Search

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.

Purpose: Monoacylglycerol lipase (MAGL) regulates cannabinoid neurotransmission and the pro-inflammatory arachidonic acid pathway by degrading endocannabinoids. MAGL inhibitors may accordingly act as cannabinoid-potentiating and anti-inflammatory agents. Although MAGL dysfunction has been implicated in neuropsychiatric disorders, it has never been visualized in vivo in human brain. The primary objective of the current study was to visualize MAGL in the human brain using the novel PET ligand 18F-T-401. Methods: Seven healthy males underwent 120-min dynamic 18F-T-401-PET scans with arterial blood sampling. Six subjects also underwent a second PET scan with 18F-T-401 within 2 weeks of the first scan. For quantification of MAGL in the human brain, kinetic analyses using one- and two-tissue compartment models (1TCM and 2TCM, respectively), along with multilinear analysis (MA1) and Logan graphical analysis were performed. Time-stability and test-retest reproducibility of 18F-T-401-PET were also evaluated.Results: 18F-T-401 showed rapid uptake and gradual washout from the brain. Logan graphical analysis showed linearity in all subjects, indicating reversible radioligand kinetics. Using a metabolite-corrected arterial input function, MA1 estimated regional total distribution volume (VT) values by best identifiability. VT values were highest in the cerebral cortex, moderate in the thalamus and putamen, and lowest in white matter and the brainstem, which was in agreement with regional MAGL expression in the human brain. Time-stability analysis showed that MA1 estimated VT values with a minimal bias even using truncated 60-min scan data. Test-retest reliability was also excellent with the use of MA1. Conclusions: Here, we provide the first demonstration of in vivo visualization of MAGL in the human brain. 18F-T-401 showed excellent test-retest reliability, reversible kinetics, and stable estimation of VT values consistent with known regional MAGL expressions. PET with 18F-T-401-PET is promising tool for measurement of central MAGL.

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-HT2A receptor availability and specify which brain networks were involved in healthy male subjects, using [18F]altanserin positron emission tomography and resting-state functional magnetic resonance imaging. Behavioral inhibition system score negatively correlated with 5-HT2A receptor availability in anterior cingulate cortex. A statistical model indicated that the behavioral inhibition system score was associated with 5-HT2A receptor availability, which was mediated by the functional connectivity between anterior cingulate cortex and left middle frontal gyrus, both of which involved in the cognitive control of negative information processing. Individuals with high behavioral inhibition system displays low 5-HT2A receptor availability in anterior cingulate cortex and this cognitive control network links with prefrontal-cingulate integrity. These findings have implications for underlying the serotonergic basis of physiologies in aversion.

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 [18F]T-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 [18F]T-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 [18F]T-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%. [18F]T-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.

We developed a human-scale single-ring OpenPET (SROP) system, which had an open space allowing us access to the subject during measurement. The SROP system consisted of 160 4-layer depth-of-interaction detectors. The open space with the axial width of 430 mm was achieved with the ring axial width of 214 mm and the ring inner diameter of 660 mm. The detectors were axially shifted to each other so that the detector ring was aligned along a plane horizontally tilted by 45° against the axial direction. The system was developed as a mobile scanner to be used not only in clinical positron emission tomography (PET) rooms but also in charged-particle therapy treatment rooms as well as animal experiment rooms. Almost uniform spatial resolution better than 3 mm throughout the entire field of view (FOV) was realized with an iterative image reconstruction method. Peak absolute sensitivity was 3.1%, and there was a region with sensitivity better than 0.8% for a length of more than 700 mm. An in-beam imaging experiment conducted at the heavy ion medical accelerator in Chiba showed that the system was operable even at the highest beam intensity available for heavy-ion therapy. In addition, we conducted entire-body monkey dynamic imaging utilizing the long region inside the gantry by positioning a monkey along the direction having the longest FOV tilted by 45° against the axial direction. We concluded the developed system has a capability to realize versatile PET applications by utilizing its wide-open space and mobility in addition to high spatial resolution with sufficiently good sensitivity. -9mm]Please consider rephrasing the sentence “We concluded the developed system” for clarity.

Patients with progressive supranuclear palsy (PSP) frequently exhibit apathy but the neuropathological processes leading to this phenotype remain elusive. We aimed to examine the involvement of tau protein depositions, oxidative stress (OS), and neuronal loss in the apathetic manifestation of PSP. Twenty patients with PSP and twenty-three healthy controls were enrolled. Tau depositions and brain volumes were evaluated via positron-emission tomography (PET) using a specific probe

Fluctuations of neuronal activities in the brain may underlie relatively slow components of neurofunctional alterations, which can be modulated by food intake and related systemic metabolic statuses. Glutamatergic neurotransmission plays a major role in the regulation of excitatory tones in the central nervous system, although just how dietary elements contribute to the tuning of this system remains elusive. Here, we provide the first demonstration by bimodal positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) that metabotropic glutamate receptor subtype 5 (mGluR5) ligand binding and glutamate levels in human brains are dynamically altered in a manner dependent on food intake and consequent changes in plasma glucose levels. The brain-wide modulations of central mGluR5 ligand binding and glutamate levels and profound neuronal activations following systemic glucose administration were further proven by PET, MRS, and intravital two-photon microscopy, respectively, in living rodents. The present findings consistently support the notion that food-associated glucose intake is mechanistically linked to glutamatergic tones in the brain, which are translationally accessible in vivo by bimodal PET and MRS measurements in both clinical and non-clinical settings.

Fluctuations of neuronal activities in the brain may underlie relatively slow components of neurofunctional alterations, which can be modulated by food intake and related systemic metabolic statuses. Glutamatergic neurotransmission plays a major role in the regulation of excitatory tones in the central nervous system, although just how dietary elements contribute to the tuning of this system remains elusive. Here, we provide the first demonstration by bimodal positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) that metabotropic glutamate receptor subtype 5 (mGluR5) ligand binding and glutamate levels in human brains are dynamically altered in a manner dependent on food intake and consequent changes in plasma glucose levels. The brain-wide modulations of central mGluR5 ligand binding and glutamate levels and profound neuronal activations following systemic glucose administration were further proven by PET, MRS, and intravital two-photon microscopy, respectively, in living rodents. The present findings consistently support the notion that food-associated glucose intake is mechanistically linked to glutamatergic tones in the brain, which are translationally accessible in vivo by bimodal PET and MRS measurements in both clinical and non-clinical settings.

Colony-stimulating factor 1 receptor (CSF1R) is a specific biomarker for microglia. In this study, we developed a novel PET radioligand for CSF1R, 11C-GW2580, and compared it to a reported CSF1R tracer, 11C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey. Dynamic 11C-GW2580- and 11C-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 AppNL-G-F/NL-G-F-knock-in mice, spatially in agreement with an increased 18-kDa translocator protein radioligand retention. Moreover, 11C-GW2580 captured changes in CSF1R availability more sensitively than 11C-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 11C-GW2580 by ∼30% in all examined brain regions except for centrum semi-ovale white matter, but did not affect the retention of 11C-CPPC. In summary, our results demonstrated that 11C-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.

Purpose Phosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [11C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7. Methods [11C]MTP38 was radiosynthesized by 11C-cyanation of a bromo precursor with [11C]HCN. PET scans of rat and rhesus monkey brains and in vitro autoradiography of brain sections derived from these species were conducted with [11C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (VT). The non-displaceable binding potential (BPND) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BPND. Results [11C]MTP38 was synthesized with radiochemical purity ≥99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated VT values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm3, respectively. The cerebellar VT value was unchanged by pretreatment with unlabeled MTP38. Striatal BPND was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill’s sigmoidal function. Conclusion We have provided the first successful preclinical demonstration of in vivo PDE7 imaging with a specific PET radioligand. [11C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.

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.

Purpose Phosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in neuropsychiatric diseases. However, in vivo visualization of PDE7 in human brains has hitherto not been possible. Using the novel PET ligand 11C-MTP38, which we recently developed, we aimed to image and quantify PDE7 in living human brains. Methods Seven healthy males underwent a 90-min PET scan after injection of 11C-MTP38. We performed arterial blood sampling and metabolite analysis of plasma in six subjects to obtain a metabolite-corrected input function. Regional total distribution volumes (VTs) were estimated using compartment models, and Logan plot and Ichise multilinear analysis (MA1). We further quantified the specific radioligand binding using the original multilinear reference tissue model (MRTMO) and standardized uptake value ratio (SUVR) method with the cerebellar cortex as reference. Results PET images with 11C-MTP38 showed relatively high retentions in several brain regions, including in the striatum, globus pallidus, and thalamus, as well as fast washout from the cerebellar cortex, in agreement with the known distribution of PDE7. VT values were robustly estimated by two-tissue compartment model analysis (mean VT = 4.2 for the pallidum), Logan plot, and MA1, all in excellent agreement with each other, suggesting the reversibility of 11C-MTP38 binding. Furthermore, there were good agreements between binding values estimated by indirect method and those estimated by both MRTMO and SUVR, indicating that these methods could be useful for reliable quantification of PDE7. Because MRTMO and SUVR do not require arterial blood sampling, they are the most practical for the clinical use of 11C-MTP38-PET. Conclusion We have provided the first demonstration of PET visualization of PDE7 in human brains. 11C-MTP38 is a promising novel PET ligand for the quantitative investigation of central PDE7.

A substantial and constitutive expression of translocator protein (TSPO) in cerebral blood vessels hampers the sensitive detection of neuroinflammation characterized by greatly induced TSPO expression in activated glia. Here, we conducted in vivo positron emission tomography (PET) and in vitro autoradiographic imaging of normal and TSPO-deficient mouse brains to compare the binding properties of 18F-FEBMP, a relatively novel TSPO radioligand developed for human studies based on its insensitivity to a common polymorphism, with 11C-PK11195, as well as other commonly used TSPO radioligands including 11C-PBR28, 11C-Ac5216 and 18F-FEDAA1106. TSPO in cerebral vessels of normal mice was found to provide a major binding site for 11C-PK11195, 11C-PBR28 and 18F-FEDAA1106, in contrast to no overt specific binding of 18F-FEBMP and 11C-Ac5216 to this vascular component. In addition, 18F-FEBMP yielded PET images of microglial TSPO with a higher contrast than 11C-PK11195 in a tau transgenic mouse modeling Alzheimer’s disease (AD) and allied neurodegenerative tauopathies. Moreover, TSPO expression examined by immunoblotting was significantly increased in AD brains compared with healthy controls, and was well correlated with the autoradiographic binding of 18F-FEBMP but not 11C-PK11195. Our findings support the potential advantage of comparatively glial TSPO-selective radioligands such as 18F-FEBMP for PET imaging of inflammatory glial cells.

Although previous studies have suggested the involvement of dopamine (DA) and noradrenaline (NA) neurotransmissions in the autism spectrum disorder (ASD) pathophysiology, few studies have examined these neurotransmissions in individuals with ASD in vivo. Here, we investigated DA D1 receptor (D1R) and noradrenaline transporter (NAT) binding in adults with ASD (n = 18) and neurotypical controls (n = 20) by utilizing two different PET radioligands, [11C]SCH23390 and (S,S)-[18F]FMeNER-D2, respectively. We found no significant group differences in DA D1R (striatum, anterior cingulate cortex, and temporal cortex) or NAT (thalamus and pons) binding. However, in the ASD group, there were significant negative correlations between DA D1R binding (striatum, anterior cingulate cortex and temporal cortex) and the “attention to detail” subscale score of the Autism Spectrum Quotient. Further, there was a significant positive correlation between DA D1R binding (temporal cortex) and emotion perception ability assessed by the neurocognitive battery. Associations of NAT binding with empathic abilities and executive function were found in controls, but were absent in the ASD group. Although a lack of significant group differences in binding might be partly due to the heterogeneity of ASD, our results indicate that central DA and NA function might play certain roles in the clinical characteristics of ASD.

Although previous studies have suggested the involvement of dopamine (DA) and noradrenaline (NA) neurotransmissions in the autism spectrum disorder (ASD) pathophysiology, few studies have examined these neurotransmissions in individuals with ASD in vivo. Here, we investigated DA D1 receptor (D1R) and noradrenaline transporter (NAT) binding in adults with ASD (n = 18) and neurotypical controls (n = 20) by utilizing two different PET radioligands, [11C]SCH23390 and (S,S)-[18F]FMeNER-D2, respectively. We found no significant group differences in DA D1R (striatum, anterior cingulate cortex, temporal cortex) or NAT (thalamus, pons) binding. However, in the ASD group, there were significant negative correlations between DA D1R binding (striatum, anterior cingulate cortex, temporal cortex) and the “attention to detail” subscale score of the Autism Spectrum Quotient. Further, there was a significant positive correlation between DA D1R binding (temporal cortex) and emotion perception ability assessed by the neurocognitive battery. Associations of NAT binding with empathic abilities and executive function were found in controls, but were absent in the ASD group. While a lack of significant group differences in binding might be partly due to the heterogeneity of ASD, our results indicate that central DA and NA function might play certain roles in the clinical characteristics of ASD.

The chemogenetic technology designer receptors exclusively activated by designer drugs (DREADDs) afford remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities and potential off-target effects of CNO represent areas for improvement. Here, we provide a new high-affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 μg per kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 μg per kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents a potent, selective, metabolically stable and fast-acting DREADD agonist with utility in both mice and nonhuman primates for a variety of applications. Deschloroclozapine (DCZ) is a broadly useful chemogenetic agonist for studies using nonhuman primates and mice. DCZ rapidly and reversibly activates DREADDs, and its binding can be visualized noninvasively by positron emission tomography.

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 [

Positron emission tomography (PET) allows biomolecular tracking but PET monitoring of brain networks has been hampered by a lack of suitable reporters. Here, we take advantage of bacterial dihydrofolate reductase, ecDHFR, and its unique antagonist, TMP, to facilitate in vivo imaging in the brain. Peripheral administration of radiofluorinated and fluorescent TMP analogs enabled PET and intravital microscopy, respectively, of neuronal ecDHFR expression in mice. This technique can be used to the visualize neuronal circuit activity elicited by chemogenetic manipulation in the mouse hippocampus. Notably, ecDHFR‐PET allows mapping of neuronal projections in non‐human primate brains, demonstrating the applicability of ecDHFR‐based tracking technologies for network monitoring. Finally, we demonstrate the utility of TMP analogs for PET studies of turnover and self‐assembly of proteins tagged with ecDHFR mutants. These results establish opportunities for a broad spectrum of previously unattainable PET analyses of mammalian brain circuits at the molecular level., Application of bacterial dihydrofolate reductase ecDHFR and its unique antagonist TMP achieves a broad spectrum of previously unattainable in vivo PET analyses of mammalian brain circuits at the molecular level.

Rationale 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. Objectives To clarify the association between individual variations in behavioral inhibition system and brain 5-HT2A receptor availability and specify which brain networks were involved in healthy male subjects, using [18F]altanserin positron emission tomography and resting-state functional magnetic resonance imaging. Results Behavioral inhibition system score negatively correlated with 5-HT2A receptor availability in anterior cingulate cortex. A statistical model indicated that the behavioral inhibition system score was associated with 5-HT2A receptor availability, which was mediated by the functional connectivity between anterior cingulate cortex and left middle frontal gyrus, both of which involved in the cognitive control of negative information processing. Conclusions Individuals with high behavioral inhibition system displays low 5-HT2A receptor availability in anterior cingulate cortex and this cognitive control network links with prefrontal-cingulate integrity. These findings have implications for underlying the serotonergic basis of physiologies in aversion.

PurposePhosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in-vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [11C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7.Methods[11C]MTP38 was radiosynthesized by 11C-cyanation of a bromo precursor with [11C]HCN. PET scans of rat and rhesus monkey brains and in-vitro autoradiography of brain sections derived from these species were conducted with [11C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (VT). The non-displaceable binding potential (BPND) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BPND.Results[11C]MTP38 was synthesized with radiochemical purity ≥ 99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In-vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated VT values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm3, respectively. The cerebellar VT value was unchanged by pretreatment with unlabeled MTP38. Striatal BPND was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill’s sigmoidal function.ConclusionWe have provided the first successful preclinical demonstration of in-vivo PDE7 imaging with a specific PET radioligand. [11C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.

Summary A panel of radiochemicals has enabled in vivo positron emission tomography (PET) of tau pathologies in Alzheimer’s disease (AD), although sensitive detection of frontotemporal lobar degeneration (FTLD) tau inclusions has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing diverse tau deposits. In vitro assays demonstrated the reactivity of this compound with tau pathologies in AD and FTLD. We could also utilize PM-PBB3 for optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of 18F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant progressive supranuclear palsy (PSP) tau topologies. Notably, the in vivo reactivity of 18F-PM-PBB3 with FTLD tau inclusion was strongly supported by neuropathological examinations of brains derived from Pick’s disease, PSP, and corticobasal degeneration patients who underwent PET scans. Finally, visual inspection of 18F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on a neuropathological basis.

Positron Emission Tomography (PET) allows biomolecular tracking, while PET monitoring of brain networks has been hampered by the lack of a suitable reporter. Here, we describe in vivo brain imaging that takes advantage of bacterial dihydrofolate reductase, ecDHFR, and its unique antagonist, TMP. In mice, peripheral administration of radiofluorinated and fluorescent TMP analogs enabled PET and intravital microscopy, respectively, of neuronal ecDHFR expressions. This technique is applicable to the visualization of neuronal ensemble activities elicited by chemogenetic manipulation in the mouse hippocampus. Notably, ecDHFR-PET offers mapping of neuronal projections in non-human primate brains, indicating the availability of ecDHFR-based tracking technologies for network monitoring. Finally, we demonstrate the utility of TMP analogs for PET assays of turnover and self-assembly of proteins tagged with ecDHFR mutants. Our findings may facilitate a broad spectrum of PET analyses of a mammalian brain circuit at molecular levels that were not previously applicable for technical reasons.

Introduction To facilitate radiotracers' development, a screening methodology using a biomathematical model and clinical usefulness index (CUI) was proposed to evaluate radiotracers' diagnostic capabilities. Methods A total of 31 amyloid positron emission tomography radiotracers were evaluated. A previously developed biomathematical model was used to simulate 1000 standardized uptake value ratios with population and noise simulations, which were used to determine the integrated receiver operating characteristics curve (Az), effect size (Es), and standardized uptake value ratio (Sr) of conditions-pairs of healthy control–mild cognitive impaired and mild cognitive impaired–Alzheimer's disease. CUI was obtained from the product of averaged Az(Az¯), Es(Es¯), and Sr(Sr¯). Results The relationships of Az¯, Es¯, and Sr¯ with CUI were different, suggesting that they assessed different radiotracer properties. The combination of Az, Es, and Sr complemented each other and resulted in CUI of 0.10 to 5.72, with clinically applied amyloid positron emission tomography radiotracers having CUI greater than 3.0. Discussion The CUI rankings of clinically applied radiotracers were close to their reported clinical results, attesting to the applicability of the screening methodology., Highlights • Clinical usefulness index was proposed to evaluate radiotracers' diagnostic power. • CUI rankings of amyloid radiotracers were close to their clinical results. • CUI allows for simultaneous and objective comparison of candidate radiotracers.