Biology subjects

Halldin, C.

Publications and source records attributed to Halldin, C..

7 recordsLinked to original sources

bioRxiv2026

In silico evaluation of the effects of temperature on the affinity of the SV2C ligand UCB-1A to SV2 isoforms

Synaptic vesicle glycoproteins 2 (SV2) are integral membrane proteins essential for neurotransmitter release and are implicated in neurological disorders including epilepsy and Parkinsons disease. In the attempt to develop a ligand selective for SV2C, and in collaboration with UCB, UCB-F was identified as a potential candidate. However, the affinity of UCB-F to SV2C was found to be temperature dependent, decreasing by about 10-fold from +4 to 37 degrees. UCB1A was subsequently identified as SV2C ligand displaying in vitro a 100-fold selectivity for SV2C compared with SV2A. In this study we investigated whether the binding of UCB-1A to SV2A and SV2C was affected by the temperature. A combination of experimental binding assay data and molecular dynamics (MD) simulations were used. The binding studies revealed that UCB1A affinity for SV2A decreased significantly at 37 {degrees}C compared with 4 {degrees}C, whereas binding to SV2C remained largely unchanged. MD simulations reproduced these observations, namely that ligand RMSD values at 310 K showed that UCB1A binding fluctuated markedly in the SV2A complex, with many trajectories exceeding the 3.0 [A] stability cutoff, whereas UCB1A remained relatively well-anchored in SV2C under the same conditions. Structural analysis showed that, while UCB1A adopts a conserved binding pose across all isoforms stabilized by {pi}- {pi} stacking and a hydrogen bond with Asp, SV2C possesses a unique stabilizing feature. In SV2C, Tyr298 is less exposed to the solvent and engages in a persistent hydrogen bond with Asparagine, a structural feature that reinforces pocket stability and limits temperature-induced destabilization. This interaction is absent in SV2A, consistent with its greater temperature sensitivity. Together, these findings provide a mechanistic explanation for the experimentally observed temperature independence of UCB1A binding to SV2C. More broadly, the results highlight the importance of incorporating physiologically relevant temperatures into SV2 ligand evaluation and demonstrate how combining experiments with simulations can uncover isoform-specific mechanisms of ligand recognition and stability.

biochemistry↗

bioRxiv2026

Discovery and characterization of UCB-1A: the first PET radioligand for imaging synaptic vesicle glycoprotein 2C

The synaptic vesicle glycoprotein 2C (SV2C) is a synaptic protein involved in the regulation of dopamine release. It is expressed in striatum, globus pallidus and substantia nigra, regions involved in the regulation of motor function. Genome-wide association studies, animal model and human brain tissue data indicate a strong link between SV2C and Parkinso[n]s disease, suggesting a potential role of SV2C as synaptic marker for Parkinso[n]s disease. We hypothesize that a positron emission tomography (PET) radioligand for SV2C can serve as imaging marker for Parkinso[n]s disease, enabling early diagnosis and assessment of disease progression. This study was therefore designed to develop a PET radioligand for imaging SV2C. UCB-1A was the lead candidate selected from a library of compounds developed by UCB BioPharma. A translational approach was used, including autoradiography and in vitro binding studies with [3H]UCB-1A, and in vivo PET studies with [11C]UCB-1A in non-human primates (NHPs). The KD of [3H]UCB-1A for rat and human SV2C ranged between 6 and 15 nM, with >100-fold selectivity towards SV2A and SV2B. Specific binding of [3H]UCB-1A in rat and NHP brains was observed in substantia nigra, globus pallidus, striatum and brainstem nuclei, consistent with the expression of SV2C, and was decreased in the striatum of 6-hydroxydopamine-lesioned rats and in the putamen of Parkinson donors. UCB-1A was successfully radiolabelled with 11C and PET studies in NHPs demonstrated that [11C]UCB-1A displays suitable pharmacokinetic properties, a brain distribution consistent with the expression of SV2C and is selective for SV2C. [11C]UCB-1A is the first PET radioligand for in vivo imaging of SV2C and a potential synaptic marker for in vivo studies in Parkinso[n]s disease.

neuroscience↗

bioRxiv2026

Imaging Synaptic Vesicle Protein SV2C with 18F-UCB-F: An In Vitro Autoradiography and In Vivo NHP PET Study

The synaptic vesicle protein SV2C, predominantly found in the basal ganglia, has been associated with Parkinsons disease through genetic studies. It plays a crucial role in regulating dopamine release and has been shown to be disrupted in PD animal models and brain tissues from PD patients. In the context of PD-related synaptopathy, SV2C may serve as a potential imaging target for monitoring disease progression and response to treatment. [18F]UCB-F is a radioligand binding to SV2C developed by UCB. Preliminary autoradiography and PET studies in rats showed that [18F]UCB-F displays a brain distribution consistent with the expression of SV2C in vitro but does not display any specific binding in vivo. This study was therefore designed to further investigate the affinity and selectivity of [18F]UCB-F for SV2C and to examine the in vitro and in vivo properties of the radioligand in non-human primates. In vitro binding studies were performed to measure the affinity of UCB-F to SV2A, SV2B, and SV2C. Insilico modeling was used to assess the binding mode and energy of UCB-F. Autoradiography studies on rat and non-human primate (NHP) brain tissues were performed to confirm that [18F]UCB-F showed similar distribution in rat and NHP tissue. Finally, PET studied in NHPs were performed to examine the in vivo pharmacokinetic properties of [18F]UCB-F. [18F]UCB-F was successfully synthesized from the corresponding precursor with high yield. Autoradiography on brain slices from rats and NHPs demonstrated specific binding of [18F]UCB-F in the pallidum, striatum, substantia nigra, and brainstem, consistent with the known brain expression of SV2C. In NHPs, [18F]UCB-F rapidly crossed the blood-brain barrier, reaching peak uptake values of 2.8 %ID in NHP1 and 2.1 %ID in NHP2 at 4 minutes post-injection. The tracer wasrapidly washed out from the brain, with no clear regional distribution. Radiometabolite analysis revealed the formation of only more polar radiometabolites, with approximately 15% of unchanged radioligand remaining in plasma at 15 minutes post-injection. In vitro and in-silico studies demonstrated that the affinity of [18F]UCB-F decreased by approximately one factor of magnitude with increase of temperature from 4{degrees} to 37{degrees} C. This temperature-related decrease of the affinity for SV2C together with rapid in vivo radiometabolism might explain the discrepancy between in vitro and in vivo performance of [18F]UCB-F. Overall, these findings suggest that [18F]UCB-F is not a suitable PET radioligand for imaging SV2C. Further research is needed to identify alternative candidates with improved in vivo stability and brain retention.

neuroscience↗

bioRxiv2025

PET imaging of an antisense oligonucleotide in the living non-human primate brain using click chemistry

Determination of a drugs biodistribution is critical to ensure it reaches the target tissue of interest. This is particularly challenging in the brain where invasive sampling methods may not be possible. Here, a pretargeted imaging methodology is disclosed that utilizes bioorthogonal click chemistry to determine the distribution of an antisense oligonucleotide in the living brain following intrathecal dosing. A novel PET tracer, [18F]BIO-687, bearing a click-reactive trans-cyclooctene (TCO) was discovered and tested in conjunction with a Malat1 antisense oligonucleotide (ASO) conjugated with a methyltetrazine (MeTz). PET imaging in rats demonstrated that the tracer possesses good kinetic properties for CNS imaging and can react to form a covalent linkage with high specificity to the MeTz-conjugated-ASO in vivo. Further, the amount of tracer reacted by cycloaddition with the Tz was determined to be dependent on the concentration of ASO-MeTz in tissue, as determined through comparison of the imaging signal with the LC-MS of the tissue homogenate. The system was evaluated in cynomolgus monkeys, with PET imaging showing favorable tracer kinetics and specific binding to the ASO in vivo. These results demonstrate that the tracer [18F]BIO-687 can image intrathecally-delivered ASO distribution in the brain, and future studies should leverage this technology to evaluate ASO distribution in human subjects to study distribution. One Sentence SummaryDistribution of an intrathecally administered antisense oligonucleotide can be imaged using a pretargeted approach in the living brains of non-human primates.

neuroscience↗

bioRxiv2019

Validity and reliability of extrastriatal raclopride binding quantification in the living human brain

[11C]raclopride is a well established PET tracer for the quantification of dopamine 2/3 receptors (D2/3R) in the striatum. Outside of the striatum the receptor density is up to two orders of magnitude lower. In contrast to striatal binding, the characteristics of extrastriatal [11C]raclopride binding quantification has not been thoroughly described. Still, binding data for e.g., neocortex is frequently reported in the scientific literature. Here we evaluate the validity and reliability of extrastriatal [11C]raclopride binding quantification. Two sets of healthy control subjects were examined with HRRT and [11C]raclopride: i) To assess the validity of extrastriatal [11C]raclopride binding estimates, eleven subjects were examined at baseline and after dosing with quetiapine, a D2/3R antagonist. ii) To assess test-retest repeatability, nine subjects were examined twice. Non displaceable binding potential (BPND) was quantified using the simplified reference tissue model. Quetiapine dosing was associated with decrease in [11C]raclopride BPND in temporal cortex (18{+/-}17% occupancy) and thalamus (20{+/-}17%), but not in frontal cortex. Extrastriatal occupancy was lower than in putamen (51{+/-}4%). The mean absolute variation was 4-7% in the striatal regions, 17% in thalamus, and 13-59% in cortical regions. Our data indicate that [11C]raclopride PET is not a suitable tool for D2/3R binding quantification in extrastriatal regions.

neuroscience↗

bioRxiv2019

Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre PBR28 HRRT PET study

PurposeTo investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [11C]PBR28. Methods[11C]PBR28 data from 140 healthy volunteers (72 males and 68 females; n=78 with HAB and n=62 MAB genotype; age range 19-80 years; BMI range 17.6 - 36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (n=53), Turku PET centre (n=62) and Yale University PET Center (n=25). The total volume of distribution (VT) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. ResultsThere were significant positive correlations between age and VT in the frontal and temporal cortex. BMI showed a significant negative correlation with VT in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher VT. A subgroup analysis revealed a positive correlation between VT and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. ConclusionThese findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.

immunology↗

bioRxiv2017

Is dopamine D1 receptor availability related to social behavior? A positron emission tomography replication study

BackgroundAssociations between dopamine receptor levels and pro- and antisocial behavior have previously been demonstrated in human subjects using positron emission tomography (PET) and self-rated measures of personality traits. So far, only one study has focused on the D1-dopamine receptor (D1-R), [fi]nding a positive correlation with the trait social desirability, which is characterized by low dominant and high af[fi]liative behavior, while physical aggression showed a negative correlation. The aim of the present study was to replicate these previous [fi]ndings using a new independent sample of subjects.\n\nMethodsTwenty-six healthy males were examined with the radioligand [11C]SCH-23390, and completed the Swedish universities Scales of Personality (SSP) which includes measures of social desirability and physical trait aggression. The simpli[fi]ed reference tissue model with cerebellum as reference region was used to calculate BPND values in the whole striatum and limbic striatum. The two regions were selected since they showed strong association between D1-R availability and personality scores in the previous study. Pearsons correlation coef[fi]cients and replication Bayes factors were then employed to assess the replicability and robustness of previous results.\n\nResultsThere were no signi[fi]cant correlations (all p values > 0.3) between regional BPND values and personality scale scores. Replication Bayes factors showed strong to moderate evidence in favor no relationship between D1-receptor availability and social desirability (striatum BF01 = 12.4; limbic striatum BF01 = 7.2) or physical aggression scale scores (limbic striatum BF01 = 3.3), compared to the original correlations.\n\nDiscussionWe could not replicate the previous [fi]ndings of associations between D1-R availability and either pro- or antisocial behavior as measured using the SSP. Rather, there was evidence in favor of failed replications of associations between BPND and scale scores. Potential reasons for these results are restrictive variance in both PET and personality outcomes due to high sample homogeneity, or that the previous [fi]ndings were false positives.

neuroscience↗