Evaluation of an Integrin αβ Radiotracer, [F]F-FPP-RGD, for Monitoring Pharmacological Effects of Integrin α siRNA in the NASH Liver.

Purpose: Integrin α is a key regulator in the pathophysiology of hepatic fibrosis. In this study, we evaluated the potential utility of an integrin αβ positron emission tomography (PET) radiotracer, F-labeled cyclic arginine-glycine-aspartic acid penta-peptide ([F]F-FPP-RGD), for detecting hepatic integrin α and function in nonalcoholic steatohepatitis (NASH) model rats using integrin α siRNA.

Methods: NASH model rats were produced by feeding a choline-deficient, low-methionine, high-fat diet for 8 weeks.

Effect of scan-time shortening on the C-PHNO binding potential to dopamine D receptor in humans and test-retest reliability.

Objective: C-PHNO is a PET radioligand most specific to dopamine D receptor (DR). The long scan duration of 120 min used in quantification of C-PHNO binding to DR in previous studies is challenging to subjects. The main objective of this study was to investigate the effects of shorter scan times on the binding of C-PHNO to DR and test-retest reliability using the latest digital whole-body PET system.

Usefulness of F-FPP-RGD PET in pathophysiological evaluation of lung fibrosis using a bleomycin-induced rat model.

Purpose: Integrins α are key molecules in the pathogenesis of fibrosis in multiple organs. To assess the potential utility of integrin αβ imaging for idiopathic pulmonary fibrosis (IPF), we evaluated an F-FPP-RGD PET probe in a rat model of bleomycin-induced lung fibrosis.

Methods: Pulmonary fibrosis was induced by single intratracheal instillation of bleomycin (3 mg/rat).

Quantitative evaluation of hepatic integrin αβ expression by positron emission tomography imaging using F-FPP-RGD in rats with non-alcoholic steatohepatitis.

Background: Integrin αβ, which are expressed by activated hepatic stellate cells in non-alcoholic steatohepatitis (NASH), play an important role in the fibrosis. Recently, we reported that an RGD peptide positron emission tomography (PET) probe is useful as a predictor of hepatic fibrosis. Kinetic analysis of the RGD PET probe has been performed in tumours, but not in hepatic fibrosis.

Pharmacological MRI responses of raclopride in rats: The relationship with D2 receptor occupancy and cataleptic behavior.

Pharmacological magnetic resonance imaging (phMRI) allows the visualization of brain pharmacological effects of drugs using functional MRI (fMRI). phMRI can help us facilitate central nervous system (CNS) drug development. However, there have been few studies demonstrating the dose relationship of the fMRI response induced by CNS drugs to underlying target engagement or behavioral efficacy.

A Novel Acetyl-CoA Carboxylase 2 Selective Inhibitor Improves Whole-Body Insulin Resistance and Hyperglycemia in Diabetic Mice through Target-Dependent Pathways.

Excess intramyocellular lipid (IMCL) deposition in skeletal muscle is closely associated with insulin resistance. Pharmacological inhibition of acetyl-CoA carboxylase (ACC) 2 offers a promising approach to treat insulin resistance through stimulation of mitochondrial fatty acid oxidation (FAO) and reduction of IMCL deposition. Previously reported experimental ACC2 inhibitors exhibited plasma glucose-lowering effects in diabetic rodents.

(R)- and (S)-ketamine induce differential fMRI responses in conscious rats.

(R,S)-ketamine exerts robust antidepressant effects in patients with depression when given at sub-anesthetic doses. Each of the enantiomers in this racemic mixture, (R)-ketamine and (S)-ketamine, have been reported to exert antidepressant effects individually. However, the neuropharmacological effects of these enantiomers and the mechanisms underlying their antidepressive actions have not yet been fully elucidated.

Evaluation of hepatic function using dynamic contrast-enhanced magnetic resonance imaging in melanocortin 4 receptor-deficient mice as a model of nonalcoholic steatohepatitis.

Introduction: Melanocortin 4 receptor-deficient (MC4R-KO) mice fed a high-fat diet (HFD) develop liver pathology similar to human nonalcoholic steatohepatitis (NASH). However, although liver histology and blood biochemistry have been reported, hepatic function has not been evaluated. In the present study, we evaluated hepatic function in MC4R-KO mice fed an HFD using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with gadolinium‑ethoxybenzyl‑diethylenetriamine pentaacetic acid (Gd-EOB-DTPA).

Detection of neuroinflammation before selective neuronal loss appearance after mild focal ischemia using [F]DPA-714 imaging.

Background: Translocator protein (TSPO) imaging can be used to detect neuroinflammation (including microglial activation) after acute cerebral infarction. However, longitudinal changes of TSPO binding after mild ischemia that induces selective neuronal loss (SNL) without acute infarction are not well understood. Here, we performed TSPO imaging with [F]DPA-714 to determine the time course of neuroinflammation and SNL after mild focal ischemia.

Evaluation of hepatic integrin αvβ3 expression in non-alcoholic steatohepatitis (NASH) model mouse by F-FPP-RGD PET.

Background: Activated hepatic stellate cells (HSCs), which express integrin αvβ3, are a major fibrogenic factor in NASH pathophysiology. F-labeled cyclic arginine-glycine-aspartic acid penta-peptide (F-FPP-RGD) has been used as a PET probe for tumors expressing integrin αvβ3. The aim of this study was to assess the potential of PET with F-FPP-RGD to detect hepatic integrin αvβ3 expression in non-alcoholic steatohepatitis (NASH) model mice.

Relationship between receptor occupancy and the antinociceptive effect of mu opioid receptor agonists in male rats.

The analgesic mechanisms of mu opioid receptor (MOR) agonists, including receptor occupancy at the site of action, are not completely understood. The aims of the present study were to evaluate: (i) receptor occupancy in the rat brain after administration of MOR agonists; (ii) the relationship between occupancy and the antinociceptive effect. Morphine (2 or 4 mg/kg) or oxycodone (1 or 3 mg/kg) was subcutaneously administered to rats.

[F]-BMS-747158-02PET imaging for evaluating hepatic mitochondrial complex 1dysfunction in a mouse model of non-alcoholic fatty liver disease.

Background: Mitochondrial dysfunction is one of the main causes of non-alcohol fatty liver disease (NAFLD). [F]-BMS-747158-02 (F-BMS) which was originally developed as a myocardial perfusion imaging agent was reported to bind mitochondrial complex-1 (MC-1). The aim of this study was to investigate the potential use of F-BMS for evaluating hepatic MC-1 activity in mice fed a methionine- and choline-deficient (MCD) diet.

Quantitative evaluation of oxygen metabolism in the intratumoral hypoxia: F-fluoromisonidazole and O-labelled gases inhalation PET.

Background: Intratumoral hypoxia is one of the resistant factors in radiotherapy and chemotherapy for cancer. Although it is detected by F-fluoromisonidazole (FMISO) PET, the relationship between intratumoral hypoxia and oxygen metabolism has not been studied. The purpose of this study was to evaluate the intratumoral perfusion and oxygen metabolism in hypoxic regions using the rat xenograft model.

Evaluation of a filament perforation model for mouse subarachnoid hemorrhage using 7.0 Tesla MRI.

The filament perforation model (FPM) in mice is becoming increasingly popular to elucidate the molecular pathogenesis of neuronal injury after subarachnoid hemorrhage (SAH). We evaluated brain MRI in a mouse FPM. A total of 28 male C57Bl/6J mice were used.

Gd-EOB-DTPA-enhanced-MR imaging in the inflammation stage of nonalcoholic steatohepatitis (NASH) in mice.

Objective: The purpose of this study is to investigate the correlation between the liver kinetics of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) and liver histopathology in a mouse model of NASH by using dynamic contrast-enhanced MRI.

Materials And Methods: Twenty male C57/BL6 mice aged 8weeks were fed a methionine-choline-deficient (MCD) diet for 2, 4 and 6weeks (MCD groups: MCD 2w, 4w, or 6w). Gd-EOB-DTPA-enhanced MR imaging of the liver was performed at 2, 4 and 6weeks after the MCD feeding.

Longitudinal imaging of the availability of dopamine transporter and D2 receptor in rat striatum following mild ischemia.

The changes in the availability of striatal dopamine transporter and dopamine D2 receptor after mild focal ischemia in rats were measured using a small animal positron emission tomography system. Mild focal ischemia was induced by 20-minute middle cerebral artery occlusion. [C]PE2I binding to dopamine transporter was transiently increased on the ipsilateral side of the striatum at 2 days after middle cerebral artery occlusion.

Time Course of Diffusion Kurtosis in Cerebral Infarctions of Transient Middle Cerebral Artery Occlusion Rat Model.

Objective: To evaluate the relationship between fiber bundle direction and changes in diffusion kurtosis, we evaluated the apparent diffusion kurtosis coefficients (AKCs) that were perpendicular to and parallel to the principal diffusion tensor eigenvector.

Materials And Methods: Adult male Wistar rats were subjected to 30 or 60 minutes of middle cerebral artery occlusion and imaged with a 7T Magnetic Resonance Imager System (Varian MRI System 7T/210: Agilent Technologies, CA). Diffusion kurtosis images were obtained before middle cerebral artery (MCA) reperfusion and 3, 6, and 24 hours after reperfusion to generate the apparent diffusion coefficient (ADC), fractional anisotropy (FA), mean apparent diffusion kurtosis coefficient (mAKC), AKC axial to the eigenvector (axAKC), and AKC radial to the eigenvector (radAKC) images.

Kinetic study of benzyl [1-14C]acetate as a potential probe for astrocytic energy metabolism in the rat brain: Comparison with benzyl [2-14C]acetate.

Brain uptake of [(14)C]acetate has been reported to be a useful marker of astrocytic energy metabolism. In addition to uptake values, the rate of radiolabeled acetate washout from the brain appears to reflect CO2 exhaustion and oxygen consumption in astrocytes. We measured the time-radioactivity curves of benzyl [1-(14)C]acetate ([1-(14)C]BA), a lipophilic probe of [1-(14)C]acetate, and compared it with that of benzyl [2-(14)C]acetate ([2-(14)C]BA) in rat brains.

Imaging of reactive oxygen species using [(3)H]hydromethidine in mice with cisplatin-induced nephrotoxicity.

Background: Reactive oxygen species (ROS) have been implicated in cisplatin-induced nephrotoxicity. The aim of this study was to investigate the potential of using [(3)H]-labeled N-methyl-2,3-diamino-6-phenyl-dihydrophenanthridine ([(3)H]hydromethidine) for ex vivo imaging of regional ROS overproduction in mouse kidney induced by cisplatin.

Methods: Male C57BL/6 J mice were intraperitoneally administered with a single dose of cisplatin (30 mg/kg).

Imaging of reactive oxygen species in focal ischemic mouse brain using a radical trapping tracer [(3)H]hydromethidine.

Background: Reactive oxygen species (ROS) have been implicated in the pathophysiology of the brain after ischemic stroke. In this study, we investigate the generation of brain ROS after transient focal ischemia in mice using a radical trapping radiotracer, [(3)H]-labeled N-methyl-2,3-diamino-6-phenyl-dihydrophenanthridine ([(3)H]hydromethidine), which we recently reported as a ROS imaging probe. We also examined the effect of dimethylthiourea (DMTU), a hydroxyl radical scavenger, on brain ROS generation and infarct volume after transient focal ischemia in mice.

Potential of (99m)Tc-MIBI SPECT imaging for evaluating non-alcoholic steatohepatitis induced by methionine-choline-deficient diet in mice.

Background: Hepatic mitochondrial dysfunction has been implicated in pathological conditions leading to non-alcoholic steatohepatitis (NASH). Technetium-99 m-2-methoxyisobutyl-isonitrile ((99m)Tc-MIBI), a lipophilic cationic myocardial perfusion agent, is retained in the mitochondria depending on membrane potential. The aim of this study was to investigate the feasibility of (99m)Tc-MIBI for evaluating the hepatic mitochondrial dysfunction induced by methionine-choline-deficient (MCD) diet in mice.

Pharmacological MRI response to a selective dopamine transporter inhibitor, GBR12909, in awake and anesthetized rats.

Pharmacological magnetic resonance imaging (phMRI) is a powerful tool for imaging the effects of drugs on brain activity. In preclinical phMRI studies, general anesthesia used for minimizing head movements is thought to influence the phMRI responses to drugs. In this study we investigated the phMRI responses to a selective dopamine transporter (DAT) inhibitor, GBR12909, and a dopamine (DA) releaser, d-amphetamine (AMPH), in the isoflurane anesthetized and awake rats using a relative cerebral blood volume (rCBV) method.

In vivo imaging of reactive oxygen species in mouse brain by using [3H]hydromethidine as a potential radical trapping radiotracer.

To assess reactive oxygen species (ROS) production by detecting the fluorescent oxidation product, hydroethidine has been used extensively. The present study was undertaken to evaluate the potential of the hydroethidine derivative as a radiotracer to measure in vivo brain ROS production. [(3)H]-labeled N-methyl-2,3-diamino-6-phenyl-dihydrophenanthridine ([(3)H]Hydromethidine) was synthesized, and evaluated using in vitro radical-induced oxidization and in vivo brain ROS production model.

Assessment of glutamine synthetase activity by [13N]ammonia uptake in living rat brain.

Glutamine synthetase (GS) plays an important role in glutamate neurotransmission or neurological disorder in the brain. [(13) N]Ammonia blood flow tracer has been reported to be metabolically trapped in the brain via the glutamate-glutamine pathway. The present study investigated the effect of an inhibitor of GS on [(13) N]ammonia uptake in order to clarify the feasibility of measuring GS activity in the living brain.

[11C]PK11195 PET imaging of spinal glial activation after nerve injury in rats.

The role of glial activation has been implicated in the development and persistence of neuropathic pain after nerve injury by recent studies. PK11195 binding to the translocator protein 18kDa (TSPO) has been shown to be enhanced in activated microglia. This study was designed to assess PK11195 imaging in spinal microglia during activation after nerve injury.