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INTRODUCTION: Tau and neurodegeneration strongly correlate with cognitive impairment, as compared to amyloid. However, their contribution in explaining cognition and predicting cognitive decline in memory clinics remains unclarified. METHODS: We included 94 participants with Mini‐Mental State Examination (MMSE), tau positron emission tomography (PET), amyloid PET, fluorodeoxyglucose (FDG) PET, and MRI scans from Geneva Memory Center. Linear regression and mediation analyses tested the independent and combined association between biomarkers, cognitive performance, and decline. Linear mixed‐effects and Cox proportional hazards models assessed biomarkers' prognostic values. RESULTS: Metabolism had the strongest association with cognition (r = 0.712; p < 0.001), followed by tau (r = ‐0.682; p < 0.001). Neocortical tau showed the strongest association with cognitive decline (r = ‐0.677; p < 0.001). Metabolism mediated the association between tau and cognition and marginally mediated the one with decline. Tau positivity represented the strongest risk factor for decline (hazard ratio = 32). DISCUSSION: Tau and neurodegeneration synergistically contribute to global cognitive impairment while tau drives decline. The tau PET superior prognostic value supports its implementation in memory clinics. Highlights: Hypometabolism has the strongest association with concurrent cognitive impairment.Neocortical tau pathology is the main determinant of cognitive decline over time.FDG‐PET has a superior value compared to MRI as a measure of neurodegeneration.The prognostic value of tau‐PET exceeded all other neuroimaging modalities. [ABSTRACT FROM AUTHOR]

N‐methyl‐D‐aspartate (NMDA) receptors play key roles in physiology by regulating the synaptic plasticity and the cellular mechanism involved in learning and memory. The GluN2A subunit is the most abundant expression of NMDA receptors in mature brain, and its dysfunction has been implicated in various neurological disorders. However, the function of GluN2A subunit in physiological and pathological conditions is not yet completely unveil due to the lack of subunit‐selective ligands, including specific positron emission tomography (PET)/single photon emission computed tomography (SPECT) imaging probes. In this review, recent progresses in understanding its pathophysiological role, the structure‐activity relationship, and the postulated mechanisms of novel GluN2A ligands as well as status of molecular imaging probes for PET are summarized. [ABSTRACT FROM AUTHOR]

The cannabinoid type 2 (CB2) receptor is an immunomodulatory receptor mainly expressed in peripheral cells and organs of the immune system. The expression level of CB2 in the central nervous system under physiological conditions is negligible, however under neuroinflammatory conditions an upregulation of CB2 protein or mRNA mainly colocalized with activated microglial cells has been reported. Consequently, CB2 agonists have been confirmed to play a role in neuroprotective and anti‐inflammatory processes. A suitable positron emission tomography radioligand for imaging CB2 would provide an invaluable research tool to explore the role of CB2 receptor expression in inflammatory disorders. In this review, we provide a summary of so far published CB2 radioligands as well as their in vitro and in vivo binding characteristics. [ABSTRACT FROM AUTHOR]

The cannabinoid receptor type 2 ( CB2) is part of the endocannabinoid system and has gained growing attention in recent years because of its important role in neuroinflammatory/neurodegenerative diseases. Recently, we reported on a carbon-11 labeled 4-oxo-quinoline derivative, designated RS-016, as a promising radiotracer for imaging CB2 using PET. In this study, three novel fluorinated analogs of RS-016 were designed, synthesized, and pharmacologically evaluated. The results of our efforts led to the identification of N-(1-adamantyl)-1-(2-(2-fluoroethoxy)ethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide ( RS-126) as the most potent candidate for evaluation as a CB2 PET ligand. [18F] RS-126 was obtained in ≥ 99% radiochemical purity with an average specific radioactivity of 98 GBq/μmol at the end of the radiosynthesis. [18F] RS-126 showed a logD7.4 value of 1.99 and is stable in vitro in rat and human plasma over 120 min, whereas 55% intact parent compound was found in vivo in rat blood plasma at 10 min post injection. In vitro autoradiographic studies with CB2-positive rat spleen tissue revealed high and blockable binding which was confirmed in in vivo displacement experiments with rats by dynamic PET imaging. Ex vivo biodistribution studies confirmed accumulation of [18F] RS-126 in rat spleen with a specificity of 79% under blocking conditions. The moderate elevated CB2 levels in LPS-treated mice brain did not permit the detection of CB2 by [18F] RS-126 using PET imaging. In summary, [18F] RS-126 demonstrated high specificity toward CB2 receptor in vitro and in vivo and is a promising radioligand for imaging CB2 receptor expression. [ABSTRACT FROM AUTHOR]

Imaging the density of metabotropic glutamate receptor 5 ( mGluR5) in brain by positron emission tomography ( PET) is of interest in relation to several brain disorders. We have recently introduced [18F] PSS232, an F-18-labeled analog of the mGluR5-targeting [11C] ABP688. Quantitative PET requires kinetic modeling with an input function ( IF) or an appropriate reference tissue model. We aimed at minimizing invasiveness of IF recording in rat and employing this protocol for mGluR5 quantitative PET with [18F] PSS232. We further aimed at defining models of low complexity for quantitative PET with [18F] PSS232. The IF was recorded in an arterio-venous shunt applied by minimally invasive cannulation. PET data were analyzed with a modified two-tissue compartment model including a single variable for radiometabolite correction in brain. We further evaluated a simple reference tissue model. Receptor-dependent accumulation was similar to [11C] ABP688 at lower unspecific accumulation of unchanged [18F] PSS232, in agreement with its higher plasma protein binding and lower lipophilicity. The minimally invasive protocol revealed similar results as the invasive shunt method and parameters calculated with the modified two-tissue compartment model were similar to those calculated with the standard model. The simple area under the curve ratios agreed with the Logan reference method. [18F] PSS232 is a promising radioligand for mGluR5 quantification. [ABSTRACT FROM AUTHOR]

The cannabinoid type 2 (CB2) receptor plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease and is therefore a very promising target for therapeutic approaches as well as for imaging. Based on the literature, we identified one 4-oxoquinoline derivative (designated KD2) as the lead structure. It was synthesized, radiolabeled and evaluated as a potential imaging tracer for CB2. [11C] KD2 was obtained in 99% radiochemical purity. Moderate blood-brain barrier ( BBB) passage was predicted for KD2 from an in vitro transport assay with P-glycoprotein-transfected Madin Darby canine kidney cells. No efflux of KD2 by P-glycoprotein was detected. In vitro autoradiography of rat and mouse spleen slices demonstrated that [11C] KD2 exhibits high specific binding towards CB2. High spleen uptake of [11C] KD2 was observed in dynamic positron emission tomography (PET) studies with Wistar rats and its specificity was confirmed by displacement study with a selective CB2 agonist, GW405833. A pilot autoradiography study with post-mortem spinal cord slices from amyotrophic lateral sclerosis ( ALS) patients with [11C] KD2 suggested the presence of CB2 receptors under disease conditions. Specificity of [11C] KD2 binding could also be demonstrated on these human tissues. In conclusion, [11C] KD2 shows good in vitro and in vivo properties as a potential PET tracer for CB2. [ABSTRACT FROM AUTHOR]

Background: The abnormal deposition of fibrillar beta‐amyloid deposits in the brain is one of the major histopathological hallmarks of Alzheimer's disease. Currently 3D imaging using positron emission tomography for plaque visualization is of a limited resolution (1 mm) in relation to the size of mouse brain in widely used AD models. Method: We developed a novel high‐resolution non‐invasive volumetric multi‐spectral optoacoustic tomography (vMSOT) of 100 mm resolution using amyloid probe AOI987 to visualize amyloid‐beta distribution in arcAβ and APP/PS1 transgenic mouse models of cerebral amyloidosis. Immunohistochemical staining was performed with AOI987, anti‐Aβ antibody 6E10 and fibrillar amyloid conformation antibody OC on mouse brain sections. Result: In vivo vMSOT detects higher Aβ load in the cortex, hippocampus and thalamus of arcAβ mice, and in the cortex of APP/PS1 mice compared to non‐transgenic littermates, corresponding with immunohistochemical staining results in mouse brain sections. Confocal microscopy showed co‐localization of AOI987, 6E10 and OC to parenchymal and cerebral amyloid angiopathy in brain tissue sections from arcAb and APP/PS1 mice, thus verifying the specificity of the vMSOT amyloid imaging approach. Conclusion: We demonstrate a new high‐resolution in vivo 3D amyloid imaging platform across the murine brain in animal models of AD pathology, which facilitates mechanistic studies and the monitoring of putative treatments targeting Aβ. [ABSTRACT FROM AUTHOR]

Background: Abnormal tauopathy accumulation play an important role in tauopathy diseases including Alzheimer’s disease and Frontotemporal dementia. There is a gap in high‐resolution non‐invasive imaging tool for detecting tauopathy deposits in animal models. Method: The binding properties of a panel of imaging probes to 4‐repeat K18 tau fibril was assessed by using Thoflavin T assay and surface plasmon resonance assay. Next we established optimal dosage for tau probes in in vivo optoacoustic imaging, and developed transcranial whole brain imaging (130 micron spatial resolution) of tauopathy in P301L model of 4‐repeat tauopathy. T2 magnetic resonance imaging at 9.4T was performed for structural information and for volume‐of‐interest analysis of optoacoustic imaging data after co‐registration. Result: In vitro assay showed binding to recombinant K18 tau fibril using PBB5, THK5351, but not T‐807 or MK‐6240. i.v. administration of PBB5 in P301L mice led to a retention of PBB5 in tau ladened cortex and hippocampus by registering with structural magnetic resonance imaging data. The specificity of PBB5 was validated by immunohistochemistry with anti‐phosphorylated tau antibody AT‐100. Conclusion: Optoacoustic imaging with PBB5 facilitates preclinical high‐resolution whole brain imaging of tauopathy, for studying the spreading and accumulation of tauopathy, and for monitoring putative treatments targeting tau. [ABSTRACT FROM AUTHOR]