The
P2X7 receptor (P2X7R) is a key neuroinflammation target in
a variety of neurodegenerative diseases. Improved radiosynthesis was
developed according to the previously reported P2X7R antagonist GSK1482160.
Biodistribution, radiometabolite, and dynamic positron emission tomography/computed
tomography-magnetic resonance imaging (PET/CT-MRI) of the lipopolysaccharide
(LPS) rat model and the transgenic mouse model of Alzheimer’s
disease (AD) revealed a stable, low uptake of [
18
F]4A in the brain of healthy rats but
a higher standardized uptake value ratio (SUVR) in LPS-treated rats
(1.316 ± 0.062, n = 3) than in sham (1.093 ±
0.029, n = 3). There were higher area under curves
(AUCs) in the neocortex (25.12 ± 1.11 vs 18.94 ± 1.47),
hippocampus (22.50 ± 3.41 vs 15.90 ± 1.59), and basal ganglia
(22.26 ± 0.81 vs 15.32 ± 1.76) of AD mice (n = 3) than the controls (n = 3) (p < 0.05). Furthermore, 50 min dynamic PET in healthy nonhuman
primates (NHPs) indicated [
18
F]4A could penetrate the blood–brain barrier
(BBB). In conclusion, [
18
F]4A from this study is a potent P2X7R PET tracer that warrants
further neuroinflammation quantification in human studies.
Monoacylglycerol
lipase (MAGL) is a 33 kDa serine protease primarily
responsible for hydrolyzing 2-arachidonoylglycerol into the proinflammatory
eicosanoid precursor arachidonic acid in the central nervous system.
Inhibition of MAGL constitutes an attractive therapeutic concept for
treating psychiatric disorders and neurodegenerative diseases. Herein,
we present the design and synthesis of multiple reversible MAGL inhibitor
candidates based on a piperazinyl azetidine scaffold. Compounds 10 and 15 were identified as the best-performing
reversible MAGL inhibitors by pharmacological evaluations, thus channeling
their radiolabeling with fluorine-18 in high radiochemical yields
and favorable molar activity. Furthermore, evaluation of [18F]10 and [18F]15 ([18F]MAGL-2102) by autoradiography and positron emission tomography
(PET) imaging in rodents and nonhuman primates demonstrated favorable
brain uptakes, heterogeneous radioactivity distribution, good specific
binding, and adequate brain kinetics, and [18F]15 demonstrated a better performance. In conclusion, [18F]15 was found to be a suitable PET radioligand for
the visualization of MAGL, harboring potential for the successful
translation into humans.
Alterations in brain cholesterol homeostasis have been broadly implicated in neurological disorders. Notwithstanding the complexity by which cholesterol biology is governed in the mammalian brain, excess neuronal cholesterol is primarily eliminated by metabolic clearance via cytochrome P450 46A1 (CYP46A1). No methods are currently available for visualizing cholesterol metabolism in the living human brain; therefore, a noninvasive technology that quantitatively measures the extent of brain cholesterol metabolism via CYP46A1 could broadly affect disease diagnosis and treatment options using targeted therapies. Here, we describe the development and testing of a CYP46A1-targeted positron emission tomography (PET) tracer,
18
F-CHL-2205 (
18
F-Cholestify). Our data show that PET imaging readouts correlate with CYP46A1 protein expression and with the extent to which cholesterol is metabolized in the brain, as assessed by cross-species postmortem analyses of specimens from rodents, nonhuman primates, and humans. Proof of concept of in vivo efficacy is provided in the well-established 3xTg-AD murine model of Alzheimer’s disease (AD), where we show that the probe is sensitive to differences in brain cholesterol metabolism between 3xTg-AD mice and control animals. Furthermore, our clinical observations point toward a considerably higher baseline brain cholesterol clearance via CYP46A1 in women, as compared to age-matched men. These findings illustrate the vast potential of assessing brain cholesterol metabolism using PET and establish PET as a sensitive tool for noninvasive assessment of brain cholesterol homeostasis in the clinic.
Autism spectrum disorder (ASD) is a basket term for neurodevelopmental disorders characterized by marked impairments in social interactions, repetitive and stereotypical behaviors, and restricted interests and activities. Subtypes include (A) disorders with known genetic abnormalities including fragile X syndrome, Rett syndrome, and tuberous sclerosis and (B) idiopathic ASD, conditions with unknown etiologies. Positron emission tomography (PET) is a molecular imaging technology that can be utilized in vivo for dynamic and quantitative research, and is a valuable tool for exploring pathophysiological mechanisms, evaluating therapeutic efficacy, and accelerating drug development in ASD. Recently, several imaging studies on ASD have been published and physiological changes during ASD progression was disclosed by PET. This paper reviews the specific radioligands for PET imaging of critical biomarkers in ASD, and summarizes and discusses the similar and different discoveries in outcomes of previous studies. It is of great importance to identify general physiological changes in cerebral glucose metabolism, cerebral blood flow perfusion, abnormalities in neurotransmitter systems, and inflammation in the central nervous system in ASD, which may provide excellent points for further ASD research.
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