A quantum chemical model for a series of self-assembled nanocages: the origin of stability behind the coordination-driven formation of transition metal complexes up to [M12L24]24.

Herein, we present a systematic computational model to study the electronic states and free energies of a self-assembled multi-metal complex series. By combining the previously developed model Hamiltonian approach for transition-metal complexes and the generalized Born model, the thermodynamics, optimized geometries, and electronic states of the [Pd12L24]24+ nanocage are revealed, together with [PdnLm]2n+ complex series. The effective model Hamiltonian is a theoretical method to obtain the d-electron wavefunction and potential energy including interaction energy between the transition-metal and ligands. In the present improvement, the electronic state on each transition-metal center is focused as a building unit and solved under the whole electronic field of the assembling system. We realize a reliable and systematic treatment of multi-transition-metal complexes with different sizes and charges. Consequently, our model could reproduce binding energies of the [PdnLm]2n+ complex series quantitatively as compared to density functional theory (DFT). Regarding free energy, we revealed that the assembling solute becomes unstable due to the electrostatic interaction, and effects of the solvent and counter anions mainly compensated it. Optimized geometries were also analysed. The local square-planar coordination structures around the palladium centres were characterized in the complex series. The relationships between the entire symmetrical geometries and the local coordination structures are also discussed. Finally, electronic structures of the [Pd12L24]24+ nanocage were well characterized as a single-determinant, where only dx2-y2 is unoccupied due to the ligand-field effect. We also found that the solvent polarized the electronic states of the Pd ions, whereas the counter anion suppressed the polarization. The present method realizes size-independent reliable and rapid computations, and therefore can be expected to further application studies on self-assembly dynamics.

Energy landscape study of water splitting and H2 evolution at a ruthenium(II) pincer complex.

A bird's-eye view of the water splitting and H2 generation at a ruthenium(II) pincer complex is presented. Using a combination of density functional theory and efficient algorithms for exploration of potential energy hypersurface (PES), a total of 197 local minima and 186 transition states are identified, and a new mechanism for water splitting and H2 evolution via hydroxycarbonyl intermediates is presented. Furthermore, a global feature of the reaction PES, so-called potential energy landscape, is discussed on analyzing the obtained structures. As a result, the landscape is characterized by hierarchical structure, namely, PES consists of many "superbasins (SBs)" that are separated by relatively high energy barriers corresponding to bond breaking around Ru(II) center. Each SB involves a set of conformational isomers that can be interchanged with each other through relatively small barriers. To the best of our best knowledge, this is the first report on the quantum chemical computation of the hierarchical structure of PES for a realistic, catalytic reaction system.

Genetic and clinical prediction models for the efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis: a multicenter cohort study.

The objective of the study is to develop genetic and clinical prediction models for the efficacy and hepatotoxicity of methotrexate (MTX) in patients with rheumatoid arthritis (RA). Among RA patients treated with MTX, 1966 polymorphisms of 246 enzymes/transporters relevant to pharmacokinetics and pharmacodynamics were measured by the Drug Metabolism Enzymes and Transporters (DMET) microarray and direct sequencing, and clinical variables at baseline were collected. For efficacy, response criteria of the European League Against Rheumatism were used to classify patients as responders or non-responders. Hepatotoxicity was defined as elevations of aspartate aminotransferase or alanine aminotransferase ≥1.5 times the reference range upper limit. Among 166 patients, a genetic prediction model for efficacy using seven polymorphisms showed the area under the receiver operating characteristic curve (AUC) was 0.822, with 74.3% sensitivity and 76.8% specificity. A combined genetic and clinical model indicated the AUC was 0.844, with 81.5% sensitivity and 76.9% specificity. By incorporating clinical variables into the genetic model, the overall category-free net reclassification improvement (NRI) was 0.663 (P < 0.0001) and the overall integrated discrimination improvement (IDI) was 0.083 (P = 0.0009). For hepatotoxicity, a genetic prediction model using seven polymorphisms showed the AUC was 0.783 with 70.0% sensitivity and 80.0% specificity, while the combined model indicated the AUC was 0.906 with 85.1% sensitivity and 87.8% specificity (overall category-free NRI: 1.002, P < 0.0001; overall IDI: 0.254, P < 0.0001). Our genetic and clinical models demonstrated moderate diagnostic accuracy for MTX efficacy and high accuracy for hepatotoxicity. These findings should, however, be validated and interpreted with a caution until external validation.

Clinical Significance of a Gene Signature Generated from Tumor Budding Grade in Colon Cancer.

BACKGROUND: Tumor budding, a microscopic finding of dedifferentiation at the invasive margin, has been reported as a definite prognostic marker in colon cancer (CC). Herein, we aimed to generate a molecular budding signature (MBS) based on DNA microarray data and to examine its prognostic significance. METHODS: Frozen tissue samples from 85 patients with stage II/III CC were used for DNA microarray analyses. First, we selected candidate genes that were differentially expressed (twofold change) between the invasive frontal regions and corresponding tumor centers of three extremely high-grade budding tumors. Subsequently, using microarray data from whole-tissue sections of the 85 patients, we selected MBS-constituent genes from the candidates based on correlation to the pathological budding grade. The MBS score was calculated using the sum of the logarithm of the expression of each gene. RESULTS: We selected seven MBS-constituent genes: MSLN, SLC4A11, WNT11, SCEL, RUNX2, MGAT3, FOXC1. A comparison of relapse-free survival (RFS) rates revealed a significant impact of the MBS score [5-year RFS, 77.4% (score-high) vs. 95.1% (score-low); P = 0.044]. Analyses of public databases revealed that low MBS score patients exhibited better prognosis than those with high-score cancers (GSE14333: 5-year RFS, 83.1% vs. 66.6%, P = 0.028; GSE39582: 5-year disease-free survival, 72.2% vs. 58.1%, P = 0.0005). Multivariate analysis revealed that the MBS score is an independent prognostic indicator in GSE39582 (hazard ratio, 1.611; P = 0.013). CONCLUSIONS: We developed a new gene classification method, i.e., MBS, and demonstrated its clinical relevance as an indicator of high recurrence risk of CC.

A kinetics study of ligand substitution reaction on dinuclear platinum complexes: Stochastic versus deterministic approach.

The kinetics on a basic ligand substitution reaction on dinuclear platinum complexes [Pt(PEt3 )2 PhPt(PEt3 )2 ]2+ and [Pt(PEt3 )2 PhCOPhPt(PEt3 )2 ]2+ , with the ligands pyridine and 3-chloropyridine, is studied. This is a fundamental step in a self-assembly, and the time evolution has been observed with a new experimental technique, QASAP (quantitative analysis of self-assembly process), which is recently developed by Hiraoka's group. As a result of numerical calculations based on master equation, we succeed in specifying the reaction rate constants with a simple reaction model. In addition, the time evolutions of all the intermediate components produced and consumed in chemical reaction are revealed, including those unobserved in the experiments. The convergence behavior of the existence ratios of specific chemical species calculated with the stochastic algorithm method is compared with those obtained from deterministic formalism based on rate equations, revealing a clear dependence on the number of constituent molecules. © 2018 Wiley Periodicals, Inc.

Theoretical approaches for dynamical ordering of biomolecular systems.

BACKGROUND: Living systems are characterized by the dynamic assembly and disassembly of biomolecules. The dynamical ordering mechanism of these biomolecules has been investigated both experimentally and theoretically. The main theoretical approaches include quantum mechanical (QM) calculation, all-atom (AA) modeling, and coarse-grained (CG) modeling. The selected approach depends on the size of the target system (which differs among electrons, atoms, molecules, and molecular assemblies). These hierarchal approaches can be combined with molecular dynamics (MD) simulation and/or integral equation theories for liquids, which cover all size hierarchies. SCOPE OF REVIEW: We review the framework of quantum mechanical/molecular mechanical (QM/MM) calculations, AA MD simulations, CG modeling, and integral equation theories. Applications of these methods to the dynamical ordering of biomolecular systems are also exemplified. MAJOR CONCLUSIONS: The QM/MM calculation enables the study of chemical reactions. The AA MD simulation, which omits the QM calculation, can follow longer time-scale phenomena. By reducing the number of degrees of freedom and the computational cost, CG modeling can follow much longer time-scale phenomena than AA modeling. Integral equation theories for liquids elucidate the liquid structure, for example, whether the liquid follows a radial distribution function. GENERAL SIGNIFICANCE: These theoretical approaches can analyze the dynamic behaviors of biomolecular systems. They also provide useful tools for exploring the dynamic ordering systems of biomolecules, such as self-assembly. This article is part of a Special Issue entitled "Biophysical Exploration of Dynamical Ordering of Biomolecular Systems" edited by Dr. Koichi Kato.

Measuring the impact of modern waste collection and processing service attributes on residents' acceptance of waste separation policy using a randomised conjoint field experiment in Yogyakarta Province, Indonesia.

Indonesia is one of the countries that is facing serious solid waste problems. Although the issue has been addressed in the capital city of Jakarta, many secondary cities have been left behind. This research attempts to analyse the impact of relevant waste management policy components on respondents' policy acceptance probabilities in Yogyakarta Province. Using a randomised conjoint field experiment based on the proposal of modern waste collection services, this article shows that a new waste management policy that includes waste separation with frequent organic waste collection will gain popular support, especially with the rich. Indeed, if the government introduces waste collection and processing services that consist of the most preferred levels of these attributes, including five-times-a-week organic waste collection, a majority of the residents will support this new waste management policy, which will reduce waste at its source.

The efficacy of neuromuscular electrical stimulation with alternating currents in the kilohertz frequency to stimulate gait rhythm in rats following spinal cord injury.

BACKGROUND: Rehabilitation facilitates the reorganization of residual/regenerated neural pathways and is key in improving motor function following spinal cord injury. Neuromuscular electrical stimulation (NMES) has been reported as being clinically effective. Although it can be used after the acute phase post-injury, the optimal stimulation conditions to improve motor function remain unclear. In this paper, we examined the effectiveness of NMES with alternating currents in the kilohertz (kHz) frequency in gait rhythm stimulation therapy. METHODS: Tests were performed using 20 mature female Fischer rats. Incomplete spinal cord injuries (T9 level) were made with an IH impactor using a force of 150 kdyn, and NMES was administered for 3 days from the 7th day post-injury. The needle electrodes were inserted percutaneously near the motor point of each muscle in conscious rats, and each muscle on the left and right leg was stimulated for 15 min at two frequencies, 75 Hz and 8 kHz, to induce a gait rhythm. Motor function was evaluated using Basso, Beattie, Bresnahan (BBB) scores and three-dimensional (3D) gait analysis. Rats were divided into four groups (5 rats/group), including the NMES treatment 75-Hz group (iSCI-NMES 75 Hz), 8-kHz group (iSCI-NMES 8 kHz), injury control group (iSCI-NT), and normal group (Normal-CT), and were compared. RESULTS: There was no significant difference in BBB scores among the three groups. In 3D gait analysis, compared with the injury control group, the 8-kHz group showed a significant improvement in synergistic movement of both hindlimbs. CONCLUSION: We suggest that kHz stimulation is effective in gait rhythm stimulation using NMES.

Cervical ossification of the posterior longitudinal ligament: Biomechanical analysis of the influence of static and dynamic factors.

OBJECTIVE: Cervical myelopathy due to ossification of the posterior longitudinal ligament (OPLL) is induced by static factors, dynamic factors, or a combination of both. We used a three-dimensional finite element method (3D-FEM) to analyze the stress distributions in the cervical spinal cord under static compression, dynamic compression, or a combination of both in the context of OPLL. METHODS: Experimental conditions were established for the 3D-FEM spinal cord, lamina, and hill-shaped OPLL. To simulate static compression of the spinal cord, anterior compression at 10, 20, and 30% of the anterior-posterior diameter of the spinal cord was applied by the OPLL. To simulate dynamic compression, the OPLL was rotated 5°, 10°, and 15° in the flexion direction. To simulate combined static and dynamic compression under 10 and 20% anterior static compression, the OPLL was rotated 5°, 10°, and 15° in the flexion direction. RESULTS: The stress distribution in the spinal cord increased following static and dynamic compression by cervical OPLL. However, the stress distribution did not increase throughout the entire spinal cord. For combined static and dynamic compression, the stress distribution increased as the static compression increased, even for a mild range of motion (ROM). CONCLUSION: Symptoms may appear under static or dynamic compression only. However, under static compression, the stress distribution increases with the ROM of the responsible level and this makes it very likely that symptoms will worsen. We conclude that cervical OPLL myelopathy is induced by static factors, dynamic factors, and a combination of both.

Artificial collagen-filament scaffold promotes axon regeneration and long tract reconstruction in a rat model of spinal cord transection.

Traumatically injured spinal cord (SC) displays structural damage that includes discontinuity of long tracts and cavitations. Axonal regrowth beyond the lesion is necessary to achieve functional recovery following SC injury. We report here the development of an artificial collagen-filament (CF) scaffold to replace the SC in 8-week-old female Fisher rats. Axonal sprouting and regrowth was very rapid following grafting of the CF. One week after implantation, the scaffold was filled with cells of host origin and with regenerated axons. Histological examination of SC adjacent to the scaffold showed little cavity formation or fibrous scarring. Eight weeks after implantation, myelinated nerve fibers were found in the scaffold and 10-25 % of rubrospinal tracts were repaired. Four to six weeks after transplantation, motor evoked potentials were recorded in CF-grafted rats but were not detectable in non-grafted rats. Electrophysiological and histological examinations revealed the grafted CF was likely to function as a nerve tract. In addition, these results suggest that collagen fibers may provide a permissive microenvironment for the elongation of SC axons and to support the process of spinal cord regeneration.

Usefulness of an early MRI-based classification system for predicting vertebral collapse and pseudoarthrosis after osteoporotic vertebral fractures.

STUDY DESIGN: Retrospective review. OBJECTIVE: To clarify whether an early magnetic resonance imaging-based classification predicts pseudoarthrosis and final vertebral collapse in osteoporotic vertebral fractures. SUMMARY OF BACKGROUND: Initial therapy for osteoporotic vertebral fractures involves bed rest, orthotic use, and plaster casts. However, in some cases, pain persists because of progressive vertebral collapse or pseudoarthrosis. Prediction of these complications immediately after fractures can facilitate early proactive treatment despite the early prognosis being generally poor. METHODS: A total of 109 patients (129 fractured vertebrae, 88 females, 21 males, and average age 79 y) followed up over 6 months after conservative treatment for thoracolumbar vertebral fractures were included. Early midsagittal T1-weighted and T2-weighted magnetic resonance images were analyzed. The incidence of final vertebral body collapse, pseudoarthrosis conversion, and delayed spinal cord paralysis were examined retrospectively for each vertebral fracture type. RESULTS: According to the T1-weighted image-based classification, 74 of the vertebrae (57%) had total-type fractures. The final vertebral body collapse rate was significantly higher in this type than in others. Pseudoarthrosis was observed in 20 total-type fractures in 20 patients (18.3%); pseudoarthrosis conversion rate was significantly higher in these patients than in others. Delayed spinal cord paralysis occurred in only 1 patient (0.9%) with total-type fracture. According to the T2-weighted image-based classification, 69 vertebrae had the hyperintense wide-type fractures, which was the most common fracture type (53%). Hypointense wide-type fractures were associated with a significantly higher incidence of final vertebral body collapse, pseudoarthrosis, and delayed spinal cord paralysis. When total-type fractures of the T1-weighted image-based classification were subclassified according to the T2-weighted image-based classification, a significantly higher pseudoarthrosis conversion rate was observed in hypointense wide-type fractures. CONCLUSIONS: Our results suggest that the radiologic prognosis can be estimated to a limited extent by determining the degree and extent of osteoporotic vertebral fractures using an early magnetic resonance imaging-based classification.

Percutaneous radiofrequency facet joint denervation with monitoring of compound muscle action potential of the multifidus muscle group for treating chronic low back pain: a preliminary report.

STUDY DESIGN: A retrospective review. OBJECTIVE: The aim of this study was to study the effectiveness of percutaneous radiofrequency neurotomy of facet joints by monitoring compound muscle action potentials (CMAPs) of the multifidus muscle group as an objective index of treatment efficacy. SUMMARY OF BACKGROUND: Percutaneous radiofrequency neurotomy of the medial branches of the dorsal rami of the lumbar nerves is a widely accepted treatment for chronic lumbar intervertebral joint pain. However, its success rate has varied in different studies because an objective method for evaluating the facet joint denervation is lacking. METHODS: Fifty-five patients (age range, 19-76 y; mean age, 55 y) with low back pain persisting for ≥3 months, in whom facet block and/or block of the medial branch of the dorsal ramus were only temporarily effective, were included. The Japanese Orthopaedic Association (JOA) scoring system for back pain was used for clinical assessment. JOA scores were measured before treatment and 1 week, 3 months, 6 months, and 12 months afterward. The improvement rate was calculated with ≥40% improvement rate defined as successful, and the success rate was subsequently evaluated. RESULTS: The patient success rate was 75% (41/55) at 1 week, 71% (39/55) at 3 months, 60% (33/55) at 6 months, and 51% (28/55) at 12 months after treatment. Two cases had minor postoperative complications, which were localized burning pain lasting <1 week at the site of electrode insertion. CONCLUSIONS: Our results suggest that percutaneous radiofrequency facet joint denervation with CMAPs monitoring is a safe, long-lasting, and effective treatment for chronic facet joint pain. CMAP monitoring may be useful as an objective index for facet denervation.

Results of surgical treatment of cervical spondylotic myelopathy in patients aged 75 years or more: a comparative study of operative methods.

INTRODUCTION: The number of surgical procedures in elderly patients has been increasing as the population has grown older; recently, spine surgeons have been more likely to encounter elderly patients with cervical myelopathy in need of surgical treatment. There are many reports about surgical treatment of elderly patients with cervical spondylotic myelopathy (CSM); however, there are no studies about the proper selection of surgical methods and comparison of their results in CSM patients aged ≥ 75 years. The objective of this study was to review the results of operative methods in CSM patients aged ≥ 75 years. METHODS: Forty-three consecutive cases with an average age of 79 years that underwent surgical treatment were included in this study. The neurological severity was assessed using the Japanese Orthopaedic Association score for cervical myelopathy (JOA). The JOA scores were evaluated before surgery and at final follow-up. There were 21 laminoplasty procedures (from C3 to C7), 13 selective laminoplasty procedures (one above and one below the affected intervertebral level), and nine anterior decompression and fusion procedures. A selective laminoplasty was performed in cases with general complications and was diagnosed as one intervertebral level both clinically and electrophysiologically. Surgical results were compared among the three treatment groups. RESULTS: The average preoperative JOA score was 7.7 points and the average JOA recovery rate was 45 %. There were three cases of C5 palsy and one wound infection. Operative time and intraoperative bleeding in the selective laminoplasty group were significantly smaller than those in the other groups. There was no significant difference in the JOA recovery rates among the groups. CONCLUSIONS: Selective laminoplasty is less invasive and the surgical results in our study were almost good. It also has good short-term results. However, the indication for surgery has to be selected carefully in elderly CSM patients.

Solvent Distribution Effects on Quantum Chemical Calculations with Quantum Computers.

We present a combination of three-dimensional reference interaction site model self-consistent field (3D-RISM-SCF) theory and the variational quantum eigensolver (VQE) to consider the solvent distribution effects within the framework of quantum-classical hybrid computing. The present method, 3D-RISM-VQE, does not include any statistical errors from the solvent configuration sampling owing to the analytical treatment of the statistical solvent distribution. We apply 3D-RISM-VQE to compute the spatial distribution functions of solvent water around a water molecule, the potential and Helmholtz energy curves of NaCl, and to analyze the Helmholtz energy component and related properties of H2O and NH4+. Moreover, we utilize 3D-RISM-VQE to analyze the extent to which solvent effects alter the efficiency of quantum calculations compared with calculations in the gas phase using the L1-norms of molecular electronic Hamiltonians. Our results demonstrate that the efficiency of quantum chemical calculations on a quantum computer in solution is virtually the same as that in the gas phase.

Disease Flares Following COVID-19 Vaccination in Patients with Inflammatory Bowel Disease.

Objective Flares of inflammatory bowel disease (IBD) can occur infrequently after vaccination for coronavirus disease 2019 (COVID-19), although the details of this phenomenon are poorly understood. To clarify the possibility of an unfavorable response in patients with IBD, we investigated IBD-related symptoms during the COVID-19 vaccination. Methods Between October 2021 and February 2022, we obtained the COVID-19 vaccination status of 411 IBD patients who were being treated at our institution. The disease course of IBD after vaccination was investigated in 188 patients with ulcerative colitis (UC) and 119 patients with Crohn's disease (CD) who had received at least one dose of the vaccine during the clinical remission phase. The baseline characteristics before vaccination were compared between the patients with UC with or without disease flares. Results During the 30-day follow-up period, eight patients with UC (4.3%) and one patient with CD (0.8%) experienced disease flares following vaccination. Disease flares occurred after the first vaccination in six patients and after the second vaccination in three patients. As for the timing of onset of disease flares, eight events (88.9%) occurred within one week of vaccination. Two patients required hospitalization, and one patient with CD required surgery for an intra-abdominal abscess. The baseline characteristics did not significantly differ between patients with UC who experienced flares and those who did not. Conclusion IBD flares following COVID-19 vaccination are rare and vaccination should therefore be recommended for patients with IBD. However, the possibility of disease flares should be considered for approximately one week after each vaccination, especially in patients with UC.

Characterization of 1-(2-[18F] fluoro-3-pyridyl)-4-(2-isopropyl-1-oxo- isoindoline-5-yl)-5-methyl-1H-1,2,3-triazole, a PET ligand for imaging the metabotropic glutamate receptor type 1 in rat and monkey brains.

We developed 1-(2-[(18) F]fluoro-3-pyridyl)-4-(2-isopropyl-1-oxo-isoindoline-5-yl)-5-methyl-1H-1,2,3-triazole ([(18) F]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 [(18) F]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 [(18) F]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 [(18) F]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. [(18) F]FPIT produced in vitro and in vivo signals to visualize mGluR1 expression in rat and monkey brains, suggesting the usefulness of [(18) F]FPIT for imaging mGluR1 in human brain.

Translocator protein (18 kDa), a potential molecular imaging biomarker for non-invasively distinguishing non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Mitochondrial dysfunction is responsible for liver damage and disease progression in non-alcoholic fatty liver disease (NAFLD). Translocator protein (18 kDa) (TSPO), a mitochondrial transmembrane protein, plays important roles in modulating mitochondrial function. This study explored whether TSPO can be used as an imaging biomarker of non-invasive diagnosis and staging of NAFLD, monitored using positron emission tomography (PET) with a TSPO radioligand [(18)F]FEDAC. METHODS: PET with [(18)F]FEDAC, non-enhanced computerized tomography (CT), autoradiography, histopathology, and gene analysis were performed to evaluate and quantify TSPO levels and NAFLD progression in methionine and choline-deficient diet-fed mice. Correlations were analyzed between uptake ratio of radioactivity and NAFLD activity score (NAS) in the liver. RESULTS: Uptake of [(18)F]FEDAC obviously increased with disease progression from simple steatosis to non-alcoholic steatohepatitis (NASH) (p<0.01). A close correlation was identified between [(18)F]FEDAC uptake ratio and NAS in the liver (Pearson's r=0.922, p=0.000). Specific binding of [(18)F]FEDAC to TSPO in the NAFLD livers was assessed in competition studies with the unlabelled TSPO-selective ligand PK11195. Autoradiography and histopathology confirmed the PET imaging results. Further, the mRNA levels of the functional macromolecular signaling complex composed of TSPO were obviously higher compared to controls. CONCLUSIONS: TSPO expression increases in NAFLD and closely correlates with NAFLD progression. TSPO as a specific molecular imaging biomarker may open a novel avenue for non-invasive, reliable, and quantitative diagnosis and staging of NAFLD.

Imaging for metabotropic glutamate receptor subtype 1 in rat and monkey brains using PET with [18F]FITM.

PURPOSE: In this study, we evaluate the utility of 4-[(18)F]fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([(18)F]FITM) as a positron emission tomography (PET) ligand for imaging of the metabotropic glutamate receptor subtype 1 (mGluR1) in rat and monkey brains. METHODS: In vivo distribution of [(18)F]FITM in brains was evaluated by PET scans with or without the mGluR1-selective antagonist (JNJ16259685). Kinetic parameters of monkey PET data were obtained using the two-tissue compartment model with arterial blood sampling. RESULTS: In PET studies in rat and monkey brains, the highest uptake of radioactivity was in the cerebellum, followed by moderate uptake in the thalamus, hippocampus and striatum. The lowest uptake of radioactivity was detected in the pons. These uptakes in all brain regions were dramatically decreased by pre-administration of JNJ16259685. In kinetic analysis of monkey PET, the highest volume of distribution (V(T)) was detected in the cerebellum (V(T) = 11.5). CONCLUSION: [(18)F]FITM has an excellent profile as a PET ligand for mGluR1 imaging. PET with [(18)F]FITM may prove useful for determining the regional distribution and density of mGluR1 and the mGluR1 occupancy of drugs in human brains.