs of R6/2 mouse brain sections with immunohistochemical images, and found a close correlation between changes in radioactive signal intensity and degree of mGluR1 expression. In conclusion, [11C]ITDM-PET is a promising tool for in vivo quantification of mGluR1 expression.

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.

Introduction [ 11 C]ABP688 is a promising positron emission tomography (PET) ligand for imaging of metabotropic glutamate receptor subtype 5 (mGlu5 receptor). Of the two geometric isomers of ABP688, ( E )-ABP688 has a greater affinity towards mGlu5 receptors than ( Z )-ABP688. Therefore, a high ratio of E -isomer is required when using [ 11 C]ABP688 as a PET probe for imaging and quantification of mGlu5 receptors. The aim of this study was to evaluate the effect ( Z )-[ 11 C]ABP688 on the synthesis of [ 11 C]ABP688 to be used for binding ( E )-[ 11 C]ABP688 in the brain. Methods We synthesized and separated ( E )- and ( Z )-[ 11 C]ABP688 by purification using an improved preparative high-performance liquid chromatography (HPLC) method equipped with a COSMOSIL Cholester column. We performed an in vitro binding assay in rat brain homogenates and PET studies of the rat brains using ( E )- and ( Z )-[ 11 C]ABP688. Results ( E )- and ( Z )-[ 11 C]ABP688 were successfully obtained with suitable radioactivity for application. In the in vitro assay, the K d value of ( E )-[ 11 C]ABP688 (5.7 nmol/L) was higher than that of ( Z )-[ 11 C]ABP688 (140 nmol/L). In the PET study of the rat brain, high radioactivity after injection of ( E )-[ 11 C]ABP688 was observed in regions rich in mGlu5 receptors such as the striatum and hippocampus. In contrast, after injection of ( Z )-[ 11 C]ABP688, radioactivity did not accumulate in the brain. Furthermore, BP ND in the striatum and hippocampus was highly correlated ( R 2 = 0.99) with the percentage of ( E )-[ 11 C]ABP688 of the total radioactivity of ( E )- and ( Z )-[ 11 C]ABP688 in the injection. Conclusion We demonstrated that including ( Z )-[ 11 C]ABP688 in the [ 11 C]ABP688 injection can decrease BP ND in regions rich in mGlu5 receptors. Routine production of ( E )-[ 11 C]ABP688 will be helpful for imaging and quantification of mGlu5 receptors in clinical studies.

A procedure for the synthesis of a11C-labeled oligopeptide containing [1-11C]1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid ([1-11C]Tpi) from the corresponding Trp•HCl-containing peptides has been developed involving a Pictet-Spengler reaction with [11C]formaldehyde. The synthesis of [1-11C]Tpi from Trp and [11C]formaldehyde was examined as a model reaction with the aim of developing a facile and effective method for the labeling of peptides with carbon-11. The Pictet-Spengler reaction of Trp and [11C]formaldehyde in acidic media (TsOH or HCl) afforded the desired [1-11C]Tpi in a moderate radiochemical yield. Herein, the application of a Pictet-Spengler reaction to an aqueous solution of Trp•HCl gave the desired product with a radiochemical yield of 45.2%. The RGD peptide cyclo[Arg-Gly-Asp-D-Tyr-Lys] was then selected as a substrate for the labeling reaction with [11C]formaldehyde. The radiolabeling of a Trp•HCl-containing RGD peptide using the Pictet-Spengler reaction was successful. Furthermore, the remote-controlled synthesis of a [1-11C]Tpi-containing RGD peptide was attempted by using an automatic production system to generate [11C]CH3I. The radiochemical yield of the [1-11C]Tpi-containing RGD at the end of synthesis (EOS) was 5.9 ± 1.9% (n = 4), for a total synthesis time of about 35 min. The specific activity was 85.7 ± 9.4 GBq/µmol at the EOS. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.

Introduction Irinotecan is a semisynthetic derivative of camptothecin that exerts potent antitumor activity by inhibiting topoisomerase I. Despite much research into the complex pharmacokinetic profile and pharmacodynamic effects of irinotecan, unpredictable and severe side effects are still commonly observed. In this study, we synthesized [ 11 C]irinotecan as a positron emission tomography (PET) probe, performed the metabolite analysis, and evaluated the biodistribution and kinetics of [ 11 C]irinotecan using small animal PET. Methods [ 11 C]Irinotecan was synthesized by two routes using [ 11 C]phosgene and [ 11 C]carbon dioxide fixation. Metabolites in the plasma of mice following injection of [ 11 C] irinotecan were investigated using a combination of column-switching high-performance liquid chromatography (HPLC) and on-line solid-phase extraction (SPE). Whole-body PET studies were conducted in wild-type mice and P-glycoprotein and breast cancer resistance protein (Pgp/Bcrp) knockout mice. Results [ 11 C]Irinotecan was successfully synthesized by the two abovementioned routes. Decay-corrected radiochemical yields based on [ 11 C]carbon dioxide using [ 11 C]phosgene and [ 11 C]carbon dioxide fixation were 8.8±2.0% ( n =8) and 16.9±2.9 % ( n =5), respectively. Metabolite analysis of the plasma of mice following injection of [ 11 C]irinotecan was successfully performed using the column-switching HPLC and on-line SPE combination resulting in greater than 87 % recovery of radioactivity from HPLC. In the PET study in mice, the radioactivity levels in the brain, liver, and small intestine were slightly increased by inhibition of the Pgp/Bcrp function for more than 30min after [ 11 C]irinotecan injection. This result demonstrated that in vivo behavior of [ 11 C] irinotecan and radioactive metabolites are influenced by the Pgp/Bcrp function. Conclusion PET studies using [ 11 C]irinotecan combined with metabolite analysis may be a useful tool for evaluating irinotecan pharmacokinetics and toxicity.

Recently, 6-[(1-cyclobutylpiperidin-4-yl)oxy]-1-(6-[In manual synthesis, we optimized the reaction conditions of desmethyl precursor 1, which contains a 2-hydroxypyridine moiety, with [Bubbling [We radiosynthesized [

We found out 3-[5-(pyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile analogues as the candidate for positron emission tomography (PET) imaging agents of metabotropic glutamate receptor subtype 5 (mGluR5). Among these compounds, 3-methyl-5-(5-(pyridin-2-yl)-2H-tetrazol-2-yl)benzonitrile (10) exhibited high binding affinity (Ki = 9.4 nM) and moderate lipophilicity (cLogD, 2.4). Subsequently, [(11)C]10 was radiosynthesized at 25 ± 14% radiochemical yield (n = 11) via C-[(11)C]methylation of the arylstannyl precursor 15 with [(11)C]methyl iodide. In vitro autoradiography and PET assessments using [(11)C]10 showed high specific binding in the striatum and hippocampus, two brain regions enriched with mGluR5. Moreover, test-retest PET studies with [(11)C]10 indicated high reliability to quantify mGluR5 density, such as the intraclass correlation coefficient (0.90) and Pearson r (0.91) in the striatum of rat brain. We demonstrated that [(11)C]10 is a useful PET ligand for imaging and quantitative analysis of mGluR5. Furthermore, [(11)C]10 might be modified using its skeleton as a lead compound.

Introduction [ 18 F]FEDAC ([ 18 F] 1 ) has potent binding affinity and selectivity for translocator protein (18kDa, TSPO), and has been used to noninvasively visualize neuroinflammation, lung inflammation, acute liver damage, nonalcoholic fatty liver disease, and liver fibrosis. We had previously synthesized [ 18 F] 1 in two steps: (i) preparation of [ 18 F]fluoroethyl bromide and (ii) coupling of [ 18 F]fluoroethyl bromide with the appropriate precursor ( 2 ) for labeling. In this study, to clinically utilize [ 18 F] 1 as a PET radiopharmaceutical and to transfer the production technique of [ 18 F] 1 to other PET centers, we simplified its preparation by using a direct, one-step, tosyloxy-for-fluorine substitution. We also performed an acute toxicity study as a major non-clinical safety test, and determined radiometabolites using human liver microsomes. Methods [ 18 F] 1 was prepared via direct 18 F-fluorination by heating the corresponding tosylated derivative ( 3 ) with [ 18 F]fluoride as its Kryptofix 222 complex in dimethyl sulfoxide at 110°C for 15min, following by HPLC purification. Non-clinical safety tests were performed for the extended single-dose toxicity study in rats, and for the in vitro metabolite analysis with human liver microsomal incubation. Results High quality batches of [ 18 F] 1 , compatible with clinical applications, were obtained. At the end of irradiation, the decay-corrected radiochemical yield of [ 18 F] 1 using 1 and 5mg of precursor based on [ 18 F]fluoride was 18.5±7.9% ( n =10) and 52.0±5.8% ( n =3), respectively. A single-dose of [ 18 F] 1 did not show toxicological effects for 14 days after the injection in male and female rats. In human liver microsomal incubations, [ 18 F] 1 was easily metabolized to [ 18 F]desbenzyl-FEDAC ([ 18 F] 10 ) by CYPs (4.2% of parent compound left 60min after incubation). Conclusion We successfully synthesized clinical grade batches of [ 18 F] 1 and verified the absence of innocuity of this radiotracer. [ 18 F] 1 will be used to first-in-human studies in our facility.

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.

The transmembrane cell adhesion receptor αVβ3 integrin (αVβ3) has been identified as an important molecular target for cancer imaging and therapy. We have developed a tetrameric cyclic RGD (Arg-Gly-Asp) peptide–based radiotracer 64Cu-cyclam-RAFT-c(-RGDfK-)4, which successfully captured αVβ3-positive tumors and angiogenesis by PET. Here, we subsequently evaluated its therapeutic potential and side effects using an established αVβ3-positive tumor mouse model. Mice with subcutaneous U87MG glioblastoma xenografts received single administrations of 37 and 74 MBq of 64Cu-cyclam-RAFT-c(-RGDfK-)4 (37 MBq/nmol), peptide control, or vehicle solution and underwent tumor growth evaluation. Side effects were assessed in tumor-bearing and tumor-free mice in terms of body weight, routine hematology, and hepatorenal functions. Biodistribution of 64Cu-cyclam-RAFT-c(-RGDfK-)4 with ascending peptide doses (0.25–10 nmol) and with the therapeutic dose of 2 nmol were determined at 3 hours and at various time points (2 minutes–24 hours) postinjection, respectively, based on which radiation-absorbed doses were estimated. The results revealed that 64Cu-cyclam-RAFT-c(-RGDfK-)4 dose dependently slowed down the tumor growth. The mean tumor doses were 1.28 and 1.81 Gy from 37 and 74 MBq of 64Cu-cyclam-RAFT-c(-RGDfK-)4, respectively. Peptide dose study showed that the tumor uptake of 64Cu-cyclam-RAFT-c(-RGDfK-)4 dose dependently decreased at doses ≥1 nmol, indicating a saturation of αVβ3 with the administered therapeutic doses (1 and 2 nmol). Combined analysis of the data from tumor-bearing and tumor-free mice revealed no significant toxicity caused by 37–74 MBq of 64Cu-cyclam-RAFT-c(-RGDfK-)4. Our study demonstrates the therapeutic efficacy and safety of 64Cu-cyclam-RAFT-c(-RGDfK-)4 for αVβ3-targeted radionuclide therapy. 64Cu-cyclam-RAFT-c(-RGDfK-)4 would be a promising theranostic drug for cancer imaging and therapy. Mol Cancer Ther; 15(9); 2076–85. ©2016 AACR.

Metabotropic glutamate receptor subtype 1 (mGluR1) is a crucial molecular target in the central nervous system disorders. 4-(18)F-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ((18)F-FITM) has been recently developed as a useful PET ligand for mGluR1 imaging in our laboratory. In this study, we aimed to measure the affinity and density of mGluR1 using PET with (18)F-FITM in rat brain under the in vivo conditions.Binding potentials (BP(ND)) and amounts of specific binding (bound ligand concentration) at equilibrium state in brain regions were noninvasively estimated using the equilibrium analysis combined with the receptor-blocked approach (EA RBA) for kinetic analysis of (18)F-FITM PET results in place of reference tissue methods. Using BP(ND) and specific binding values of rats treated with multidose ligand, we performed Scatchard analyses for in vivo measurements of mGluR1 density (maximum number of binding sites, or B(max)) and ligand affinity (dissociation constant, or K(d)) in brain regions, respectively.The pretreatment of rats with unlabeled FITM (1 mg/kg) occupied an mGluR1 binding site of (18)F-FITM by more than 99% and did not affect the input function. Hence, we used the tissue time-activity curve for receptor-blocked rats as representative of the nondisplaceable (free and nonspecific binding of radioligand) compartment. The BP(ND) based on EA RBA showed a high correlation with the BP(ND) based on invasive Logan plot graphical analysis in the thalamus, hippocampus, striatum, and cingulate cortex. The K(d) (nM) and B(max) (pmol/mL) obtained by the Scatchard analyses with the multidose ligand assays were 2.1 and 36.3, respectively, for the thalamus; 2.1 and 27.5, respectively, for the hippocampus; 1.5 and 22.2, respectively, for the striatum; and 1.5 and 20.5, respectively, for the cingulate cortex with a high confidence.Our study is the first to our knowledge to measure the in vivo affinity (K(d) and binding potential) of (18)F-FITM and mGluR1 density (B(max)) with a high correlation to in vitro values in rat brain regions. This measurement using PET with (18)F-FITM would be a useful index for research about mGluR1 functions in central nervous system disorders and development of new pharmaceuticals.

Introduction We recently developed a selective 11 C-labeled I 2 -imidazoline receptor (I 2 R) ligand, 2-(3-fluoro-4-[ 11 C]tolyl)-4,5-dihydro-1 H -imidazole ([ 11 C]FTIMD). [ 11 C]FTIMD showed specific binding to I 2 Rs in rat brains having a high density of I 2 R, as well as to I 2 Rs those in monkey brains, as illustrated by positron emission tomography (PET) and autoradiography. However, [ 11 C]FTIMD also showed moderate non-specific binding in rat brains. In order to increase the specificity for I 2 R in rat brains, we synthesized [ 11 C]FTIMD with ultra-high specific activity and evaluated its binding. Methods [ 11 C]FTIMD with ultra-high specific activity was prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [ 11 C]methyl iodide, which was produced by iodination of [ 11 C]methane using the single-pass method. Dynamic PET scans were conducted in rats, and the kinetic parameters were estimated. Results [ 11 C]FTIMD with ultra-high specific activity was successfully synthesized with an appropriate level of radioactivity and ultra-high specific activity (4470±1660 GBq/μmol at end of synthesis, n =11) for injection. In the PET study, distribution volume ( V T ) values in all the brain regions investigated whether I 2 R expression was greatly reduced in BU224-pretreatead rats compared with control rats (29–45% decrease). Differences in V T values between control and BU224-pretreated rats using [ 11 C]FTIMD with ultra-high specific activity were greater than those using [ 11 C]FTIMD with normal specific activity (17–34% decrease) in all brain regions investigated. Conclusion Quantitative PET using [ 11 C]FTIMD with ultra-high specific activity can contribute to the detection of small changes in I 2 R expression in the brain.

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.

To develop a PET ligand for imaging TSPO in peripheral organs, we designed three novel oxopurine analogues [11C]3a–c (LogD: 1.81–2.17) by introducing a pyridine ring in place of a benzene ring in the lead compound [11C]2 (LogD: 3.48). The desmethyl precursors 10 for radiosynthesis were synthesized by reacting glycine 7 with picolylamines 4, followed by hydrolysis and by Curtius rearrangement with diphenylphosphoryl azide. Methylation of 10a–c with methyl iodide produced unlabeled compounds 3a–c. The radiosynthesis of [11C]3a–c was performed by reacting 10a–c with [11C]methyl iodide. Compounds 3a–c displayed high or moderate in vitro binding affinities (Ki: 5–40 nM) for TSPO. PET with [11C]3a–c in rats showed high uptake in the lung, heart, and kidney, which are organs with high TSPO expression. Metabolite analysis with [11C]3a showed that radioactivity in these organs mainly corresponded with unchanged [11C]3a. PET with [11C]3a using a rat model of lung inflammation showed a significant signal in the lipopolysaccharide-treated lung.

J. Neurochem. (2012) 121, 115–124. Abstract We developed 1-(2-[18F]fluoro-3-pyridyl)-4-(2-isopropyl-1-oxo-isoindoline-5-yl)-5-methyl-1H-1,2,3-triazole ([18F]FPIT) as a promising positron emission tomography (PET) ligand for in vitro and in vivo imaging of metabotropic glutamate receptor type 1 (mGluR1) in rat and monkey brains. In vitro autoradiography with [18F]FPIT was used to determine the distribution of radioactivity in rat and monkey brains. In vivo experiments were performed using dissection and small-animal PET on rats, and PET on monkey. Metabolite analysis was performed on rat plasma and brain, and monkey plasma. Autoradiography of rat and monkey brains showed that [18F]FPIT binding is aligned with the reported distribution of mGluR1 with high specific binding in the cerebellum and thalamus. PET study on rat and monkey showed high brain uptake and distribution patterns consistent with those seen in the autoradiographic studies. The radioactivity in the brain was significantly decreased by pre-treatment with unlabeled FPIT, indicative of a specific signal for mGluR1 that was inhibited by mGluR1-selective ligand JNJ-16259865 in the brain. Metabolite analysis showed that the percentage of unchanged [18F]FPIT was 89% in the brain homogenate of rat at 90 min after injection. In the monkey plasma, the percentage of unchanged form was 50% at 90 min. [18F]FPIT produced in vitro and in vivo signals to visualize mGluR1 expression in rat and monkey brains, suggesting the usefulness of [18F]FPIT for imaging mGluR1 in human brain.

Introduction Topotecan (TPT) is a camptothecin derivative and is an anticancer drug working as a topoisomerase-I-specific inhibitor. But TPT cannot penetrate through the blood–brain barrier. In this study, we synthesized a new positron emission tomography (PET) probe, [ 11 C]TPT, to evaluate the P-glycoprotein (Pgp)- and breast cancer resistance protein (BCRP)-mediated brain penetration of [ 11 C]TPT using small-animal PET. Methods [ 11 C]TPT was synthesized by the reaction of a desmethyl precursor with [ 11 C]CH 3 I. In vitro study using [ 11 C]TPT was carried out in MES-SA and doxorubicin-resistant MES-SA/Dx5 cells in the presence or absence of elacridar, a specific inhibitor for Pgp and BCRP. The biodistribution of [ 11 C]TPT was determined using small-animal PET and the dissection method in mice. Results The transport of [ 11 C]TPT to the extracellular side was determined in MES-SA/Dx5 cells exhibiting the expressions of Pgp and BCRP at high levels. This transport was inhibited by coincubation with elacridar. In Mdr1a/b −/− Bcrp1 −/− mice, PET results indicated that the brain uptake of [ 11 C]TPT was about two times higher than that in wild-type mice. Similarly, the brain penetration of [ 11 C]TPT in wild-type mice was increased by treatment with elacridar. The radioactivity in the brain of elacridar-treated mice was maintained at a certain level after the injection of [ 11 C]TPT, although the radioactivity in the blood decreased with time. Conclusions We demonstrated the increase of brain penetration of [ 11 C]TPT by deficiency and inhibition of Pgp and BCRP functions using small-animal PET in mice.

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.

I2 imidazoline receptors (I2Rs) are associated with depression, Alzheimer's disease, and Huntington's disease. However, in vivo imaging of I2Rs in the monkey brain has not been reported until now. We performed in vitro and in vivo imaging of (I2Rs) in the monkey brain using 11C-labeled 2-(3-fluoro-4-tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD) which has high and selective affinity of I2Rs. In an auto-radiography (ARG) study, the distribution pattern of [11C]FTIMD in the monkey brain was similar to that of [3H]idazoxan binging to I2Rs in the human brain, which was previously described. The specific binding of [11C]FTIMD accounted for >97% of total binding in brain regions existing I2Rs. In positron emission tomography (PET) studies, the radioactivity was accumulated in brain regions existing I2Rs ligand BU224, the accumulated radioactivity was decreased to approximately 66%–75% of the baseline measurement at 15–45 min after injection of [11C]FTIMD. These results suggest that [11C]FTIMD shows the specific-binging to I2Rs in the monkey brain as depicted by PET and ARG. We performed the first in vivo imaging of I2Rs using [11C]FTIMD in the monkey brain. Synapse, 2011. © 2010 Wiley-Liss, Inc.

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.

The purpose of this study was to synthesize 6-[1-(2-[(18)F]fluoro-3-pyridyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline ([(18)F]FPTQ, [(18)F]7a) and to evaluate its potential as a positron emission tomography ligand for imaging metabotropic glutamate receptor type 1 (mGluR1) in the rat brain. Compound [(18)F]7a was synthesized by [(18)F]fluorination of 6-[1-(2-bromo-3-pyridyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline (7b) with potassium [(18)F]fluoride. At the end of synthesis, 1280-1830MBq (n=8) of [(18)F]7a was obtained with98% radiochemical purity and 118-237GBq/μmol specific activity using 3300-4000MBq of [(18)F]F(-). In vitro autoradiography showed that [(18)F]7a had high specific binding with mGluR1 in the rat brain. Biodistribution study using a dissection method and small-animal PET showed that [(18)F]7a had high uptake in the rat brain. The uptake of radioactivity in the cerebellum was reduced by unlabeled 7a and mGluR1-selective ligand JNJ-16259685 (2), indicating that [(18)F]7a had in vivo specific binding with mGluR1. Because of a low amount of radiolabeled metabolite present in the brain, [(18)F]7a may have a limiting potential for the in vivo imaging of mGluR1 by PET.

The purpose of this study was to synthesize two new positron emission tomography (PET) probes, N -(4-(2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl)phenyl)-9,10-dihydro-5-[ 18 F]fluoroethoxy-9-oxo-4-acridine carboxamide ([ 18 F] 3 ) and quinoline-3-carboxylic acid [2-(4-{2-[7-(2-[ 18 F]fluoroethoxy)-6-methoxy-3,4-dihydro-1 H -isoquinolin-2-yl]ethyl}phenylcarbamoyl)-4,5-dimethoxyphenyl]amide ([ 18 F] 4 ), and to evaluate the potential of these PET probes for assessing the function of two major drug efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). [ 18 F] 3 and [ 18 F] 4 were synthesized by 18 F-alkylation of each O -desmethyl precursor with [ 18 F]2-fluoroethyl bromide for injection as PET probes. In vitro accumulation assay showed that treatment with P-gp/BCRP inhibitors ( 1 and 2 ) enhanced the intracellular accumulation capacity of P-gp- and BCRP-overexpressing MES-SA/Dx5 cells. In PET studies, the uptake (AUC brain [0–60 min] ) of [ 18 F] 3 and [ 18 F] 4 in wild-type mice co-injected with 1 were approximately sevenfold higher than that in wild-type mice, and the uptake of [ 18 F] 3 and [ 18 F] 4 in P-gp/Bcrp knockout mice were eight- to ninefold higher than that in wild-type mice. The increased uptake of [ 18 F] 3 and [ 18 F] 4 was similar to that of parent compounds ([ 11 C] 1 and [ 11 C] 2 ) previously described, indicating that radioactivity levels in the brain after injection of [ 18 F] 3 and [ 18 F] 4 are related to the function of drug efflux transporters. Also, these results suggest that the structural difference between parent compounds ([ 11 C] 1 and [ 11 C] 2 ) and fluoroethyl analogs ([ 18 F] 3 and [ 18 F] 4 ) do not obviously affect the potency against drug efflux transporters. In metabolite analysis of mice, the unchanged form in the brain and plasma at 60 min after co-injection of [ 18 F] 4 plus 1 were higher (95% for brain; 81% for plasma) than that after co-injection of [ 18 F] 3 plus 1 . [ 18 F] 4 is a promising PET probe to assess the function of drug efflux transporters.