scholarly journals Adenosine A2A receptor in schizophrenia: an in vivo brain PET imaging study

2021 ◽  
Author(s):  
Tiago Reis Marques ◽  
Sridhar Natesan ◽  
Eugenii A. Rabiner ◽  
Graham E. Searle ◽  
Roger Gunn ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Tracer Uptake ◽  
Psychotic Symptoms ◽  
Binding Potential ◽  
Primary Role ◽  
Healthy Controls ◽  
Pet Tracer ◽  
A2a Receptor ◽  
Globus Pallidum

AbstractAdenosine A2A receptors are highly enriched in the basal ganglia system, a region that is functionally implicated in schizophrenia. Preclinical evidence suggests a cross-regulation between adenosine A2A and dopamine D2 receptors in this region and that it is linked to the sensitization of the dopamine system. However, the relationship between A2A receptor availability and schizophrenia has not been directly examined in vivo in patients with this disorder. To investigate, using positron emission tomography (PET), the availability of A2A receptors in patients diagnosed with schizophrenia in comparison to matched healthy controls. A2A receptor availability was measured using the PET tracer [11C]SCH442416. Twelve male patients with chronic schizophrenia were compared to 13 matched healthy subjects. All patients were medicated with antipsychotics and none presented with any motor or extrapyramidal symptoms. Binding potential (BPND), a ratio measure between specific and non-specific tracer uptake, were compared between the groups for the caudate, putamen, accumbens and globus pallidum. There was no differences between A2A receptor binding potential (BPND) of schizophrenia patients in the caudate (p = 0.16), putamen (p = 0.86), accumbens (p = 0.44) and globus pallidum (p = 0.09) to that of matched healthy subjects. There was also no significant correlation between [11C]SCH442416 binding and severity of psychotic symptoms (p = 0.2 to 0.82) or antipsychotic dosage (p = 0.13 to 0.34). By showing that A2A receptor availability in medicated patients with chronic male schizophrenia is not different than in healthy controls, this study does not support the primary role of this receptor in the pathogenesis of schizophrenia.

scholarly journals The P2X7 receptor tracer [11C]SMW139 as an in vivo marker of neuroinflammation in multiple sclerosis: a first-in man study

2019 ◽  
Vol 47 (2) ◽  
pp. 379-389 ◽  
Author(s):  
Marloes H. J. Hagens ◽  
Sandeep S. V. Golla ◽  
Bieneke Janssen ◽  
Danielle J. Vugts ◽  
Wissam Beaino ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Specific Binding ◽  
Compartment Model ◽  
Brain Regions ◽  
Binding Potential ◽  
Healthy Controls ◽  
Time Activity ◽  
Tissue Compartment ◽  
Pet Tracer

Abstract Purpose The novel PET tracer [11C]SMW139 binds with high affinity to the P2X7 receptor, which is expressed on pro-inflammatory microglia. The purposes of this first in-man study were to characterise pharmacokinetics of [11C]SMW139 in patients with active relapsing remitting multiple sclerosis (RRMS) and healthy controls (HC) and to evaluate its potential to identify in vivo neuroinflammation in RRMS. Methods Five RRMS patients and 5 age-matched HC underwent 90-min dynamic [11C]SMW139 PET scans, with online continuous and manual arterial sampling to generate a metabolite-corrected arterial plasma input function. Tissue time activity curves were fitted to single- and two-tissue compartment models, and the model that provided the best fits was determined using the Akaike information criterion. Results The optimal model for describing [11C]SMW139 kinetics in both RRMS and HC was a reversible two-tissue compartment model with blood volume parameter and with the dissociation rate k4 fixed to the whole-brain value. Exploratory group level comparisons demonstrated an increased volume of distribution (VT) and binding potential (BPND) in RRMS compared with HC in normal appearing brain regions. BPND in MS lesions was decreased compared with non-lesional white matter, and a further decrease was observed in gadolinium-enhancing lesions. In contrast, increased VT was observed in enhancing lesions, possibly resulting from disruption of the blood-brain barrier in active MS lesions. In addition, there was a high correlation between parameters obtained from 60- to 90-min datasets, although analyses using 60-min data led to a slight underestimation in regional VT and BPND values. Conclusions This first in-man study demonstrated that uptake of [11C]SMW139 can be quantified with PET using BPND as a measure for specific binding in healthy controls and RRMS patients. Additional studies are warranted for further clinical evaluation of this novel neuroinflammation tracer.

scholarly journals Clinical evaluation of [18F] JNJ-64326067, a novel candidate PET tracer for the detection of tau pathology in Alzheimer’s disease

2020 ◽  
Vol 47 (13) ◽  
pp. 3176-3185
Author(s):  
Mark E. Schmidt ◽  
Luc Janssens ◽  
Diederik Moechars ◽  
Frederik J. R. Rombouts ◽  
Maarten Timmers ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Healthy Subjects ◽  
Graphical Analysis ◽  
Whole Body ◽  
Healthy Controls ◽  
Pet Tracer ◽  
Cortical Regions ◽  
Pet Scans ◽  
Pet Amyloid

Abstract Purpose The accumulation of misfolded tau is a common feature of several neurodegenerative disorders, with Alzheimer’s disease (AD) being the most common. Earlier we identified JNJ-64326067, a novel isoquinoline derivative with high affinity and selectivity for tau aggregates from human AD brain. We report the dosimetry of [18F] JNJ-64326067 and results of a proof-of-concept study comparing subjects with probable Alzheimer’s disease to age-matched healthy controls. Methods [18F] JNJ-64326067 PET scans were acquired for 90 min and then from 120 to 180 min in 5 participants with [18F]-florbetapir PET amyloid positive probable AD (73 ± 9 years) and 5 [18F]-florbetapir PET amyloid negative healthy controls (71 ± 7 years). Whole-body [18F] JNJ-64326067 PET CT scans were acquired in six healthy subjects for 5.5 h in 3 scanning sessions. Brain PET scans were visually reviewed. Regional quantification included kinetic analysis of distribution volume ration (DVR) estimated by Logan graphical analysis over the entire scan and static analysis of SUVr in late frames. Both methods used ventral cerebellar cortex as a reference region. Results One of the healthy controls had focal areas of PET signal in occipital and parietal cortex underlying the site of a gunshot injury as an adolescent; the other four healthy subjects had no tau brain signal. Four of the 5 AD participants had visually apparent retention of [18F] JNJ-64326067 in relevant cortical regions. One of the AD subjects was visually negative. Cortical signal in visually positive subjects approached steady state by 120 min. Temporal and frontal cortical SUVr/DVR values in visually positive AD subjects ranged from 1.21 to 3.09/1.2 to 2.18 and from 0.92 to 1.28/0.91 to 1.16 in healthy controls. Whole-body effective dose was estimated to be 0.0257 mSv/MBq for females and 0.0254 mSv/MBq for males. Conclusions [18F] JNJ-64326067 could be useful for detection and quantitation of tau aggregates.

Effect of dihydroergocristine administration on serum prolactin and growth hormone levels in normal, hyperprolactinaemic, and acromegalic subjects: further evidence for pituitary dopamine deficiency in these conditions

1983 ◽  
Vol 103 (1) ◽  
pp. 1-6 ◽  
Author(s):  
C. Ferrari ◽  
M. Romussi ◽  
R. Benco ◽  
P. Rampini ◽  
F. Mailland
Keyword(s):  
Growth Hormone ◽  
Healthy Subjects ◽  
Normal Subjects ◽  
Serum Prolactin ◽  
Pharmacological Properties ◽  
Healthy Controls ◽  
Oral Doses ◽  
Resumption Of Menses ◽  
Lowering Activity

Abstract. To evaluate further the pharmacological properties of dihydroergocristine in vivo, this drug (6 mg) or a placebo were administered orally on separate days to 11 healthy controls, 11 patients with adenomatous (n = 4) or idiopathic hyperprolactinaemia (n = 7), and 5 acromegalics with raised serum prolactin levels; serum prolactin (Prl) and growth hormone (GH) were measured at hourly intervals for 6 h. Dihydroergocristine induced a significant Prl decrease versus placebo in hyperprolactinaemics and acromegalics, but had no effect in healthy subjects. GH levels did not change in normals and hyperprolactinaemics, but decreased significantly in acromegalics. The Prl decrease induced by dihydroergocristine was significantly lower than that induced by l-dopa (500 mg po) in 9 hyperprolactinaemics so tested. Nomifensine (200 mg po) administered to 7 hyperprolactinaemics had no effect. Similarly, the GH decrease induced by the drug in acromegalics was significantly lower than that exerted by l-dopa, while nomifensine had no effect. Five hyperprolactinaemic patients were also given 12–18 mg dihydroergocristine daily for 3 months. There was evidence of partial or total Prl suppression and resumption of menses in all patients. These data indicate that dihydroergocristine is a relatively weak dopamine agonist at pituitary level and that oral doses, insufficient to exert Prl-lowering activity in normal subjects, are able to inhibit Prl and GH release in hyperprolactinaemics and dopamine-responsive acromegalics. These findings further support the existence of a 'denervation' supersensitivity to dopamine in these conditions, in which dopamine deficiency at pituitary level has been suggested on the basis of other experiments.

scholarly journals Staging and quantification of florbetaben PET images using machine learning: impact of predicted regional cortical tracer uptake and amyloid stage on clinical outcomes

2019 ◽  
Vol 47 (8) ◽  
pp. 1971-1983 ◽  
Author(s):  
Jun Pyo Kim ◽  
Jeonghun Kim ◽  
Yeshin Kim ◽  
Seung Hwan Moon ◽  
Yu Hyun Park ◽  
...  
Keyword(s):  
Machine Learning ◽  
Learning Algorithm ◽  
Tracer Uptake ◽  
Mediation Effect ◽  
Support Vector ◽  
Amyloid Pet ◽  
Mediation Effects ◽  
Pet Tracer ◽  
The Impact

Abstract Purpose We developed a machine learning–based classifier for in vivo amyloid positron emission tomography (PET) staging, quantified cortical uptake of the PET tracer by using a machine learning method, and investigated the impact of these amyloid PET parameters on clinical and structural outcomes. Methods A total of 337 18F-florbetaben PET scans obtained at Samsung Medical Center were assessed. We defined a feature vector representing the change in PET tracer uptake from grey to white matter. Using support vector machine (SVM) regression and SVM classification, we quantified the cortical uptake as predicted regional cortical tracer uptake (pRCTU) and categorised the scans as positive and negative. Positive scans were further classified into two stages according to the striatal uptake. We compared outcome parameters among stages and further assessed the association between the pRCTU and outcome variables. Finally, we performed path analysis to determine mediation effects between PET variables. Results The classification accuracy was 97.3% for cortical amyloid positivity and 91.1% for striatal positivity. The left frontal and precuneus/posterior cingulate regions, as well as the anterior portion of the striatum, were important in determination of stages. The clinical scores and magnetic resonance imaging parameters showed negative associations with PET stage. However, except for the hippocampal volume, most outcomes were associated with the stage through the complete mediation effect of pRCTU. Conclusion Using a machine learning algorithm, we achieved high accuracy for in vivo amyloid PET staging. The in vivo amyloid stage was associated with cognitive function and cerebral atrophy mostly through the mediation effect of cortical amyloid.

scholarly journals Synthesis and Initial Characterization of a Reversible, Selective 18F-Labeled Radiotracer for Human Butyrylcholinesterase

2021 ◽  
Author(s):  
Christian Gentzsch ◽  
Xinyu Chen ◽  
Philipp Spatz ◽  
Urban Košak ◽  
Damijan Knez ◽  
...  
Keyword(s):  
Dissociation Constants ◽  
Colorimetric Assay ◽  
Amyloid Β ◽  
Radiochemical Yield ◽  
Time Frame ◽  
Binding Potential ◽  
Pet Tracer ◽  
Imaging Probes

Abstract Purpose A neuropathological hallmark of Alzheimer’s disease (AD) is the presence of amyloid-β (Aβ) plaques in the brain, which are observed in a significant number of cognitively normal, older adults as well. In AD, butyrylcholinesterase (BChE) becomes associated with Aβ aggregates, making it a promising target for imaging probes to support diagnosis of AD. In this study, we present the synthesis, radiochemistry, in vitro and preliminary ex and in vivo investigations of a selective, reversible BChE inhibitor as PET-tracer for evaluation as an AD diagnostic. Procedures Radiolabeling of the inhibitor was achieved by fluorination of a respective tosylated precursor using K[18F]. IC50 values of the fluorinated compound were obtained in a colorimetric assay using recombinant, human (h) BChE. Dissociation constants were determined by measuring hBChE activity in the presence of different concentrations of inhibitor. Results Radiofluorination of the tosylate precursor gave the desired radiotracer in an average radiochemical yield of 20 ± 3 %. Identity and > 95.5 % radiochemical purity were confirmed by HPLC and TLC autoradiography. The inhibitory potency determined in Ellman’s assay gave an IC50 value of 118.3 ± 19.6 nM. Dissociation constants measured in kinetic experiments revealed lower affinity of the inhibitor for binding to the acylated enzyme (K2 = 68.0 nM) in comparison to the free enzyme (K1 = 32.9 nM). Conclusions The reversibly acting, selective radiotracer is synthetically easily accessible and retains promising activity and binding potential on hBChE. Radiosynthesis with 18F labeling of tosylates was feasible in a reasonable time frame and good radiochemical yield.

scholarly journals Synthesis and Biological Evaluation of a Radiolabeled PET Probe for Visualization of In Vivo α-Fucosidase Expression

2021 ◽  
Vol 14 (8) ◽  
pp. 745
Author(s):  
Jonathan Cotton ◽  
Chris Marc Goehring ◽  
Anna Kuehn ◽  
Andreas Maurer ◽  
Kerstin Fuchs ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Sodium Hydride ◽  
Biological Evaluation ◽  
Tracer Uptake ◽  
Mouse Serum ◽  
Molar Activity ◽  
Pet Tracer ◽  
Positron Emission

The acidic hydrolase α-fucosidase (AF) is a biomarker for maladies such as cancer and inflammation. The most advanced probes for α-fucosidase are unfortunately constrained to ex vivo or in vitro applications. The in vivo detection and quantification of AF using positron emission tomography would allow for better discovery and diagnosis of disease as well as provide better understanding of disease progression. We synthesized, characterized, and evaluated a radiolabeled small molecule inhibitor of AF based on a known molecule. The radiosynthesis involved the 11C methylation of a phenoxide, which was generated in situ by ultrasonification of the precursor with sodium hydride. The tracer was produced with a decay corrected yield of 41.7 ± 16.5% and had a molar activity of 65.4 ± 30.3 GBq/μmol. The tracer was shown to be stable in mouse serum at 60 min. To test the new tracer, HCT116 colorectal carcinoma cells were engineered to overexpress human AF. In vitro evaluation revealed 3.5-fold higher uptake in HCT116AF cells compared to HCT116 controls (26.4 ± 7.8 vs. 7.5 ± 1.0 kBq/106 cells). Static PET scans 50 min post injection revealed 2.5-fold higher tracer uptake in the HCT116AF tumors (3.0 ± 0.8%ID/cc (n = 6)) compared with the controls (1.2 ± 0.8 (n = 5)). Dynamic scans showed higher uptake in the HCT116AF tumors at all time-points (n = 2). Ex vivo analysis of the tumors, utilizing fluorescent DDK2 antibodies, confirmed the expression of human AF in the HCT116AF xenografts. We have developed a novel PET tracer to image AF in vivo and will now apply this to relevant disease models.

In vivo molecular imaging reveals distinct distributions of the serotonin transporter, the major inhibitory and excitatory serotonin receptors

2011 ◽  
Vol 26 (S2) ◽  
pp. 953-953
Author(s):  
M. Savli ◽  
A. Bauer ◽  
D. Häusler ◽  
T. Kroll ◽  
A. Hahn ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Receptor Expression ◽  
Binding Potential ◽  
Common Mechanism ◽  
List Type ◽  
Genetic Studies ◽  
Specific Effects ◽  
Way 100635 ◽  
Topological Pattern

IntroductionBased on evidences in molecular neuroimaging, postmortem and genetic studies, impaired serotonergic neurotransmission has been implicated with affective disorders. Moreover, a growing number of evidences showed strong interrelations within the serotonergic system suggesting a common mechanism in the modulation of receptor and transporter densities.ObjectiveHere we directly investigated the regional expression of the 5-HT1A, 5-HT2A and 5-HTT using PET and the three highly selective and specific radioligands [carbonyl-11C]WAY-100635, [18F]Altanserin and [11C]DASB in healthy subjects.MethodsA total of 55 healthy subjects (5-HT1A: 36 subjects, 18 males, age = 26.0 ± 4.9; 5-HT2A: 19 subjects, 11 males, age = 28.2 ± 5.9; 5-HTT: 8 males, age = 28.12 ± 3.6) were included in this study. Binding potential (BPND) values were quantified according to the AAL parcellation scheme.ResultsBPND values averaged over both hemispheres ranged from 0.40–6.35 for the 5-HT1A receptor; 0.01–2.01 for the 5-HT2A receptor and 0.09–2.05 for the 5-HTT, respectively. There was a specific topological pattern according to the ratio between the 5-HT1A, 5-HT2A receptors and 5-HTT (“fingerprints”).ConclusionsSuch information can be essential for detecting potential local alterations in the ratio between different binding proteins on a network level in pathological conditions.Moreover, these data might provide further insight in area-specific effects of frequently prescribed selective serotonin re-uptake inhibitors (SSRI): 1)due to the distinct local receptor and transporter availability;2)SSRI application alters the postsynaptic receptor expression and thus;3)leads to a modified interaction of inhibitory and exhibitory receptors.

scholarly journals Neurodevelopmental indices and the development of psychotic symptoms in subjects at high risk of schizophrenia

2001 ◽  
Vol 178 (6) ◽  
pp. 524-530 ◽  
Author(s):  
Stephen M. Lawrie ◽  
Majella Byrne ◽  
Patrick Miller ◽  
Ann Hodges ◽  
Robert A. Clafferty ◽  
...  
Keyword(s):  
High Risk ◽  
Sensory Integration ◽  
Healthy Subjects ◽  
Psychotic Symptoms ◽  
First Episode ◽  
Healthy Controls ◽  
Genetic Associations ◽  
Genetic Liability ◽  
Minor Physical Anomalies ◽  
Drug Free

BackgroundNeurological ‘soft signs’ and minor physical anomalies (MPAs) are reported to be more frequent in patients with schizophrenia than in controls.AimsTo determine whether these disturbances are genetically mediated, and whether they are central to the genesis of symptoms or epiphenomena.MethodWe obtained ratings in 152 individuals who were antipsychotic drug-free and at high risk, some of whom had experienced psychotic symptoms, as well as 30 first-episode patients and 35 healthy subjects.ResultsMPAs and Neurological Evaluation Scale (NES) ‘sensory integration abnormalities’ were more frequent in high-risk subjects than in healthy controls, but there were no reliable differences between high-risk subjects with and without psychotic symptoms. MPAs were most frequent in high-risk subjects with least genetic liability and NES scores showed no genetic associations.ConclusionsThe lack of associations with psychotic symptoms and genetic liability to schizophrenia suggests that soft signs and physical anomalies are non-specific markers of developmental deviance that are not mediated by the gene(s) for schizophrenia.

scholarly journals Neuroinflammation in schizophrenia: meta-analysis of in vivo microglial imaging studies

2018 ◽  
Vol 49 (13) ◽  
pp. 2186-2196 ◽  
Author(s):  
Tiago Reis Marques ◽  
Abhishekh H Ashok ◽  
Toby Pillinger ◽  
Mattia Veronese ◽  
Federico E. Turkheimer ◽  
...  
Keyword(s):  
Outcome Measure ◽  
Meta Analysis ◽  
Volume Of Distribution ◽  
Axonal Guidance ◽  
Translocator Protein ◽  
Binding Potential ◽  
Healthy Controls ◽  
Imaging Studies ◽  
The Difference

AbstractBackgroundConverging lines of evidence implicate an important role for the immune system in schizophrenia. Microglia are the resident immune cells of the central nervous system and have many functions including neuroinflammation, axonal guidance and neurotrophic support. We aimed to provide a quantitative review of in vivo PET imaging studies of microglia activation in patients with schizophrenia compared with healthy controls.MethodsDemographic, clinical and imaging measures were extracted from each study and meta-analysis was conducted using a random-effects model (Hedge's g). The difference in 18-kDa translocator protein (TSPO) binding between patients with schizophrenia and healthy controls, as quantified by either binding potential (BP) or volume of distribution (VT), was used as the main outcome. Sub-analysis and sensitivity analysis were carried out to investigate the effects of genotype, ligand and illness stage.ResultsIn total, 12 studies comprising 190 patients with schizophrenia and 200 healthy controls met inclusion criteria. There was a significant elevation in tracer binding in schizophrenia patients relative to controls when BP was used as an outcome measure, (Hedge's g = 0.31; p = 0.03) but no significant differences when VT was used (Hedge's g = −0.22; p = 0.29).ConclusionsIn conclusion, there is evidence for moderate elevations in TSPO tracer binding in grey matter relative to other brain tissue in schizophrenia when using BP as an outcome measure, but no difference when VT is the outcome measure. We discuss the relevance of these findings as well as the methodological issues that may underlie the contrasting difference between these outcomes.

scholarly journals Development and preclinical evaluation of [68Ga]Ga-Alb-FAPtp-01, a novel tumour-associated fibroblast activation protein tracer for PET imaging of xenograft glioma

2021 ◽  
Author(s):  
Jia-Jia Lin ◽  
Chia-Pao Chuang ◽  
Jia-Yu Lin ◽  
Feng-Ting Huang ◽  
chiun-wei Huang
Keyword(s):  
Pet Imaging ◽  
Specific Binding ◽  
Fibroblast Activation Protein ◽  
Tracer Uptake ◽  
Cell Uptake ◽  
Response Monitoring ◽  
Tumour Uptake ◽  
Fibroblast Activation ◽  
Pet Tracer

Abstract Purpose Dynamic changes in tumour-associated fibroblast activation protein (FAP) expression in tumours of different stages may be helpful for prognostic evaluation and treatment response monitoring, making this protein a promising surveillance biomarker for timely diagnosis of malignant tumours and effective planning of patient care. Thus, novel FAP-PET imaging tracers were developed and evaluated for the diagnosis of xenograft glioma tumours. Methods To prospectively verify the prognostic value of the developed FAP tracers, [68Ga]Ga-FAPtp and [68Ga]Ga-Alb-FAPtp-01, measurements of FAP expression and cell uptake and specific binding assays were conducted in U87MG glioma cells. Dynamic/static PET/CT scans were acquired for tumour targeting studies in vivo and in comparison with the reference tracer [68Ga]Ga-FAPI-04 to evaluate diagnostic efficacy. Tumour autoradiography and immunohistochemistry images were acquired to confirm the tracer distribution within the tumour to determine whether it was in accordance with the pathologic data. Results Both [68Ga]Ga-FAPI-04 and [68Ga]Ga-FAPtp demonstrated marked tumour uptake and comparable pharmaceutical profiles in 1 h dynamic PET scans, and [68Ga]Ga-FAPtp had marginally favourable tumour uptake and less kidney and liver uptake. However, both tracers demonstrated rapid clearance from tumours. Thus, the optimized rationally designed FAP-targeting PET tracer [68Ga]Ga-Alb-FAPtp-01, with albumin binding capability, demonstrated prominent longitudinal tumour uptake in tumour xenografts and displayed significant tumour-to-background contrast over time. The tracer uptake values and T/M ratio were 1.775 ± 0.179 SUV and T/M = 5.9, 1.533 ± 0.222 SUV and T/M = 6.7, and 1.425 ± 0.204 SUV and T/M = 9.5, respectively, at 1 h, 2 h and 3 h. Major organs, such as the heart (0.504 ± 0.125% ID/g), muscle (0.156 ± 0.043% ID/g) and brain (0.119 ± 0.039% ID/g), all displayed comparatively low levels of tracer uptake. Conclusion Its improved tumour uptake and pharmacokinetics suggest that the [68Ga]Ga-Alb-FAPtp-01 tracer can noninvasively detect FAP activation in vivo, permitting a precise definition of its roles in tumours of different stages and yielding insights regarding novel FAP-targeted radiotherapeutic strategies at the molecular level.

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