First-in-Human Study of [C]NCGG401 for Imaging Colony-Stimulating Factor 1 Receptors in the Brain.

Microglia, the immune cells in the brain, play a significant role in the pathophysiology of neurodegenerative diseases. To visualize these cells in the living brain, we developed a PET ligand, [C]NCGG401 (4-{2-[((1,2)-2-hydroxycyclohexyl)(methyl)amino]benzothiazol-6-yloxy}--methylpicolinamide, NCGG401), that targets colony-stimulating factor 1 receptor (CSF1R). In this study, we present the first-in-human evaluation of [C]NCGG401 to assess its safety profile and then to evaluate its kinetics to quantify CSF1R in the human brain.

Evaluation of specific binding of [C]TZ7774 to the receptor-interacting protein kinase 1 (RIPK1) in the brain.

Microglia, a type of immune cells of the central nervous system, play a critical role in the pathophysiology of neurodegenerative disorders including Alzheimer's disease (AD). Recently, efforts for drug discovery have focused on modifying the function of microglia to halt AD progression. One such effort targets a multifaceted kinase called receptor-interacting protein kinase 1 (RIPK1) that controls inflammation and cell death.

MicroRNA-5572 Is Associated with Endoplasmic Reticulum Stress Responses in Low Zinc Treated and SOD1 G85R-Transfected HEK293 Cells.

Amyotrophic lateral sclerosis (ALS) is a fetal neurodegenerative disease. The mechanism of sporadic ALS onset remains unclarified in detail. Disruption of zinc homeostasis could be related to sporadic ALS.

Trait-anxiety and glial-related neuroinflammation of the amygdala and its associated regions in Alzheimer's disease: A significant correlation.

Background: Positron emission tomography, which assesses the binding of translocator protein radiotracers, C-DPA-713, may be a sensitive method for determining glial-mediated neuroinflammation levels. This study investigated the relationship between regional C-DPA713 binding potential (BP) and anxiety in patients with Alzheimer's disease (AD) continuum.

Methods: Nineteen patients with AD continuum determined to be amyloid-/p-tau 181-positive via cerebrospinal fluid analysis were included in this cross-sectional study (mild cognitive impairment [MCI, n = 5] and AD [n = 14]).

A novel PET probe to selectively image heat shock protein 90α/β isoforms in the brain.

Background: Heat shock proteins (HSPs) are present throughout the brain. They function as molecular chaperones, meaning they help with the folding and unfolding of large protein complexes. These chaperones are vital in the development of neuropathological conditions such as Alzheimer's disease and Lewy body disease, with HSP90, a specific subtype of HSP, playing a key role.

Synthesis and evaluation of a novel PET ligand, a GSK'963 analog, aiming at autoradiography and imaging of the receptor interacting protein kinase 1 in the brain.

Background: Receptor interacting protein kinase 1 (RIPK1) is a serine/threonine kinase, which regulates programmed cell death and inflammation. Recently, the involvement of RIPK1 in the pathophysiology of Alzheimer's disease (AD) has been reported; RIPK1 is involved in microglia's phenotypic transition to their dysfunctional states, and it is highly expressed in the neurons and microglia in the postmortem brains in AD patients. They prompt neurodegeneration leading to accumulations of pathological proteins in AD.

Noradrenaline transporter PET reflects neurotoxin-induced noradrenaline level decrease in the rat hippocampus.

Background: The neuropathological changes of early Alzheimer's disease (AD) include neurodegenerative loss of noradrenaline neurons in the locus coeruleus with decreasing noradrenaline availability in their projection areas such as the hippocampus. This diminishing noradrenaline availability is thought to play an important role pathophysiologically in the development of cognitive impairment in AD, because noradrenaline is not only essential for maintaining cognitive functions such as memory, learning and attention, but also its anti-inflammatory action, where its lack is known to accelerate the progression of AD in the mouse model. Therefore, the availability of in vivo biomarkers of the integrity of noradrenaline neurons may be beneficial for furthering our understanding of the role played by the noradrenaline system in the progressive cognitive dysfunction seen in AD patients.

Neuroimaging biomarkers of glial activation for predicting the annual cognitive function decline in patients with Alzheimer's disease.

Background: Glial activation is central to the pathogenesis of Alzheimer's disease (AD). However, researchers have not demonstrated its relationship to longitudinal cognitive deterioration. We aimed to compare the prognostic effects of baseline positron emission tomography (PET) imaging of glial activation and amyloid/tau pathology on the successive annual cognitive decline in patients with AD.

Sasa veitchii extracts protect phenytoin-induced cell proliferation inhibition in human lip mesenchymal cells through modulation of miR-27b-5p.

A cleft lip, with or without a cleft palate, is a common birth defect caused by environmental factors or genetic mutations. Environmental factors, such as pharmaceutical exposure in pregnant women, are known to induce cleft lip, with or without cleft palate in the child. This study aimed to investigate the protective effect of Sasa veitchii extract (SE) on phenytoin-induced inhibition of cell proliferation in human lip mesenchymal cells (KD cells) and human embryonic palatal mesenchymal cells (HEPM cells).

C-Labeling of acyclic retinoid peretinoin by rapid C-[C]methylation to disclose novel brain permeability and central nervous system activities hidden in antitumor agent.

Recently, retinoid actions on the central nervous system (CNS) have attracted considerable attention from the perspectives of brain disease diagnosis and drug development. Firstly, we successfully synthesized [C]peretinoin esters (methyl, ethyl, and benzyl) using a Pd(0)-mediated rapid C-[C]methylation of the corresponding stannyl precursors without geometrical isomerization in 82%, 66%, and 57% radiochemical yields (RCYs). Subsequent hydrolysis of the C-labeled ester produced [C]peretinoin in 13 ± 8% RCY (n = 3).

Involvement of inflammation in the medial temporal region in the development of agitation in Alzheimer's disease: an in vivo positron emission tomography study.

Background: The evaluation of C-DPA-713 binding using positron emission tomography for quantifying the translocator protein can be a sensitive approach in determining the level of glial activation induced by neuroinflammation. Herein, we aimed to investigate the relationship between regional C-DPA713-binding potential (BP ) and neuropsychiatric symptoms (NPS) in amyloid-positive Alzheimer's disease (AD) patients.

Methods: Fifteen AD patients were enrolled in this study.

Estimation of blood-based biomarkers of glial activation related to neuroinflammation.

Background: Neuroinflammation is a well-known feature of Alzheimer's disease (AD), and a blood-based test for estimating the levels of neuroinflammation would be expected. In this study, we examined and validated a model using blood-based biomarkers to predict the level of glial activation due to neuroinflammation, as estimated by C-DPA-713 positron emission tomography (PET) imaging.

Methods: We included 15 patients with AD and 10 cognitively normal (CN) subjects.

[C]NCGG401, a novel PET ligand for imaging of colony stimulating factor 1 receptors.

Colony-stimulating factor 1 receptors (CSF1R) are expressed exclusively on microglia in the central nervous system. The receptors regulate immune responses by controlling the survival and activity of microglia and are intricately involved in the pathophysiology of Alzheimer's disease. In this study, we developed [C]NCGG401, a positron emission tomography (PET) ligand, targeting for CSF1R as an imaging biomarker for microglial pathophysiology in Alzheimer's disease.

Kinetic modeling and non-invasive approach for translocator protein quantification with C-DPA-713.

Introduction: C-DPA-713 is a positron emission tomography (PET) radiotracer developed for imaging the expression of the translocator protein (TSPO) in glial cells, which is considered to be a marker of the neuroinflammatory burden. This study investigated the pharmacokinetic profile of C-DPA-713 and evaluated kinetic modeling and non-invasive TSPO quantification using dynamic PET imaging data in the Alzheimer's disease (AD) and cognitive normal (CN) participants.

Methods: Eleven patients with AD and 6 CN participants were examined using dynamic C-DPA-713 PET imaging for 60 min with arterial blood sampling.

Synthesis of (R,S)-isoproterenol, an inhibitor of tau aggregation, as an C-labeled PET tracer via reductive alkylation of (R,S)-norepinephrine with [2-C]acetone.

(R,S)-Isoproterenol inhibits the formation of toxic granular tau oligomers associated with neuronal loss and development of cognitive disorders, and is an attractive drug candidate for Alzheimer's disease. To elucidate its behavior in the brain by positron emission tomography, we synthesize (R,S)-[C]isoproterenol by reductive alkylation of (R,S)-norepinephrine with [2-C]acetone, which was in turn synthesized in situ under improved conditions afforded a decay-corrected radiochemical yield of 54%. The reductive alkylation using NaBH(OAc) as reducing agent in the presence of benzoic acid in DMSO/DMF (60:40 v/v) at 100 °C for 10 min gave (R,S)-[C]isoproterenol in an 87% radio-high performance liquid chromatography (HPLC) analytical yield.

Synthesis of antisense oligonucleotides containing acyclic alkynyl nucleoside analogs and their biophysical and biological properties.

The synthesis of oligonucleotide (ON) analogs, which can be used as antisense molecules, has recently gained much attention. Here, we report the synthesis and properties of an ON analog containing acyclic thymidine and cytidine analogs with a 4-pentyl-1,2-diol instead of the d-ribofuranose moiety. The incorporation of these analogs into the ON improved its nuclease resistance to 3'-exonucleases.

Incorporation of an acyclic alkynyl nucleoside analog into siRNA improves silencing activity and nuclease resistance.

In order to improve the silencing activity and nuclease resistance of small interfering RNA (siRNA), we designed and synthesized an acyclic thymidine analog containing 4-pentyne-1,2-diol instead of d-ribofuranose. The incorporation of this analog into siRNAs at specific positions in the strands was found to enhance the silencing activity of siRNAs and to increase the resistance of the siRNA to hydrolytic degradation by a 3' exonuclease.

Autoactivation of pancreatic trypsinogen is controlled by carbohydrate-specific interaction.

Activation of bovine pancreatic trypsinogen (BPTG) by trypsin (BPT) was found to be inhibited by d GalN/GalNAc at pH 5.5, the pH of secretory granules in the pancreas. Binding studies with biotinylated sugar-polymers indicated that BPTG and BPT bind to α-GalNAc, α-Man, and α-Gal better at pH 5.

MicroRNAs miR-199a-5p and -3p target the Brm subunit of SWI/SNF to generate a double-negative feedback loop in a variety of human cancers.

The chromatin remodeling complex SWI/SNF is an important epigenetic regulator that includes one Brm or BRG1 molecule as catalytic subunit. Brm and BRG1 do not function identically, so this complex can regulate gene expression either positively or negatively, depending on the promoter to which it is recruited. Notably, Brm attenuation due to posttranscription suppression occurs often in human tumor cells, in which this event contributes to their oncogenic potential.

Incorporation of biaryl units into the 5' and 3' ends of sense and antisense strands of siRNA duplexes improves strand selectivity and nuclease resistance.

Small interfering RNA (siRNA) is a noncoding RNA with considerable potential as a new therapeutic drug for intractable diseases. siRNAs can be rationally designed and synthesized if the sequences of the disease-causing genes are known. In this paper, we describe the synthesis and properties of siRNAs modified with biaryl units.

Biaryl modification of the 5'-terminus of one strand of a microRNA duplex induces strand specificity.

MicroRNAs (miRNAs) are single-stranded non-coding RNAs composed of 20-23 nucleotides. They are initially transcribed in the nucleus as pri-miRNAs. After processing, one strand from the miRNA duplex (miR-5p/miR-3p duplex) is loaded onto the RNA-induced silencing complex (RISC) to produce a functional, mature miRNA that inhibits the expression of multiple target genes.