Isoindolinone-Based PET Tracers for Imaging Mutant Huntingtin Aggregates.

Huntington's disease (HD) is caused by the repeat expansion of the CAG trinucleotide in the mutant Huntingtin gene (m) within the exon1 region, resulting in an expanded polyglutamine-containing mHTT exon1 protein that serves as the source of the hallmark mHTT aggregates in people with HD (PwHD). To better understand aggregation formation during disease progression and its utility as a pharmacodynamic biomarker, we have been targeting mHTT aggregates for developing PET imaging tracers and have identified a series of isoindolinones that show significantly higher binding potential (BP, a ratio of Bmax over ) in HD mouse models as well as increased binding in HD post-mortem brains, compared to first generation ligands. We present the structure-activity relationship (SAR) work leading to three candidate tracers progressed for human studies: [C]CHDI-009 (), [F]CHDI-385 () and [F]CHDI-386 ().

PET imaging with [¹¹C]CHDI-00485180-R, designed as radioligand for aggregated mutant huntingtin, in people with Huntington's disease.

Purpose: [C]CHDI-00485180-R ([C]CHDI-180R) is a novel PET radioligand developed to image aggregated mutant huntingtin (mHTT). Data from mouse models of Huntington's disease (HD) and biodistribution studies in healthy volunteers suggested that [C]CHDI-180R is a promising candidate for in vivo determination of cerebral aggregated mHTT levels using PET. In the iMagemHTT study reported here, we investigated [C]CHDI-180R kinetic properties and suitability to quantify aggregated mHTT in brains of people with HD (pwHD).

An LSTM-driven thermoelectric coupling response prediction method for shape memory alloy actuators.

Shape memory alloys (SMAs) show exceptional potential in actuator design due to their shape memory effect and superelasticity, yet their thermoelectric hysteresis challenges accurate modeling. This study proposes a hybrid framework integrating long short-term memory (LSTM) networks with physical kinematics to predict SMA actuator responses. Unlike conventional approaches, our method decouples material behavior prediction from actuator geometry: A single-layer LSTM network processes voltage-time sequences to predict SMA wire's temperature and resistance dynamics, while a physics-based model computes angular displacement through phase transformation and constitutive equations.

Assessment of changes in synaptic density in the zQ175DN mouse model of Huntington's disease: a [F]SynVesT-1 study.

Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary movements, cognitive decline and psychiatric problems. HD has been associated with synaptic dysfunction and loss of the synaptic vesicle protein 2A (SV2A). SV2A can readily be quantified via positron emission tomography (PET) using the selective and high affinity SV2A radiotracer [F]SynVesT-1 that we previously characterized in C57BL/6J mice.

Biodistribution and dosimetry of the PET radioligand [F]CHDI-650 in mice for detection of mutant huntingtin aggregates.

Background: Huntington's disease (HD) is a rare neurodegenerative disorder caused by an expansion of the CAG trinucleotide repeat in the huntingtin gene which encodes the mutant huntingtin protein (mHTT) that is associated with HD-related neuropathophysiology. Noninvasive visualization of mHTT aggregates in the brain, with positron emission tomography (PET), will allow to reliably evaluate the efficacy of therapeutic interventions in HD. This study aimed to assess the radiation burden of [F]CHDI-650, a novel fluorinated mHTT radioligand, in humans based on both in vivo and ex vivo biodistribution in mice and subsequent determination of dosimetry for dosing in humans.

Preclinical validation and kinetic modelling of the SV2A PET ligand [F]UCB-J in mice.

Synaptic vesicle protein 2A (SV2A) is ubiquitously expressed in presynaptic terminals where it functions as a neurotransmission regulator protein. Synaptopathy has been reported during healthy ageing and in a variety of neurodegenerative diseases. Positron emission tomography (PET) imaging of SV2A can be used to evaluate synaptic density.

Preclinical evaluation of the novel [F]CHDI-650 PET ligand for non-invasive quantification of mutant huntingtin aggregates in Huntington's disease.

Purpose: Positron emission tomography (PET) imaging of mutant huntingtin (mHTT) aggregates is a potential tool to monitor disease progression as well as the efficacy of candidate therapeutic interventions for Huntington's disease (HD). To date, the focus has been mainly on the investigation of C radioligands; however, favourable F radiotracers will facilitate future clinical translation. This work aimed at characterising the novel [F]CHDI-650 PET radiotracer using a combination of in vivo and in vitro approaches in a mouse model of HD.

Research on one-dimensional phase change heat transfer characteristics based on instrument compartment structure.

To address the issue of electronic equipment failure inside the instrument compartment due to aerodynamic heating during high-speed flight. Combining the heat transfer characteristics of phase change materials, a new instrument compartment structure was proposed as the research subject based on phase change materials. While studying the heat transfer characteristics of this structure, one-dimensional phase change heat transfer theoretical model was constructed based on the Lightfoot integral equation method, and the corresponding analytical solution was obtained.

Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington's Disease.

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin () gene. We report the design of a series of pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of mRNA transcripts and protein levels.

In Vivo Cerebral Imaging of Mutant Huntingtin Aggregates Using C-CHDI-180R PET in a Nonhuman Primate Model of Huntington Disease.

Huntington disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine (CAG) trinucleotide expansion in the huntingtin () gene that encodes the mutant huntingtin protein (mHTT). Visualization and quantification of cerebral mHTT will provide a proxy for target engagement and a means to evaluate therapeutic interventions aimed at lowering mHTT in the brain. Here, we validated the novel radioligand C-labeled 6-(5-((5-methoxypyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)-2-methylpyridazin-3(2H)-one (C-CHDI-180R) using PET imaging to quantify cerebral mHTT aggregates in a macaque model of HD.

Longitudinal investigation of changes in resting-state co-activation patterns and their predictive ability in the zQ175 DN mouse model of Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder caused by expanded (≥ 40) glutamine-encoding CAG repeats in the huntingtin gene, which leads to dysfunction and death of predominantly striatal and cortical neurons. While the genetic profile and clinical signs and symptoms of the disease are better known, changes in the functional architecture of the brain, especially before the clinical expression becomes apparent, are not fully and consistently characterized. In this study, we sought to uncover functional changes in the brain in the heterozygous (HET) zQ175 delta-neo (DN) mouse model at 3, 6, and 10 months of age, using resting-state functional magnetic resonance imaging (RS-fMRI).

Resting-state fMRI reveals longitudinal alterations in brain network connectivity in the zQ175DN mouse model of Huntington's disease.

Huntington's disease is an autosomal, dominantly inherited neurodegenerative disease caused by an expansion of the CAG repeats in exon 1 of the huntingtin gene. Neuronal degeneration and dysfunction that precedes regional atrophy result in the impairment of striatal and cortical circuits that affect the brain's large-scale network functionality. However, the evolution of these disease-driven, large-scale connectivity alterations is still poorly understood.

Design and Evaluation of [F]CHDI-650 as a Positron Emission Tomography Ligand to Image Mutant Huntingtin Aggregates.

Therapeutic interventions are being developed for Huntington's disease (HD), a hallmark of which is mutant huntingtin protein (mHTT) aggregates. Following the advancement to human testing of two [C]-PET ligands for aggregated mHTT, attributes for further optimization were identified. We replaced the pyridazinone ring of CHDI-180 with a pyrimidine ring and minimized off-target binding using brain homogenate derived from Alzheimer's disease patients.

Biodistribution and dosimetry in human healthy volunteers of the PET radioligands [C]CHDI-00485180-R and [C]CHDI-00485626, designed for quantification of cerebral aggregated mutant huntingtin.

Purpose: Huntington's disease is caused by a trinucleotide expansion in the HTT gene, which leads to aggregation of mutant huntingtin (mHTT) protein in the brain and neurotoxicity. Direct in vivo measurement of mHTT aggregates in human brain parenchyma is not yet possible. In this first-in-human study, we investigated biodistribution and dosimetry in healthy volunteers of [C]CHDI-00485180-R ([C]CHDI-180R) and [C]CHDI-00485626 ([C]CHDI-626), two tracers designed for PET imaging of aggregated mHTT in the brain that have been validated in preclinical models.

Validation, kinetic modeling, and test-retest reproducibility of [F]SynVesT-1 for PET imaging of synaptic vesicle glycoprotein 2A in mice.

Alterations in synaptic vesicle glycoprotein 2 A (SV2A) have been associated with several neuropsychiatric and neurodegenerative disorders. Therefore, SV2A positron emission tomography (PET) imaging may provide a unique tool to investigate synaptic density dynamics during disease progression and after therapeutic intervention. This study aims to extensively characterize the novel radioligand [F]SynVesT-1 for preclinical applications.

Development of a ligand for in vivo imaging of mutant huntingtin in Huntington's disease.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin () gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (polyQ) tract. Whereas several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, methods to visualize mHTT protein species in the living brain are lacking. Here, we demonstrate the development and characterization of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates.

Predictive value of using plasma long non-coding RNAs ANRIL and HOXA11-AS for in-stent restenosis.

In-stent restenosis (ISR) can pose serious challenges for cardiologists following coronary stent implantation. Early identification of patients at high risk of ISR is considered to be effective for its prevention. However, factors that can reliably predict the risk of ISR remain elusive at present.

[The Role of Nrf2 Pathway Activation in Hippocampal Neuron Injury of Neonatal Rats with Bilirubin Encephalopathy].

Objective: To explore the effect of nuclear factor-erythroid 2-related factor (Nrf2) pathway activation on hippocampal neuron damage in neonatal rats with bilirubin encephalopathy.

Methods: Neonatal rats were randomly assigned to a control group (Control), a model group (Model) and an Nrf2 activator TBHQ (tert-Butylhydroquinone) group (TBHQ), with 20 rats in each group. Bilirubin solution was injected through the cerebellomedullary cistern to establish the neonatal rat model of bilirubin encephalopathy.

Effects of Pulmonary Surfactant Combined with Noninvasive Positive Pressure Ventilation on KRT-14 and ET-1 Levels in Peripheral Blood and Therapeutic Effects in Neonates with Respiratory Distress Syndrome.

This study is aimed at exploring the effect of pulmonary surfactant (PS) combined with noninvasive positive pressure ventilation on the levels of Keratin-14 (KRT-14) and Endothelin-1 (ET-1) in peripheral blood and the therapeutic effect of neonatal respiratory distress syndrome (NRDS). Altogether 137 cases of neonates with respiratory distress syndrome treated in our hospital from April 2016 to July 2018 were collected. Among them, 64 cases treated with noninvasive positive pressure ventilation were considered as the control group, and 73 cases treated with PS combined with noninvasive positive pressure ventilation were considered as the observation group.

Longitudinal preclinical evaluation of the novel radioligand [11C]CHDI-626 for PET imaging of mutant huntingtin aggregates in Huntington's disease.

Purpose: As several therapies aimed at lowering mutant huntingtin (mHTT) brain levels in Huntington's disease (HD) are currently being investigated, noninvasive positron emission tomography (PET) imaging of mHTT could be utilized to directly evaluate therapeutic efficacy and monitor disease progression. Here we characterized and longitudinally assessed the novel radioligand [C]CHDI-626 for mHTT PET imaging in the zQ175DN mouse model of HD.

Methods: After evaluating radiometabolites and radioligand kinetics, we conducted longitudinal dynamic PET imaging at 3, 6, 9, and 13 months of age (M) in wild-type (WT, n = 17) and heterozygous (HET, n = 23) zQ175DN mice.

Synaptic Vesicle Glycoprotein 2A Is Affected in the Central Nervous System of Mice with Huntington Disease and in the Brain of a Human with Huntington Disease Postmortem.

Synaptic dysfunction is a primary mechanism underlying Huntington disease (HD) progression. This study investigated changes in synaptic vesicle glycoprotein 2A (SV2A) density by means of C-UCB-J small-animal PET imaging in the central nervous system of mice with HD. Dynamic C-UCB-J small-animal PET imaging was performed at clinically relevant disease stages (at 3, 7, 10, and 16 mo) in the heterozygous knock-in Q175DN mouse model of HD and wild-type littermates (16-18 mice per genotype and time point).

Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates.

Huntington's disease (HD) is caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin (HTT) gene coding for the huntingtin (HTT) protein. The misfolding and consequential aggregation of CAG-expanded mutant HTT (mHTT) underpin HD pathology. Our interest in the life cycle of HTT led us to consider the development of high-affinity small-molecule binders of HTT oligomerized/amyloid-containing species that could serve as either cellular and in vivo imaging tools or potential therapeutic agents.

[C]CHDI-626, a PET Tracer Candidate for Imaging Mutant Huntingtin Aggregates with Reduced Binding to AD Pathological Proteins.

The expanded polyglutamine-containing mutant huntingtin (mHTT) protein is implicated in neuronal degeneration of medium spiny neurons in Huntington's disease (HD) for which multiple therapeutic approaches are currently being evaluated to eliminate or reduce mHTT. Development of effective and orthogonal biomarkers will ensure accurate assessment of the safety and efficacy of pharmacologic interventions. We have identified and optimized a class of ligands that bind to oligomerized/aggregated mHTT, which is a hallmark in the HD postmortem brain.

Kinetic Modelling and Test-Retest Reproducibility for the Dopamine DR Radioligand [C]SCH23390 in Healthy and Diseased Mice.

Purpose: Our aim in this study was to compare different non-invasive pharmacokinetic models and assess test-retest reproducibility of the radioligand [C]SCH23390 for the quantification of dopamine D-like receptor (DR) in both wild-type (WT) mice and heterozygous (HET) Q175DN mice as Huntington's disease (HD) model.

Procedures: Adult WT (n = 9) and HET (n = 14) mice underwent a 90-min [C]SCH23390 positron emission tomography (PET) scan followed by computed tomography (CT) to evaluate the pharmacokinetic modelling in healthy and diseased conditions. Additionally, 5 WT mice and 7 HET animals received a second [C]SCH23390 PET scan for test-retest reproducibility.