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 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.

Development of caspase-3-selective activity-based probes for PET imaging of apoptosis.

Background: The cysteine-aspartic acid protease caspase-3 is recognized as the main executioner of apoptosis in cells responding to specific extrinsic and intrinsic stimuli. Caspase-3 represents an interesting biomarker to evaluate treatment response, as many cancer therapies exert their effect by inducing tumour cell death. Previously developed caspase-3 PET tracers were unable to reach routine clinical use due to low tumour uptake or lack of target selectivity, which are two important requirements for effective treatment response evaluation in cancer patients.

Dynamic neuroreceptor positron emission tomography in non-anesthetized rats using point source based motion correction: A feasibility study with [C]ABP688.

To prevent motion artifacts in small animal positron emission tomography (PET), animals are routinely scanned under anesthesia or physical restraint. Both may potentially alter metabolism and neurochemistry. This study investigates the feasibility of fully awake acquisition and subsequent absolute quantification of dynamic brain PET data via pharmacokinetic modelling in moving rats using the glutamate 5 receptor radioligand [C]ABP688 and point source based motion correction.

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.

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.

Site-specific Ga-labeled nanobody for PET imaging of CD70 expression in preclinical tumor models.

Background: CD70-CD27 is a costimulatory ligand-receptor pair in the tumor necrosis factor receptor family. With only limited expression in normal tissues, CD70 is constitutively expressed in a variety of solid tumors and hematologic malignancies, facilitating immunosuppression through CD27 signaling in the tumor microenvironment by enhanced survival of regulatory T cells, induction of T cell apoptosis, and T cell exhaustion. Consequently, CD70 is an increasingly recognized target for developing antibody-based therapies, but its expression patterns vary among different tumor types in spatial distribution, magnitude of expression and percentage of positive cells.

Identification of pre-synaptic density networks using [C]UCB-J PET imaging and ICA in mice.

Background: Synaptic vesicle glycoprotein 2A (SV2A) is a vesicle glycoprotein involved in neurotransmitter release. SV2A is located on the pre-synaptic terminals of neurons and visualized using the radioligand [C]UCB-J and positron emission tomography (PET) imaging. Thus, SV2A PET imaging can provide a proxy for pre-synaptic density in health and disease.

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.

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).

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.

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.

Progression of obsessive compulsive disorder-like grooming in Sapap3 knockout mice: A longitudinal [C]ABP688 PET study.

Unlabelled: We aimed to evaluate [3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-0-C-methyloxime] ([C]ABP688) small animal positron emission tomography (μPET) as a biomarker to visualize possible longitudinal changes in metabotropic glutamate receptor 5 (mGluR5) availability in the brain of SAP90/PSD-95 associated protein 3 (Sapap3) knockout (ko) mice, showing obsessive compulsive disorder (OCD)-like behavior.

Methods: Alongside the assessment of grooming, we performed [C]ABP688 μPET/CT imaging in wildtype (wt; n=10) and ko (n=11) mice both at 3 and 9 months. Using the simplified reference tissue method (SRTM), the nondisplaceable binding potential (BP) was calculated representing the in vivo availability of the metabotropic glutamate receptor 5 (mGluR5) in the brain with the cerebellum as a reference region.

Motion Dependent and Spatially Variant Resolution Modeling for PET Rigid Motion Correction.

Recent advances in positron emission tomography (PET) have allowed to perform brain scans of freely moving animals by using rigid motion correction. One of the current challenges in these scans is that, due to the PET scanner spatially variant point spread function (SVPSF), motion corrected images have a motion dependent blurring since animals can move throughout the entire field of view (FOV). We developed a method to calculate the image-based resolution kernels of the motion dependent and spatially variant PSF (MD-SVPSF) to correct the loss of spatial resolution in motion corrected reconstructions.

Elevated Type 1 Metabotropic Glutamate Receptor Availability in a Mouse Model of Huntington's Disease: a Longitudinal PET Study.

Impairment of group I metabotropic glutamate receptors (mGluRs) results in altered glutamate signalling, which is associated with several neurological disorders including Huntington's Disease (HD), an autosomal neurodegenerative disease. In this study, we assessed in vivo pathological changes in mGluR1 availability in the Q175DN mouse model of HD using longitudinal positron emission tomography (PET) imaging with the radioligand [C]ITDM. Ninety-minute dynamic PET imaging scans were performed in 22 heterozygous (HET) Q175DN mice and 22 wild-type (WT) littermates longitudinally at 6, 12, and 16 months of age.

In vitro and In vivo Assessment of Suitable Reference Region and Kinetic Modelling for the mGluR1 Radioligand [C]ITDM in Mice.

Purpose: This study aimed at investigating binding specificity, suitability of reference region-based kinetic modelling, and pharmacokinetics of the metabotropic glutamate receptor 1 (mGluR1) radioligand [C]ITDM in mice.

Procedures: We performed in vivo blocking as well as displacement of [C]ITDM during positron emission tomography (PET) imaging using the specific mGluR1 antagonist YM-202074. Additionally, we assessed in vitro blocking of [H]ITDM at two different doses of YM-202074.