Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase that cleaves monoacylglycerols into fatty acids and is a potential target for the novel treatment of CNS disorders related to the ...endocannabinoid system and neuroinflammation. We have developed 18FT-401 as a selective Positron emission tomography (PET) imaging agent for MAGL. In this study, we determined an analytical method to quantify MAGL availability and its occupancy by an exogenous inhibitor in rhesus monkey brains using 18FT-401-PET. In rhesus monkeys, regional time-activity curves were described well when using an extended 2-tissue compartment model that accommodated the formation of a radiometabolite in the brain. This model yielded reliable estimates of the total distribution volume (VT), and the rank order of VT was consistent with known regional activity of MAGL enzyme in primates. The pretreatment of monkeys with JW642 resulted in a dose-dependent reduction of 18FT-401 retentions in the brain, and VT. Lassen's graphical analysis indicated a VND of 0.69 mL/cm3 and a plasma JW642 concentration of 126 ng/mL for inhibiting the specific binding by 50%. 18FT-401 and the method established can be used for quantification of MAGL in healthy brain and in disease conditions, and is suitable for evaluations of target engagement at cerebral MAGL.
PET reporter systems for the brain Nerella, Sridhar Goud; Michaelides, Michael; Minamimoto, Takafumi ...
Trends in neurosciences (Regular ed.),
November 2023, 2023-11-00, 20231101, Volume:
46, Issue:
11
Journal Article
Peer reviewed
Positron emission tomography (PET) is a noninvasive modality for in vivo assessment of pathophysiological processes in living subjects.PET imaging detects γ-rays produced by the decay of a ...radioactive compound (radiotracer) to infer the location of the binding of that compound within the brain, thus revealing the location of the receptor to which it bound.PET reporter systems are used to monitor the progression of disease and the expression of therapeutic transgenes, for instance in the context of stem cell and molecular genetic therapies.Successful PET reporter systems for the brain are improving the treatment of neurological diseases, and hold promise for the advancement of novel treatments for neuropsychiatric disorders.
Positron emission tomography (PET) can be used as a noninvasive method to longitudinally monitor and quantify the expression of proteins in the brain in vivo. It can be used to monitor changes in biomarkers of mental health disorders, and to assess therapeutic interventions such as stem cell and molecular genetic therapies. The utility of PET monitoring depends on the availability of a radiotracer with good central nervous system (CNS) penetration and high selectivity for the target protein. This review evaluates existing methods for the visualization of reporter proteins and/or protein function using PET imaging, focusing on engineered systems, and discusses possible approaches for future success in the development of high-sensitivity and high-specificity PET reporter systems for the brain.
Positron emission tomography (PET) can be used as a noninvasive method to longitudinally monitor and quantify the expression of proteins in the brain in vivo. It can be used to monitor changes in biomarkers of mental health disorders, and to assess therapeutic interventions such as stem cell and molecular genetic therapies. The utility of PET monitoring depends on the availability of a radiotracer with good central nervous system (CNS) penetration and high selectivity for the target protein. This review evaluates existing methods for the visualization of reporter proteins and/or protein function using PET imaging, focusing on engineered systems, and discusses possible approaches for future success in the development of high-sensitivity and high-specificity PET reporter systems for the brain.
Chemogenetic tools provide an opportunity to manipulate neuronal activity and behavior selectively and repeatedly in nonhuman primates (NHPs) with minimal invasiveness. Designer Receptors Exclusively ...Activated by Designer Drugs (DREADDs) are one example that is based on mutated muscarinic acetylcholine receptors. Another channel-based chemogenetic system available for neuronal modulation in NHPs uses pharmacologically selective actuator modules (PSAMs), which are selectively activated by pharmacologically selective effector molecules (PSEMs). To facilitate the use of the PSAM/PSEM system, the selection and dosage of PSEMs should be validated and optimized for NHPs. To this end, we used a multimodal imaging approach. We virally expressed excitatory PSAM (PSAM4-5HT3) in the striatum and the primary motor cortex (M1) of two male macaque monkeys, and visualized its location through positron emission tomography (PET) with the reporter ligand
18
FASEM. Chemogenetic excitability of neurons triggered by two PSEMs (uPSEM817 and uPSEM792) was evaluated using
18
Ffluorodeoxyglucose-PET imaging, with uPSEM817 being more efficient than uPSEM792. Pharmacological magnetic resonance imaging (phMRI) showed that increased brain activity in the PSAM4-expressing region began ∼13 min after uPSEM817 administration and continued for at least 60 min. Our multimodal imaging data provide valuable information regarding the manipulation of neuronal activity using the PSAM/PSEM system in NHPs, facilitating future applications.
SIGNIFICANCE STATEMENT
Like other chemogenetic tools, the ion channel-based system called pharmacologically selective actuator module/pharmacologically selective effector molecule (PSAM/PSEM) allows remote manipulation of neuronal activity and behavior in living animals. Nevertheless, its application in nonhuman primates (NHPs) is still limited. Here, we used multitracer positron emission tomography (PET) imaging and pharmacological magnetic resonance imaging (phMRI) to visualize an excitatory chemogenetic ion channel (PSAM4-5HT3) and validate its chemometric function in macaque monkeys. Our results provide the optimal agonist, dose, and timing for chemogenetic neuronal manipulation, facilitating the use of the PSAM/PSEM system and expanding the flexibility and reliability of circuit manipulation in NHPs in a variety of situations.
In autism spectrum disorder (ASD), disrupted functional and structural connectivity in the social brain has been suggested as the core biological mechanism underlying the social recognition deficits ...of this neurodevelopmental disorder. In this study, we aimed to identify genetic and neurostructural abnormalities at birth in a non-human primate model of ASD, the common marmoset with maternal exposure to valproic acid (VPA), which has been reported to display social recognition deficit in adulthood. Using a comprehensive gene expression analysis, we found that 20 genes were significantly downregulated in VPA-exposed neonates. Of these, Frizzled3 (FZD3) and PIK3CA were identified in an axon guidance signaling pathway. FZD3 is essential for the normal development of the anterior commissure (AC) and corpus callosum (CC); hence, we performed diffusion tensor magnetic resonance imaging with a 7-Tesla scanner to measure the midsagittal sizes of these structures. We found that the AC size in VPA-exposed neonates was significantly smaller than that in age-matched controls, while the CC size did not differ. These results suggest that downregulation of the genes related to axon guidance and decreased AC size in neonatal primates may be linked to social brain dysfunctions that can happen later in life.
•Common marmosets were exposed to VPA in utero as a model of ASD.•FZD3 and PIK3CA were downregulated in the social brain cortex of VPA-exposed neonates.•Midsagittal AC size in VPA-exposed neonates was smaller than that in controls.•Our findings may provide novel genetic and neurostructural signatures at birth and potential targets for early intervention.
Colony-stimulating factor 1 receptor (CSF1R) is a specific biomarker for microglia. In this study, we developed a novel PET radioligand for CSF1R,
C-GW2580, and compared it to a reported CSF1R ...tracer,
C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey. Dynamic
C-GW2580- and
C-CPPC-PET images were quantified by reference tissue-based models and standardized uptake value ratio. Both tracers exhibited increased uptake in the lesioned striata of lipopolysaccharide-injected mice and in the forebrains of
-knock-in mice, spatially in agreement with an increased 18-kDa translocator protein radioligand retention. Moreover,
C-GW2580 captured changes in CSF1R availability more sensitively than
C-CPPC, with a larger dynamic range and a smaller inter-individual variability, in these model animals. PET imaging of CSF1R in a rhesus monkey displayed moderate-to-high tracer retention in the brain at baseline. Homologous blocker (i. e. unlabeled tracer) treatment reduced the uptake of
C-GW2580 by ∼30% in all examined brain regions except for centrum semi-ovale white matter, but did not affect the retention of
C-CPPC. In summary, our results demonstrated that
C-GW2580-PET captured inflammatory microgliosis in the mouse brain with higher sensitivity than a reported radioligand, and displayed saturable binding in the monkey brain, potentially providing an imaging-based quantitative biomarker for reactive microgliosis.
To study roles of cortico-basal ganglia loops in action planning, we examined interactions between the activities of simultaneously recorded neurons in the striatum of monkeys performing sequence ...motor tasks by cross-correlation analysis. Serial activation occurred between projection neurons in a motor sequence-dependent manner, and was in the direction of a neuron encoding an early event in the sequence to a neuron encoding the same event or later, but closer event to the reward. Synchronous activation occurred between pairs of interneurons. The serial activation seems to originate through the cortico-basal ganglia loops, because projection neurons are inhibitory. We propose that the task-dependent serial and synchronous activation of striate neurons may be a neural substrate for goal-directed planning through the basal ganglia.
Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in these illnesses has been ...challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing α-synuclein deposits in the brains of living subjects. In vivo optical and positron emission tomography (PET) imaging of mouse and marmoset models demonstrated that C05-05 captured a dynamic propagation of fibrillogenesis along neural pathways, followed by disruptions of these structures. High-affinity binding of 18F-C05-05 to α-synuclein aggregates in human brain tissues was also proven by in vitro assays. Notably, PET-detectable 18F-C05-05 signals were intensified in the midbrains of PD and DLB patients as compared with healthy controls, providing the first demonstration of visualizing α-synuclein pathologies in these illnesses. Collectively, we propose a new imaging technology offering neuropathology-based translational assessments of PD and allied disorders toward diagnostic and therapeutic research and development.
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