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We recently developed a positron emission tomography (PET) probe, [sup18/supF]PM-PBB3, to detect tau lesions in diverse tauopathies, including mixed three-repeat and four-repeat (3R + 4R) tau fibrils in Alzheimer's disease (AD) and 4R tau aggregates in progressive supranuclear palsy (PSP). For wider availability of this technology for clinical settings, bias-free quantitative evaluation of tau images without a priori disease information is needed.We aimed to establish tau PET pathology indices to characterize PSP and AD using a machine learning approach and test their validity and tracer capabilities.Data were obtained from 50 healthy control subjects, 46 patients with PSP Richardson syndrome, and 37 patients on the AD continuum. Tau PET data from 114 regions of interest were subjected to Elastic Net cross-validation linear classification analysis with a one-versus-the-rest multiclass strategy to obtain a linear function that discriminates diseases by maximizing the area under the receiver operating characteristic curve. We defined PSP- and AD-tau scores for each participant as values of the functions optimized for differentiating PSP (4R) and AD (3R + 4R), respectively, from others.The discriminatory ability of PSP- and AD-tau scores assessed as the area under the receiver operating characteristic curve was 0.98 and 1.00, respectively. PSP-tau scores correlated with the PSP rating scale in patients with PSP, and AD-tau scores correlated with Mini-Mental State Examination scores in healthy control-AD continuum patients. The globus pallidus and amygdala were highlighted as regions with high weight coefficients for determining PSP- and AD-tau scores, respectively.These findings highlight our technology's unbiased capability to identify topologies of 3R + 4R versus 4R tau deposits. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Positron emission tomography (PET) with

The tendency to avoid punishment, called behavioral inhibition system, is an essential aspect of motivational behavior. Behavioral inhibition system is related to negative affect, such as anxiety, depression and pain, but its neural basis has not yet been clarified. To clarify the association between individual variations in behavioral inhibition system and brain 5-HT

Unlike an electrical circuit, the hardware of the brain is susceptible to change. Repeated electrical brain stimulation mimics epileptogenesis. After such “kindling” process, a moderate stimulus would become sufficient in triggering a severe seizure. Here, we report that optogenetic neuronal stimulation can also convert the rat brain to a hyperexcitable state. However, continued stimulation once again converted the brain to a state that was strongly resistant to seizure induction. Histochemical examinations showed that moderate astrocyte activation was coincident with resilience acquisition. Administration of an adenosine A1 receptor antagonist instantly reverted the brain back to a hyperexcitable state, suggesting that hyperexcitability was suppressed by adenosine. Furthermore, an increase in basal adenosine was confirmed using in vivo microdialysis. Daily neuron-to-astrocyte signaling likely prompted a homeostatic increase in the endogenous actions of adenosine. Our data suggest that a certain stimulation paradigm could convert the brain circuit resilient to epilepsy without exogenous drug administration.

Histamine HTo measure the histamine HAdministration of enerisant hydrochloride decreased the radioligand binding in a dose-dependent manner. The estimated receptor occupancy values at 2 h varied as a function of its dose or plasma concentration. The time course of the occupancy showed persistently high levels ( 85%) in the two subjects with higher doses (25 and 12.5 mg). The occupancy was also initially high at 2 h and 6 h with the lower dose of 5 mg, but it decreased to 69.7% at 26 h.The target engagement of enerisant was demonstrated in the brains of living human subjects. The occupancy of histamine HThis study was retrospectively registered with ClinicalTrials.gov (NCT04631276) on November 17, 2020.

Positron emission tomography (PET) has been used to investigate changes in the concentration of endogenous neurotransmitters. Recently, this technique has been applied to the imaging of serotoninFirst, in the simulations, the time-activity curves at baseline and the stimulated states were generated using an extended compartment model including the competition for the receptors between the administered [In the simulations, the BP estimate of the stimulated state was smaller than that of the baseline state, and their reduction was related to the amount of change in the serotonin concentration. BP reduction was also affected by the onset of serotonin elevation. In the mouse studies, the BP of the cerebral cortex decreased in the scans with SSRI treatment.The reduction in BP estimated using the SRTM from [

Objectives In PET studies for neuroreceptors, tracer kinetics are described by the two-tissue compartment model (2-TCM), and binding parameters, including the total distribution volume (V T), non-displaceable distribution volume (V ND), and binding potential (BPND), can be determined from model parameters estimated by kinetic analysis. The stability of binding parameter estimates depends on the kinetic characteristics of radioligands. To describe these kinetic characteristics, we previously developed a two-phase graphic plot analysis in which V ND and V T can be estimated from the x-intercept of regression lines for early and delayed phases, respectively. In this study, we applied this graphic plot analysis to visual evaluation of the kinetic characteristics of radioligands for neuroreceptors, and investigated a relationship between the shape of these graphic plots and the stability of binding parameters estimated by the kinetic analysis with 2-TCM in simulated brain tissue time-activity curves (TACs) with various binding parameters. Methods 90-min TACs were generated with the arterial input function and assumed kinetic parameters according to 2-TCM. Graphic plot analysis was applied to these simulated TACs, and the curvature of the plot for each TAC was evaluated visually. TACs with several noise levels were also generated with various kinetic parameters, and the bias and variation of binding parameters estimated by kinetic analysis were calculated in each TAC. These bias and variation were compared with the shape of graphic plots. Results The graphic plots showed larger curvature for TACs with higher specific binding and slower dissociation of specific binding. The quartile deviations of V ND and BPND determined by kinetic analysis were smaller for radioligands with slow dissociation. Conclusions The larger curvature of graphic plots for radioligands with slow dissociation might indicate a stable determination of V ND and BPND by kinetic analysis. For investigation of the kinetics of radioligands, such kinetic characteristics should be considered.

The beneficial effects of psychostimulant drugs in the treatment of psychiatric disorders occur because they increase the extracellular dopamine concentration by inhibiting re-uptake of extracellular dopamine at dopamine transporters. However, the psychological effects at low dopamine transporter occupancy have not been well demonstrated. The purpose of the study was to evaluate the psychological effects, dopamine transporter occupancy, and dopamine release induced by a single oral administration of a clinical dose of mazindol. Ten healthy male volunteers were orally administered a placebo and a clinical dose of mazindol (1.5 mg) on separate days. The psychological effects of mazindol were assessed using a visual analogue scale to detect alterations in the state of consciousness. The amount of blockade of dopamine transporters was assessed using positron emission tomography with [18F]FE-PE2I and extracellular dopamine release was measured as the amount of change in [11C]raclopride binding. Following administration of a clinical dose of mazindol, the dopamine transporters were blocked by 24–25 %, and the binding potential of [11C]raclopride was reduced by 2.8–4.6 %. The differences of a score measuring derealisation and depersonalization associated with a positive basic mood were significantly correlated with the change in the [11C]raclopride binding in the limbic striatum. A subtle alteration in the state of consciousness was detected with a correlation to the changes in the [11C]raclopride binding, which implies that a subtle alteration in extracellular dopamine concentration in the limbic striatum by a small amount of dopamine transporter occupancy can affect the state of consciousness. UMIN000008232

Simultaneous measurements of multiple physiological parameters are essential for the study of brain disease mechanisms and the development of suitable therapies to treat them. In this study, we developed a measurement system for simultaneous optical imaging and PET for awake mice. The key elements of this system are the OpenPET, optical imaging and fixation apparatus for an awake mouse. The OpenPET is our original open-type PET geometry, which can be used in combination with another device because of the easily accessible open space of the former. A small prototype of the axial shift single-ring OpenPET was used. The objective lens for optical imaging with a mounted charge-coupled device camera was placed inside the open space of the AS-SROP. Our original fixation apparatus to hold an awake mouse was also applied. As a first application of this system, simultaneous measurements of cerebral blood flow (CBF) by laser speckle imaging (LSI) and [(11)C]raclopride-PET were performed under control and 5% CO2 inhalation (hypercapnia) conditions. Our system successfully obtained the CBF and [(11)C]raclopride radioactivity concentration simultaneously. Accumulation of [(11)C]raclopride was observed in the striatum where the density of dopamine D2 receptors is high. LSI measurements could be stably performed for more than 60 minutes. Increased CBF induced by hypercapnia was observed while CBF under the control condition was stable. We concluded that our imaging system should be useful for investigating the mechanisms of brain diseases in awake animal models.

The histamine H3 receptors are presynaptic neuroreceptors that inhibit the release of histamine and other neurotransmitters. The receptors are considered a drug target for sleep disorders and neuropsychiatric disorders with cognitive decline. We developed a novel PET ligand for the H3 receptors, [11C]TASP0410457 ([11C]TASP457), with high affinity, selectivity and favorable kinetic properties in the monkey, and evaluated its kinetics and radiation safety profile for quantifying the H3 receptors in human brain. Ten healthy men were scanned for 120 min with a PET scanner for brain quantification and three healthy men were scanned for radiation dosimetry after injection of 386 ± 6.2 MBq and 190 ± 7.5 MBq of [11C]TASP457, respectively. For brain quantification, arterial blood sampling and metabolite analysis were performed using high-performance liquid chromatography. Distribution volumes (V T) in brain regions were determined by compartment and graphical analyses using the Logan plot and Ichise multilinear analysis (MA1). For dosimetry, radiation absorbed doses were estimated using the Medical Internal Radiation Dose scheme. [11C]TASP457 PET showed high uptake (standardized uptake values in the range of about 3 – 6) in the brain and fast washout in cortical regions and slow washout in the pallidum. The two-tissue compartment model and graphical analyses estimated V T with excellent identification using 60-min scan data (about 16 mL/cm3 in the pallidum, 9 – 14 in the basal ganglia, 6 – 9 in cortical regions, and 5 in the pons), which represents the known distribution of histamine H3 receptors. For parametric imaging, MA1 is recommended because of minimal underestimation with small intersubject variability. The organs with the highest radiation doses were the pancreas, kidneys, and liver. The effective dose delivered by [11C]TASP457 was 6.9 μSv/MBq. [11C]TASP457 is a useful novel PET ligand for the investigation of the density of histamine H3 receptors in human brain.

Tau accumulation in the brain is a pathologic hallmark of Alzheimer disease and other tauopathies. Quantitative visualization of tau pathology in humans can be a powerful method as a diagnostic aid and for monitoring potential therapeutic interventions. We established methods of PET quantification of tau pathology with 11C-PBB3 (2-((1E,3E)-4-(6-(11C-methylamino)pyridin-3-yl)buta-1,3-dienyl) benzo[d]thiazol-6-ol), considering its radiometabolite entering the brain. Methods: Seven Alzheimer disease patients and 7 healthy subjects underwent dynamic 11C-PBB3 PET scanning. Arterial blood was sampled to obtain the parent and metabolite input functions. Quantification of 11C-PBB3 binding was performed using dual-input models that take the brain metabolite activity into consideration, traditional single-input models without such considerations, and the reference tissue model (MRTMO) and standardized uptake value ratio (SUVR). The cerebellar cortex was used as the reference tissue for all methods. Results: The dual-input graphical models estimated binding parameter ( B P ND * ) stably (∼0.36 in high-binding regions). The MRTMO B P ND * matched the corresponding B P ND * by the dual-input graphical model (r2 = 1.00). SUVR minus 1 correlated well with MRTMO B P ND * (r2 > 0.97). However, BPND by the single-input models did not correlate with B P ND * by the dual-input graphical model (r2 = 0.04). Conclusion: The dual-input graphical model B P ND * is consistent with the reference tissue B P ND * and SUVR-1, suggesting that these parameters can accurately quantify binding of 11C-PBB3 despite the entry of its radiometabolites into the brain.

Effects of chronic hypoxia on hemodynamic response to sensory stimulation were investigated. Using laser-Doppler flowmetry, change in cerebral blood flow ( CBF) was measured in awake mice, which were housed in a hypoxic chamber (8% O2) for 1 month. The degree of increase in CBF evoked by sensory stimulation was gradually decreased over 1 month of chronic hypoxia. No significant reduction of increase in CBF induced by hypercapnia was observed during 1 month. Voltage-sensitive dye (VSD) imaging of the somatosensory cortex showed no significant decrease in neural activation over 1 month, indicating that the reduction of increase in CBF to sensory stimulation was not caused by cerebrovascular or neural dysfunction. The simulation study showed that, when effective diffusivity for oxygen in the capillary bed ( D) value increases by chronic hypoxia due to an increase in capillary blood volume, an increase in the cerebral metabolic rate of oxygen utilization during neural activation can occur without any increase in CBF. Although previous study showed no direct effects of acute hypoxia on CBF response, our finding showed that hemodynamic response to neural activation could be modified in response to a change in their balance to energy demand using chronic hypoxia experiments.

Norepinephrine transporter (NET) in the brain plays important roles in human cognition and the pathophysiology of psychiatric disorders. Two radioligands, (

The serotonin transporter (5-HTT) and other markers of the serotonergic system have been of interest in the pathophysiology of obsessive-compulsive disorder (OCD). Previous studies using single photon emission computed tomography (SPECT) with [(123)I]beta-CIT or positron emission tomography (PET) with [(11)C]McN5652 have not shown consistent findings about 5-HTT in OCD patients. The aim of the present study was to investigate 5-HTT binding using [(11)C]DASB, which has higher selectivity or specific binding-to-nonspecific binding ratios for 5-HTT compared to the aforementioned radioligands. Four drug-naive and 6 drug-free patients with OCD who were free of comorbid depression and 18 gender and age-matched healthy subjects underwent PET scans with [(11)C]DASB. The severity of OCD was assessed by Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) (mean+/-SD: 22+/-7.6, range: 7-32). The binding potential (BP(ND)) of [(11)C]DASB was calculated using a two-parameter multilinear reference tissue model (MRTM2). The parametric images of BP(ND) were analyzed using a statistical parametric mapping system. Significant reductions of BP(ND) were observed in the right posterior and left anterior insular cortices in patients with OCD compared to controls. Region-of-interest analysis has also confirmed significant reduction of BP(ND) in the insular cortex. Although significantly reduced BP(ND) in the orbitofrontal cortex was also observed in patients with OCD compared to controls, this finding should be considered with caution because of the very low 5-HTT binding in the region. On the other hand, no significant correlation was observed between the Y-BOCS score and BP(ND). The change in [(11)C]DASB binding in the insular cortex suggests that dysfunction of the serotonergic system in the limbic area might be involved in the pathophysiology of OCD.

In positron emission tomography (PET) studies with radioligands for neuroreceptors, tracer kinetics have been described by the standard two-tissue compartment model that includes the compartments of nondisplaceable binding and specific binding to receptors. In the present study, we have developed a new graphic plot analysis to determine the total distribution volume (V(T)) and nondisplaceable distribution volume (V(ND)) independently, and therefore the binding potential (BP(ND)). In this plot, Y(t) is the ratio of brain tissue activity to time-integrated arterial input function, and X(t) is the ratio of time-integrated brain tissue activity to time-integrated arterial input function. The x-intercept of linear regression of the plots for early phase represents V(ND), and the x-intercept of linear regression of the plots for delayed phase after the equilibrium time represents V(T). BP(ND) can be calculated by BP(ND)=V(T)/V(ND)-1. Dynamic PET scanning with measurement of arterial input function was performed on six healthy men after intravenous rapid bolus injection of [(11)C]FLB457. The plot yielded a curve in regions with specific binding while it yielded a straight line through all plot data in regions with no specific binding. V(ND), V(T), and BP(ND) values calculated by the present method were in good agreement with those by conventional non-linear least-squares fitting procedure. This method can be used to distinguish graphically whether the radioligand binding includes specific binding or not.

The effects of antipsychotic drugs have generally been considered to be mediated by blockade of dopamine D2 receptors. The concept of limbic and cortical selectivity of second-generation antipsychotics, i.e. higher dopamine D2 receptor occupancy in the cerebral cortices than in the striatum, has been suggested to explain their clinical efficacy with lower incidence of extrapyramidal side-effects. In this study, regional distribution of dopamine D2 receptor occupancy by risperidone was determined in order to elucidate the limbic and cortical selectivity of second-generation antipsychotics. Striatal and extrastriatal dopamine D2 receptor binding at baseline and after oral administration of 2 mg risperidone were measured in ten healthy men by positron emission tomography (PET) using different tracers with different affinity for the receptors, [11C]raclopride and [11C]FLB 457, respectively. Striatal and extrastriatal occupancies of dopamine D2 receptors were calculated for each brain region. Occupancies of dopamine D2 receptors were about 70% and 60% in the striatum and extrastriatum, respectively. A simulation study showed that non-negligible specific binding in the reference region (cerebellum), could cause systemic underestimation of occupancy in [11C]FLB 457 PET studies, indicating that occupancies in both the striatum and extrastriatum may not have differed. Among the extrastriatal regions including limbic and neocortical regions, no significant regional differences in dopamine D2 receptor occupancy were observed. Thus, limbic and cortical selectivity was not observed by one of the second-generation antipsychotics, risperidone.

Dopamine D(2) receptor occupancy by antipsychotic drugs has been measured with positron emission tomography (PET) by comparing the binding potential (BP) values before and after drug administration. This occupancy has been found to be related to clinical effects and side effects. In this study, we evaluated the uncertainty of the quantitative analysis for estimating the dopamine D(2) receptor occupancy by antipsychotics in simulation and human studies of [(11)C]raclopride and for the high affinity ligand [(11)C]FLB 457. Time-activity curves of [(11)C]raclopride and [(11)C]FLB 457 were simulated, and the reliability of BP estimated by a simplified reference tissue model and the calculated occupancy were investigated for various noise levels, BP values, and scan durations. Then, in the human PET study with and without antipsychotics, the uncertainty of BP and occupancy estimates and the scan duration required for a reliable estimation were investigated by a bootstrap approach. Reliable and unbiased estimates of [(11)C]raclopride BP(ND) could be obtained with recording as short as 32 min, with the relative standard deviation (SD) of the striatal occupancy remaining less than 10%. Conversely, in [(11)C]FLB 457 studies, the mean value increased and SD of the temporal cortex and thalamus exceeded 10% when the scan duration was shorter than 60 min. These results demonstrated that dopamine D(2) receptor occupancy by antipsychotics can be estimated precisely with an optimal scan duration with [(11)C]raclopride and [(11)C]FLB 457.

We evaluated the noise reduction capability of wavelet denoising for estimated binding potential (BP) images (k 3/k 4) of the peripheral benzodiazepine receptor using 18F-FEDAA1106 and nonlinear least-square fitting. Wavelet denoising within a three-dimensional discrete dual-tree complex wavelet transform was applied to simulate data and clinical dynamic positron emission tomography images of 18F-FEDAA1106. To eliminate noise components in wavelet coefficients, real and imaginary coefficients for each subband were thresholded individually using NormalShrink. A simulated dynamic brain image of 18F-FEDAA1106 was generated and Gaussian noise was added to mimic PET dynamic scan. The derived BP images were compared with true images using 156 rectangular regions of interest. Wavelet denoising was also applied to data derived from seven young normal volunteers. In the simulations, estimated BP by denoised image showed better correlation with the true BP values (Y = 0.83X + 0.94, r = 0.80), although no correlation was observed in the estimates between noise-added and true images (Y = 1.2X + 0.78, r = 0.49). For clinical data, there were visual improvements in the signal-to-noise ratio for estimated BP images. Wavelet denoising improved the bias and reduced the variation of pharmacokinetic parameters for BP.

The Logan plot is a widely used algorithm for the quantitative analysis of neuroreceptors using PET because it is easy to use and simple to implement. The Logan plot is also suitable for receptor imaging because its algorithm is fast. However, use of the Logan plot, and interpretation of the formed receptor images should be regarded with caution, because noise in PET data causes bias in the Logan plot estimates. In this paper, we describe the basic concept of the Logan plot in detail and introduce three algorithms for the Logan plot. By comparing these algorithms, we demonstrate the pitfalls of the Logan plot and discuss the solution.

Objective We investigated the effects of the baseline CBF level at resting state on neurovascular coupling. Methods Diameters of arterioles, capillaries, and venulas in awake mouse brain were measured by a two-photon microscope. Vasodilation in each of the cerebral vessels was caused by three experimental conditions: (1) sensory stimulation, (2) 5% CO2 inhalation (hypercapnia), (3) simultaneous exposure to sensory stimulation and 5% CO2 inhalation. CBF and CBV were also measured by a microscope and a CCD camera. Results Increases in CBF and CBV were observed under all experimental conditions. After the increases in CBF and CBV due to hypercapnia, additional increases in CBF and CBV occurred during sensory stimulation. Diameter changes in arterioles were significantly larger than those in capillaries and venulas under both sensory stimulation and 5% CO2 inhalation. Additional vasodilation from sensory stimulation was observed under hypercapnia. The diameter change in each vessel type during sensory stimulation was maintained under simultaneous exposure to sensory stimulation and hypercapnia. Conclusions The diameter change of cerebral vessels during neural activation is reproducible regardless of whether baseline CBF has increased or not. Our finding directly demonstrates the concept of uncoupling between energy consumption and energy supply during cortical activation.

Peripheral benzodiazepine receptor (PBR) is expressed in most organs and its expression is reported to be increased in activated microglia in the brain. [(11)C]PK11195 has been widely used for the in vivo imaging of PBRs, but its signal in the brain was not high enough for stable quantitative analysis. We synthesized a novel positron emission tomography (PET) ligand, [(11)C]DAA1106, for PBR and investigated its in vivo properties in rat and monkey brain. High uptake of [(11)C]DAA1106 was observed in the olfactory bulb and choroid plexus area, followed by the pons/medulla and cerebellum by in vivo autoradiography of rat brain, correlating with the binding in vitro. [(11)C]DAA1106 binding was increased in the dorsal hippocampus with neural destruction, suggesting glial reaction. [(11)C]DAA1106 binding was both inhibited and displaced by 1.0 mg/kg of DAA1106 and 5 mg/kg of PK11195 by 80% and 70%, respectively. Specific binding was estimated as 80% of total binding. [(11)C]DAA1106 binding was four times higher compared to the binding of [(11)C]PK11195 in the monkey occipital cortex. These results indicated that [(11)C]DAA1106 might be a good ligand for in vivo imaging of PBR.

In-beam positron emission tomography (PET) is expected to enable visualization of a dose verification using positron emitters (β+ decay). For accurate dose verification, correction of the washout of the positron emitters should be made. In addition, the quantitative washout rate has a potential usefulness as a diagnostic index, but modeling for this has not been studied yet. In this paper, therefore, we applied compartment analyses to in-beam PET data acquired by our small OpenPET prototype, which has a physically opened field-of-view (FOV) between two detector rings. A rat brain was located at the FOV and was irradiated by a (11)C beam. Time activity curves of the irradiated field were measured immediately after the irradiations, and the washout rate was obtained based on two models: the two-washout model (medium decay, k2m; slow decay, k2s) developed in a study of rabbit irradiation; and the two-compartment model used in nuclear medicine, where efflux from tissue to blood (k2), influx (k3) and efflux (k4) from the first to second compartments in tissue were evaluated. The observed k2m and k2s were 0.34 and 0.005 min(-1), respectively, which was consistent with the rabbit study. Also k2m was close to the washout rate in cerebral blood flow (CBF) measurements by dynamic PET with (15)O-water, while, k2, k3, and k4 were 0.16, 0.15 and 0.007 min(-1). Our present work suggested the dynamics of (11)C might be relevant to CBF or permeability of a molecule containing (11)C atoms might be regulated by a transporter because the k2 was relatively low compared with a simple diffusion tracer.

Because of its role in multiple central nervous system (CNS) pathways, metabotropic glutamate receptor type 1 (mGluR1) is a crucial target in the development of pharmaceuticals for CNS disorders. N-[4-[6-(isopropylamino)-pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[(11)C]-methylbenzamide ([(11)C]ITDM) was recently developed as a positron emission tomography (PET) ligand for mGluR1. To devise a method for measurement of the binding potential (BPND) of [(11)C]ITDM to mGluR1, reference tissue methods aimed at replacing measurement of the arterial input function are desirable. In this study, we evaluated a noninvasive quantification method of mGluR1 with [(11)C]ITDM, demonstrating its accuracy using Huntington disease model R6/2 mice. The BPND measurements based on the Logan reference (Logan Ref) method have closely approximated that based on the arterial input method. We performed PET analysis with Logan Ref to assess its accuracy in quantifying the decline of mGluR1 expression in R6/2 mice. Significant decreases in BPND values in R6/2 mice were detected in cerebellum, thalamus, striatum, and cingulate cortex. We compared autoradiographs of R6/2 mouse brain sections with immunohistochemical images, and found a close correlation between changes in radioactive signal intensity and degree of mGluR1 expression. In conclusion, [(11)C]ITDM-PET is a promising tool for in vivo quantification of mGluR1 expression.

Background Microglial activation and disrupted neurotransmissions may herald symptomatic manifestations in neurodegenerative tauopathies. Methods We investigated microglial activation with [ 11 C]DAA1106 positron emission tomography (PET), striatal dopaminergic function with l -[β- 11 C]dopa PET, acetylcholinesterase (AChE) activity with [ 11 C] N -methylpiperidin-4-yl acetate PET, and morphologic brain changes with MRI in three persons (aged 38–41 years) with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), who were presymptomatic gene carriers (PGCs) from an American kindred with pallidopontonigral degeneration. The results from these 3 PGCs were compared with [ 11 C]DAA1106 PET results from age-matched 9 healthy volunteers (HV), and with l -[β- 11 C]dopa and [ 11 C]MP4A PET results from 10 HV. Values considered significant were more than 2 SDs greater or less than the normal control mean, as the number of subjects was small for group comparisons. Results Glial activities were increased in the frontal cortex of one PGC, the occipital cortex of two PGCs, and the posterior cingulate cortex of one PGC, although none of the PGCs showed overt glial activation in the brain. Only one of the PGCs showed reduced AChE activity in the temporo-parietal cortex. Three PGCs showed low dopamine synthesis rates in the putamen. Hippocampal atrophy was observed in two PGCs. Conclusions Hippocampal atrophy and striatal dopaminergic dysfunction may be early disease processes in the pathogenesis of FTDP-17. Neuroinflammation may also be an in vivo signature of tau pathology at a prodromal stage, although current PET techniques may not constantly reveal it as the earliest neuroimaging abnormality.

OBJECTIVE: Dopamine transporter (DAT) is a reuptake carrier of dopamine at presynapse that regulates dopaminergic neural transmission. [(11)C]PE2I is a cocaine analog developed as a potent positron emission tomography (PET) ligand for DAT with high selectivity. The aim of this study was to evaluate the applicability of quantification methods using reference tissue models for [(11)C]PE2I. METHODS: Dynamic PET scans were performed in 6 young healthy male volunteers after an intravenous bolus injection of [(11)C]PE2I. Metabolite-corrected arterial plasma-input functions were obtained. Compartment model analysis and plasma-input Logan analysis were performed to determine the kinetic parameters and distribution volume (V (T)). The distribution volume ratio (DVR) was calculated as the ratio of V (T) in the cerebral region to that in the cerebellum. DVRs were also determined by the original multilinear reference tissue model method (MRTMo) and the simplified reference tissue model method (SRTM), comparing the results with those obtained from graphical analysis using arterial input function. To estimate errors in DVR calculated using the reference tissue model, a simulation study that focused on cerebellar kinetics and scan duration was performed. RESULTS: The highest [(11)C]PE2I binding was observed in the striatum, followed by the midbrain and thalamus. The 2-tissue model was preferable to the 1-tissue model for describing the [(11)C]PE2I kinetics in the cerebellum. Both the measured and 90-min simulated data showed that reference tissue models caused an underestimation of DVR in the striatum. The simulation showed that 90-min scan duration was insufficient when cerebellar kinetics was described as a 1-tissue model. Nevertheless, DVR values determined by MRTMo and SRTM were in good agreement with those by the graphical approach in other lower binding regions. CONCLUSION: Due to the [(11)C]PE2I kinetics in the cerebellum and limited scan duration for (11)C, MRTMo and SRTM underestimated the striatal DVR. Despite this limitation, the present study demonstrated the applicability of reference tissue models. Since DAT in the midbrain and thalamus is of interest in the pathophysiology of neuropsychiatric disease, this noninvasive quantitative analysis will be useful for clinical investigations.

Gamma-aminobutyric acid (GABA)A/benzodiazepine (BZ) receptor chloride channel consists of several subunits. The diversity of the α subunits results in the various ligand selectivity and functionally different properties of the GABAA/BZ receptor. Although [¹¹C] Ro15-4513 is reported to be a radioligand that has relatively high affinity for α5 subunit-containing GABAA/BZ receptor, it remained to be evaluated fully.The aim of this study was to evaluate the quantitative analyses of [¹¹C]Ro15-4513 in the living human brain.Positron emission tomography examinations were performed in eight healthy male volunteers after intravenous injection of [¹¹C]Ro15-4513. Kinetic analysis of data was performed with the two-compartment and three-compartment models using arterial input function. Linear graphical analysis and the simplified reference tissue model analysis (SRTM) were also performed using pons as a reference region. In a simulation study, the effects of noise to the estimation of binding potentials were evaluated.The accumulation of [¹¹C]Ro15-4513 in the limbic system was relatively higher than in other cortex. The bindings were well described by the three-compartment model in the regions with specific binding. Binding potentials obtained from the graphical method and SRTM correlated well with those obtained from the three-compartment model. In the simulation study, estimated parameters from SRTM were less affected by noise compared with those from the graphical method.The reference tissue methods using pons as a reference region can be used for quantitative analysis of [¹¹C]Ro15-4513 binding. SRTM seemed less susceptible to noise than does graphical analysis.

Positron emission tomography (PET) with [ 11 C]raclopride is widely used to investigate temporal changes in the dopamine D 2 receptor system attributed to the dopamine release. The simplified reference tissue model (SRTM) can be used to determine the binding potential (BP ND ) value using the time–activity curve (TAC) of the reference region as input function. However, in assessing temporal changes in BP ND using the SRTM, multiple [ 11 C]raclopride PET scans are required, and a second scan must be performed after the disappearance of the [ 11 C]raclopride administered in the first scan. In this study, we have developed an extended multiple-injection SRTM to estimate the BP ND change, from a single PET scan with multiple injections of [ 11 C]raclopride, and we have validated this approach by performing numerous simulations and studies on monkeys. In the computer simulations, TACs were generated for dual injections of [ 11 C]raclopride, in which binding conditions changed during the scans, and the BP ND values before, and after, the second injection were estimated by the proposed method. As a result, the reduction in BP ND was correlated, either with the integral of released dopamine, or with the administered mass of raclopride. This method was applied to studies on monkeys, and was capable of determining two identical BP ND values when there were no changes in binding conditions. The BP ND after the second injection decreased when binding conditions changed due to an increase in administered raclopride. An advantage of the proposed method is the shortened scan period for the quantitative assessment of the BP ND change for neurotransmitter competition studies.

N-methyl-D-aspartate (NMDA) receptors are of major interest in brain functions and neuropsychiatric disorders. However, at present there are few suitable radioligands for in vivo imaging of NMDA receptors. 7-choloro-4-hydroxy-3-[3-(4-methoxybenzyl) phenyl]-2(1H)-quinolone (L-703,717) is one of the potent ligands for the glycine-binding site of NMDA receptors. 4-Acetoxy derivative of L-703,717 (AcL703) is a candidate, as a positron emission tomography (PET) ligand for NMDA receptors, because of its better permeability at the blood-brain barrier compared with L-703,717. After intravenous injection of 624-851 MBq of [11C]AcL703, dynamic PET scan was performed on six healthy males for 90 min. Regions-of-interest were located on the cerebral cortices, cerebellar cortex, and cerebral white matter. The binding potential (BP) was calculated from the ratio of the area under the curve (AUC) of radioactivities from 40 to 90 min in the target region to that in white matter. Regional radioactivities reached close to equilibrium in all regions after about 40 min postinjection. Regional brain uptake of [11C]AcL703 at 40 min after injection was 0.00028-0.00065% of the injected dose/milliliter. Radioactivity concentration of [11C]AcL703 was highest in the cerebellar cortex and lowest in white matter. AUC in the cerebellar cortex was higher than those of cerebral cortices, thalamus, striatum, and white matter. BP in the cerebellar cortex was twofold higher than in the cerebral cortices (cerebellar cortex: BP=2.20+/-0.72; cerebral cortices: BP=1.05+/-0.45). Despite the low brain uptake of [11C]AcL703, regional distributions were in good agreement with our previous studies of rodents. This indicates the possibility of in vivo evaluation of NMDA receptors using PET with [11C]AcL703 in living human brain.

Metabotropic glutamate receptor subtype 1 (mGluR1) is a crucial target in the development of new medications to treat central nervous system (CNS) disorders. Recently, we developed N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-[11C]methoxy-N-methyl-benzamide ([11C]ITMM) as a useful positron emission tomography (PET) probe for mGluR1 in clinical studies. Here, we aimed to improve visualization and threshold of specific binding for mGluR1 using [11C]ITMM with ultra-high specific activity (SA) of > 3,500 GBq/μmol in rat brains. A two-tissue compartment model indicated large differences between the two SAs in the constants k3 and k4, representing binding ability for mGluR1, while constants K 1 and k2 showed no differences. The total distribution volume (VT) values of conventional and ultra-high SA were 9.1 and 11.2 in the thalamus, 7.7 and 9.7 in the striatum, and 6.4 and 8.5 mL/cm3 in the substantia nigra, respectively. The specific binding of [11C]ITMM with ultra-high SA was significantly higher than the conventional SA, especially in the basal ganglia. Parametric PET images scaled with VT of the ultra-high SA clearly identified regional differences in the rat brain. In conclusion, PET studies using [11C]ITMM with ultra-high SA could sufficiently improve visualization and specific binding for mGluR1, which could help further understanding for mGluR1 functions in CNS disorders.

Background and objectives To estimate the presynaptic function of the central dopaminergic system, the rate of endogenous dopamine synthesis has been measured by using L-[β- 11 C]DOPA or 6-[ 18 F]fluoro-L-DOPA with positron emission tomography. However, the regional kinetics of L-[β- 11 C]DOPA in human brain have not been investigated in detail. In the present study, the regional kinetics of L-[β- 11 C]DOPA in normal human brain and the accuracy of the method for quantifying L-[β- 11 C]DOPA kinetics, employing reference regions, were investigated. Methods After intravenous injection of L-[β- 11 C]DOPA, dynamic scanning was performed on ten healthy subjects for 89 min. The overall uptake rate constant K was calculated by the kinetic and graphical approaches, in which the occipital cortex was used as a reference brain region. Results Regional distribution of K was similar to those of dopamine D 2 receptor. A significant negative correlation was observed between the neutral amino acid concentration in plasma and the influx rate constant through the blood-brain barrier (K 1 ). The K values calculated by graphical approach were in good agreement with the values calculated by kinetic approach for both experimental and simulated data. Conclusions The regional distribution of K corresponds to that of the nigrostriatal and mesolimbic dopaminergic system. Negative correlation between neutral amino acid concentration and K 1 supports the suggestion that L-DOPA is transported in a competitive fashion via the same carrier system as neutral amino acids at the blood-brain barrier. Because the graphical approach can obviate the need for an arterial input function, it is useful for investigating the rate of regional dopamine synthesis in neuropsychiatric and neurodegenerative diseases.

OBJECTIVES: Both reconstruction algorithms, filtered backprojection (FBP) and ordered subsets expectation maximization (OSEM), are widely used in clinical positron emission tomography (PET) studies. Image reconstruction for most neurotransmission PET scan data is performed by FBP, while image reconstruction for whole-body [18F]FDG scan data is usually performed by OSEM. Although several investigators have compared FBP and OSEM in terms of the quantification of regional radioactivity and physiological parameters calculated from PET data, only a few studies have compared the two reconstruction algorithms in PET studies that estimate neurotransmission, i.e., neuroreceptor and neurotransporter binding. In this study we compared mean regional radioactivity concentration in the late phase and binding potential (BP) between FBP and OSEM algorithms in neurotransmission PET studies for [11C]raclopride and [11C]DASB. METHODS: Dynamic PET scans with [11C]raclopride in 3-dimensional mode were performed on seven healthy subjects. Dynamic PET scans with [11C]DASB in 2-dimensional mode were performed on another seven subjects. OSEM images were post-filtered so that its transverse spatial resolution became similar to that of FBP with the same Hanning filter (Kernel FWHM 6 mm). In both PET studies we calculated the BP of [11C]raclopride and [11C]DASB by a reference tissue model for each ROI (region of interest). RESULTS: There was no significant difference in mean regional radioactivity concentration between FBP and OSEM for [11C]raclopride and [11C]DASB. Only +2.4 - +3.2%, but still a significant difference in BP of [11C]raclopride between FBP and OSEM was observed in the striatum. There was no significant difference in BP between FBP and OSEM in other than the striatum for [11C]raclopride and in all regions for [11C]DASB. In addition, there was no significant difference in root mean square error between FBP and OSEM when BP was calculated. CONCLUSIONS: The BP values were similar between FBP and OSEM algorithms with [11C]raclopride and [11C]DASB. This study indicates that OSEM can be used for human neurotransmission PET studies for calculating BP although OSEM was not necessarily superior to FBP in the present study.

[11C]DAA1106 is a potent and selective ligand for the peripheral benzodiazepine receptor (PBR) with high affinity. It has been reported that the density of PBR is related to brain damage, so a reliable tracer method for the evaluation of PBR would be of use. We evaluated a quantification method of [11C]DAA1106 binding in simulated data and human brain data. In the simulation study, the reliability of parameters estimated from the nonlinear least-squares (NLS) method, graphical analysis (GA), and multilinear analysis (MA) was evaluated. In GA, variation of the estimated distribution volume (DV) was small. However, DV was underestimated as noise increased. In MA, bias was smaller, and variation of the estimated DV was larger than in GA. In NLS, although variation was larger than in GA, it was small enough in regions of interest analysis, and not only DV but also binding potential (BP), determined from the k3 /k4 without any constraint, could be estimated. The variation of BP estimated with NLS became larger as k3 or k4 became smaller. In human studies with normal volunteers, regions of interest were drawn on several brain regions, BP was calculated by NLS, and DV was also estimated by NLS, GA, and MA. As a result, DVs estimated with each method were well correlated. However, there was no correlation between BP with NLS and DV with NLS, GA, and MA, because of the variation of K1 /k2 between individuals. In conclusion, BP is estimated most reliably by NLS with the two-tissue compartment model.

N-(5-Fluoro-2-phenoxyphenyl)-N-(2-(18)F-fluoroethyl-5-methoxybenzyl)acetamide ((18)F-FEDAA1106) is a potential PET ligand with highly selective and specific binding to peripheral benzodiazepine receptor (PBR). It has been reported that the regional density of PBR in the brain is increased in several neurodegenerative and psychiatric disorders. Thus, a reliable tracer method for evaluating PBR would be of use clinically and for research. To our knowledge, this is the first study to investigate the (18)F-FEDAA1106 binding to PBR in living human brain by PET. We also aimed to evaluate various analytic methods to quantify the density of PBR.PET studies with (18)F-FEDAA1106 were performed on 7 healthy men. Volumes of interest (VOIs) were drawn on PET images. In each VOI, binding potential (BP) was calculated by nonlinear least-squares (NLS) fitting based on the 2-tissue compartment model, and the distribution volume (DV) was also estimated by NLS, Logan plot, and multilinear analysis (MA) methods. To estimate errors in calculation of BP and DV, simulation studies were also performed.The DVs estimated with each of the methods were significantly correlated. There was also significant correlation between BP with NLS and DV with NLS, Logan plot, or MA. But the interindividual differences in the distribution volume of the free and nonspecific binding compartment (K(1)/k(2)) were relatively large. In a simulation study, variation of the DV estimated by Logan plot was relatively small, but it was underestimated as the noise increased. By MA, the bias of DV was smaller, but the variation of DV was larger than by Logan plot. Within a 3% noise level, there was almost no difference between Logan plot and MA in both bias and variation. DVs estimated by both Logan plot and MA were underestimated by 10%-20%. Although the variation of DV was larger by NLS than by Logan plot, it was small enough in the noise level of VOI analysis, and the bias of DV was 0%-2%.The simulation studies indicated that NLS is a suitable method for the estimation of (18)F-FEDAA1106 binding to PBRs.