Biology subjects

Staelens, S.

Publications and source records attributed to Staelens, S..

4 recordsLinked to original sources

bioRxiv2025

Preclinical evaluation of CHDI-009R for quantification of mutant huntingtin aggregates

Huntingtons disease (HD) is a neurodegenerative disorder caused by an expanded trinucleotide repeat in the huntingtin gene (HTT) that subsequently leads to aggregation of the mutant huntingtin (mHTT) protein. Thus, lowering mHTT is a key therapeutic approach used by several candidate therapeutics currently under investigation. Visualization of the efficiency of these therapeutics through in vivo mHTT quantification rises in importance. For positron emission tomography (PET) imaging of mHTT aggregates, it is critical to characterize the in vivo kinetic profile of newly identified mHTT binders to assess their translational application. Here, we report the evaluation of [11C]CHDI-009R, a PET imaging radioligand with higher affinity and selectivity for mHTT aggregates than previously reported radioligands, in the heterozygous (HET) zQ175DN mouse model of HD and wild-type (WT) littermates at 9 and 3 months of age. [11C]CHDI-009R displayed high stability in plasma and brain, which was reflected in brain kinetics as demonstrated by rapid uptake followed by relatively slow elimination. Kinetic modeling and volume of distribution VT (IDIF) indicated the radioligands ability to quantify mHTT aggregation at 9 months of age with clear genotype differentiation (p<0.0001). [11C]CHDI-009R showed an excellent test-retest reliability in 9-month-old mice (intraclass correlation coefficient: 0.62 - 0.79). A phenotypic difference in mHTT aggregates was also observed in 3-month-old mice in several brain structures (p<0.05) and was confirmed with [3H]CHDI-009R autoradiography. Overall, this study suggests [11C]CHDI-009R is a promising radioligand for the detection of cerebral mHTT aggregates in a mouse model of HD and supports its advance to clinical evaluation.

neuroscience↗

bioRxiv2024

Preclinical validation and kinetic modelling of the SV2A PET ligand 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. The PET ligand [11C]UCB-J has high binding affinity and selectivity for SV2A but has a short physical half-life due to the 11C isotope. Here we report the characterization and validation of its 18F-labeled equivalent, [18F]UCB-J, in terms of specificity, reproducibility and stability in C57BL/6J mice. Plasma analysis revealed at least one polar radiometabolite. Kinetic modelling was performed using a population-based metabolite corrected image-derived input function (IDIF). [18F]UCB-J showed relatively fast kinetics and a reliable measure of the IDIF-based volume of distribution (VT(IDIF)). [18F]UCB-J specificity for SV2A was confirmed through a levetiracetam blocking assay (50 to 200 mg/kg). Reproducibility of the VT(IDIF) was determined through test-retest analysis, revealing significant correlation (r2=0.773, p<0.0001). Time-stability analyses indicate a scan duration of 60 min to be sufficient to obtain a reliable VT(IDIF). In conclusion, [18F]UCB-J is a selective SV2A ligand with optimal kinetics in mice. Further investigation is warranted for (pre)clinical applicability of [18F]UCB-J in synaptopathies.

neuroscience↗

bioRxiv2024

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

PurposePositron 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 Huntingtons disease (HD). To date, the focus has been mainly on the investigation of 11C radioligands; however, favourable 18F radiotracers will facilitate future clinical translation. This work aimed at characterising the novel [18F]CHDI-650 PET radiotracer using a combination of in vivo and in vitro approaches in a mouse model of HD. MethodsAfter characterising [18F]CHDI-650 using in vitro autoradiography, we assessed in vivo plasma and brain radiotracer stability as well as kinetics through dynamic PET imaging in the heterozygous (HET) zQ175DN mouse model of HD and wild-type (WT) littermates at 9 months of age. Additionally, we performed a head-to-head comparison study at 3 months with the previously published [11C]CHDI-180R radioligand. ResultsPlasma and brain radiometabolite profiles indicated a suitable metabolic profile for in vivo imaging of [18F]CHDI-650. Both in vitro autoradiography and in vivo [18F]CHDI-650 PET imaging at 9 months of age demonstrated a significant genotype effect (p<0.0001) despite the poor test-retest reliability. [18F]CHDI-650 PET imaging at 3 months of age displayed higher differentiation between genotypes when compared to [11C]CHDI-180R. ConclusionOverall, [18F]CHDI-650 allows for discrimination between HET and WT zQ175DN mice at 9 and 3 months of age. [18F]CHDI-650 represents the first suitable 18F radioligand to image mHTT aggregates in mice and its clinical evaluation is underway.

neuroscience↗

bioRxiv2021

A novel imaging ligand as a biomarker for mutant huntingtin-lowering in Huntington's disease

Huntingtons disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (PolyQ) tract. While several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, no method is currently available to visualize mHTT levels in the living brain. Here we demonstrate the development of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with 11C ([11C]CHDI-180R) enables non-invasive monitoring of mHTT pathology in the brain and can track region-and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression. We further show that therapeutic agents that lower mHTT in the striatum have a functional restorative effect that can be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.

neuroscience↗