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.

Accurate image derived input function in [F]SynVesT-1 mouse studies using isoflurane and ketamine/xylazine anesthesia.

Background: Kinetic modeling in positron emission tomography (PET) requires measurement of the tracer plasma activity in the absence of a suitable reference region. To avoid invasive blood sampling, the use of an image derived input function has been proposed. However, an accurate delineation of the blood pool region in the PET image is necessary to obtain unbiased blood activity.

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.

Correction of motion tracking errors for PET head rigid motion correction.

. In positron emission tomography (PET) rigid motion correction, erroneous tracking information translates into reduced quality in motion corrected reconstructions. We aim to improve the accuracy of the motion tracking data, to improve the quality of motion corrected reconstructions.

Isoflurane and ketamine-xylazine modify pharmacokinetics of [F]SynVesT-1 in the mouse brain.

We investigated the effect of isoflurane and ketamine-xylazine anesthesia on the positron emission tomography (PET) tracer [F]SynVesT-1 in the mouse brain. [F]SynVesT-1 PET scans were performed in C57BL/6J mice in five conditions: isoflurane anesthesia (ANISO), ketamine-xylazine (ANKX), awake freely moving (AW), awake followed by isoflurane administration (AW/ANISO) or followed by ketamine-xylazine (AW/ANKX) 20 min post tracer injection. ANISO, ANKX and AW scans were also performed in mice administered with levetiracetam (LEV, 200 mg/kg) to assess non-displaceable binding.

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.

F-FDG and F-FLT Uptake Profiles for Breast Cancer Cell Lines Treated with Targeted PI3K/Akt/mTOR Therapies.

To evaluate F-fluoro-2-deoxy-glucose (F-FDG) and F-fluorothymidine (F-FLT) as early-response biomarkers for phosphoinositide-3-kinase/Akt/mammalian-target-of-rapamycin (PI3K/Akt/mTOR) inhibition in breast cancer (BC) models. Two human epidermal growth factor receptor 2 (HER2)-positive (trastuzumab-sensitive SKBR3; trastuzumab-resistant JIMT1) and one triple-negative BC cell line (MDA-MB-231, trastuzumab, and everolimus resistant) were treated with trastuzumab (HER2 antagonist), PIK90 (PI3K inhibitor), or everolimus (mTOR inhibitor). Radiotracer uptake was measured before, 24, and 72 h after drug exposure and correlated with changes in cell number, glucose transporter 1 (GLUT1), cell cycle phase, and downstream signaling activation.

Spatiotemporal Kernel Reconstruction for Linear Parametric Neurotransmitter PET Kinetic Modeling in Motion Correction Brain PET of Awake Rats.

The linear parametric neurotransmitter positron emission tomography (lp-ntPET) kinetic model can be used to detect transient changes (activation) in endogenous neurotransmitter levels. Preclinical PET scans in awake animals can be performed to investigate neurotransmitter transient changes. Here we use the spatiotemporal kernel reconstruction (Kernel) for noise reduction in dynamic PET, and lp-ntPET kinetic modeling.

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.

SV2A PET Imaging Is a Noninvasive Marker for the Detection of Spinal Damage in Experimental Models of Spinal Cord Injury.

Traumatic spinal cord injury (SCI) is a neurologic condition characterized by long-term motor and sensory neurologic deficits as a consequence of an external physical impact damaging the spinal cord. Anatomic MRI is considered the gold-standard diagnostic tool to obtain structural information for the prognosis of acute SCI; however, it lacks functional objective information to assess SCI progression and recovery. In this study, we explored the use of synaptic vesicle glycoprotein 2A (SV2A) PET imaging to detect spinal cord lesions noninvasively after SCI.

Quantification of Metabotropic Glutamate Receptor 5 Availability With Both [C]ABP688 and [F]FPEB Positron Emission Tomography in the Sapap3 Knockout Mouse Model for Obsessive-Compulsive-like Behavior.

Background: This study provides a first direct comparison between positron emission tomography radioligands targeting the allosteric site of the metabotropic glutamate receptor 5 (mGluR5): [C]ABP688 and [F]FPEB. A blocking paradigm was set up to substantiate the common binding site of both radioligands. Second, both radioligands were applied in Sapap3 knockout (KO) mice showing compulsive-like behavior characterized by a lower in vivo mGluR5 availability.

Translation of Preclinical PET Imaging Findings: Challenges and Motion Correction to Overcome the Confounding Effect of Anesthetics.

Preclinical brain positron emission tomography (PET) in animals is performed using anesthesia to avoid movement during the PET scan. In contrast, brain PET scans in humans are typically performed in the awake subject. Anesthesia is therefore one of the principal limitations in the translation of preclinical brain PET to the clinic.

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).

Early Changes in [F]FDG Uptake as a Readout for PI3K/Akt/mTOR Targeted Drugs in HER-2-Positive Cancer Xenografts.

We investigated the potential use of [F]FDG PET as a response biomarker for PI3K pathway targeting therapies in two HER-2-overexpressing cancer models. . CD-1 nude mice were inoculated with HER-2-overexpressing JIMT1 (trastuzumab-resistant) or SKOV3 (trastuzumab-sensitive) human cancer cells.

TSPO PET upregulation predicts epileptic phenotype at disease onset independently from chronic TSPO expression in a rat model of temporal lobe epilepsy.

Neuroinflammation is a key component of epileptogenesis, the process leading to acquired epilepsy. In recent years, with the development of non-invasive in vivo positron emission tomography (PET) imaging of translocator protein 18 kDa (TSPO), a marker of neuroinflammation, it has become possible to perform longitudinal studies to characterize neuroinflammation at different disease stages in animal models of epileptogenesis. This study aimed to utilize the prognostic capability of TSPO PET imaging at disease onset (2 weeks post-SE) to categorize epileptic rats with distinct seizure burden based on TSPO levels at disease onset and investigate their association to TSPO expression at the chronic epilepsy stage.

Low activity [C]raclopride kinetic modeling in the mouse brain using the spatiotemporal kernel method.

Depending on the molar activity of the tracer, the maximal allowable injected activity in mouse brain PET studies can be extremely low in order to avoid receptor saturation. Therefore, a high level of noise can be present in the image. We investigate several dynamic PET reconstruction methods in reduced counts, or equivalently in reduced injected activity, data exemplified in [C]racloprideandR1quantification using the simplified reference tissue model (SRTM).

Estimation of the net influx rate K and the cerebral metabolic rate of glucose MR using a single static [F]FDG PET scan in rats.

Since accurate quantification of 2-deoxy-2-F-fluoro-D-glucose ([F]FDG) positron emission tomography (PET) requires dynamic acquisition with arterial input function, more practical semi-quantitative (static) approaches are often preferred. However, static standardized uptake values (SUV) are typically biased due to large variations in body weight (BW) occurring over time in animal studies. This study aims to improve static [F]FDG PET SUV quantification by better accounting for BW variations in rats.

Validation of a spatially variant resolution model for small animal brain PET studies.

In small animal positron emission tomography (PET) studies, given the spatial resolution of preclinical PET scanners, quantification in small regions can be challenging. Moreover, in scans where animals are placed away from the center of the field of view (CFOV), e.g.

Sapap3 deletion causes dynamic synaptic density abnormalities: a longitudinal [C]UCB-J PET study in a model of obsessive-compulsive disorder-like behaviour.

Background: Currently, the evidence on synaptic abnormalities in neuropsychiatric disorders-including obsessive-compulsive disorder (OCD)-is emerging. The newly established positron emission tomography (PET) ligand ((R)-1-((3-((11)C-methyl-(11)C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) ([C]UCB-J) provides the opportunity to visualize synaptic density changes in vivo, by targeting the synaptic vesicle protein 2A (SV2A). Here, we aim to evaluate such alterations in the brain of the SAP90/PSD-95-associated protein 3 (Sapap3) knockout (ko) mouse model, showing an abnormal corticostriatal neurotransmission resulting in OCD-like behaviour.