scholarly journals [18F]F13640, a 5-HT1A Receptor Radiopharmaceutical Sensitive to Brain Serotonin Fluctuations

2021 ◽  
Vol 15 ◽  
Author(s):  
Matthieu Colom ◽  
Benjamin Vidal ◽  
Sylvain Fieux ◽  
Jérôme Redoute ◽  
Nicolas Costes ◽  
...  
Keyword(s):  
Intravenous Injection ◽  
Gray Matter ◽  
Dissociation Rate ◽  
Serotonin Release ◽  
Pet Scan ◽  
Anterior Cingulate ◽  
Acquisition Time ◽  
Positron Emission ◽  
Pet Radiopharmaceutical

IntroductionSerotonin is involved in a variety of physiological functions and brain disorders. In this context, efforts have been made to investigate the in vivo fluctuations of this neurotransmitter using positron emission tomography (PET) imaging paradigms. Since serotonin is a full agonist, it binds preferentially to G-protein coupled receptors. In contrast, antagonist PET ligands additionally interact with uncoupled receptors. This could explain the lack of sensitivity to serotonin fluctuations of current 5-HT1A radiopharmaceuticals which are mainly antagonists and suggests that agonist radiotracers would be more appropriate to measure changes in neurotransmitter release. The present study evaluated the sensitivity to endogenous serotonin release of a recently developed, selective 5-HT1A receptor PET radiopharmaceutical, the agonist [18F]F13640 (a.k.a. befiradol or NLX-112).Materials and MethodsFour cats each underwent three PET scans with [18F]F13640, i.e., a control PET scan of 90 min, a PET scan preceded 30 min before by an intravenous injection 1 mg/kg of d-fenfluramine, a serotonin releaser (blocking challenge), and a PET scan comprising the intravenous injection of 1 mg/kg of d-fenfluramine 30 min after the radiotracer injection (displacement challenge). Data were analyzed with regions of interest and voxel-based approaches. A lp-ntPET model approach was implemented to determine the dynamic of serotonin release during the challenge study.ResultsD-fenfluramine pretreatment elicited a massive inhibition of [18F]F13640 labeling in regions known to express 5-HT1A receptors, e.g., raphe nuclei, hippocampus, thalamus, anterior cingulate cortex, caudate putamen, occipital, frontal and parietal cortices, and gray matter of cerebellum. Administration of d-fenfluramine during PET acquisition indicates changes in occupancy from 10% (thalamus) to 31% (gray matter of cerebellum) even though the dissociation rate of [18F]F13640 over the 90 min acquisition time was modest. The lp-ntPET simulation succeeded in differentiating the control and challenge conditions.ConclusionThe present findings demonstrate that labeling of 5-HT1A receptors with [18F]F13640 is sensitive to serotonin concentration fluctuations in vivo. Although the data underline the need to perform longer PET scan to ensure accurate measure of displacement, they support clinical development of [18F]F13640 as a tool to explore experimental paradigms involving physiological or pathological (neurological or neuropsychiatric pathologies) fluctuations of extracellular serotonin.

Cerebral Metabolism during Propofol Anesthesia in Humans Studied with Positron Emission Tomography 

1995 ◽  
Vol 82 (2) ◽  
pp. 393-403 ◽  
Author(s):  
Michael T. Alkire ◽  
Richard J. Haier ◽  
Steven J. Barker ◽  
Nitin K. Shah ◽  
Joseph C. Wu ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Animal Studies ◽  
Cerebral Metabolism ◽  
Anterior Cingulate ◽  
Emission Tomography ◽  
Whole Brain ◽  
Metabolic Pattern ◽  
Positron Emission ◽  
Cortical Regions

Background Although the effects of propofol on cerebral metabolism have been studied in animals, these effects have yet to be directly examined in humans. Consequently, we used positron emission tomography (PET) to demonstrate in vivo the regional cerebral metabolic changes that occur in humans during propofol anesthesia. Methods Six volunteers each underwent two PET scans; one scan assessed awake-baseline metabolism, and the other assessed metabolism during anesthesia with a propofol infusion titrated to the point of unresponsiveness (mean rate +/- SD = 7.8 +/- 1.5 mg.kg-1.h-1). Scans were obtained using the 18fluorodeoxyglucose technique. Results Awake whole-brain glucose metabolic rates (GMR) averaged 29 +/- 8 mumoles.100 g-1.min-1 (mean +/- SD). Anesthetized whole-brain GMR averaged 13 +/- 4 mumoles.100 g-1.min-1 (paired t test, P < or = 0.007). GMR decreased in all measured areas during anesthesia. However, the decrease in GMR was not uniform. Cortical metabolism was depressed 58%, whereas subcortical metabolism was depressed 48% (P < or = 0.001). Marked differences within cortical regions also occurred. In the medial and subcortical regions, the largest percent decreases occurred in the left anterior cingulate and the inferior colliculus. Conclusion Propofol produced a global metabolic depression on the human central nervous system. The metabolic pattern evident during anesthesia was reproducible and differed from that seen in the awake condition. These findings are consistent with those from previous animal studies and suggest PET may be useful for investigating the mechanisms of anesthesia in humans.

Nuclear Medicine Imaging and Therapy in Rheumatology

2013 ◽  
pp. 531-539
Author(s):  
Adil Al-Nahhas ◽  
Imene Zerizer
Keyword(s):  
Nuclear Medicine ◽  
Gamma Camera ◽  
Structural Changes ◽  
Response To Treatment ◽  
Nuclear Medicine Imaging ◽  
Inflammatory Conditions ◽  
Positron Emission ◽  
Pet Radiopharmaceutical ◽  
Monitoring Response

The application of nuclear medicine techniques in the diagnosis and management of rheumatological conditions relies on its ability to detect physiological and pathological changes in vivo, usually at an earlier stage compared to structural changes visualized on conventional imaging. These techniques are based on the in-vivo administration of a gamma-emitting radionuclide whose distribution can be monitored externally using a gamma camera. To guide a radionuclide to the area of interest, it is usually bound to a chemical label to form a ’radiopharmaceutical’. There are hundreds of radiopharmaceuticals in clinical use with different ’homing’ mechanisms, such as 99 mTc HDP for bone scan and 99 mTc MAA for lung scan. Comparing pre- and posttherapy scans can aid in monitoring response to treatment. More recently, positron emission tomography combined with simultaneous computed tomography (PET/CT) has been introduced into clinical practice. This technique provides superb spatial resolution and anatomical localization compared to gamma-camera imaging. The most widely used PET radiopharmaceutical, flurodeoxyglucose (18F-FDG), is a fluorinated glucose analogue, which can detect hypermetabolism and has therefore been used in imaging and monitoring response to treatment of a variety of cancers as well as inflammatory conditions such as vasculitis, myopathy, and arthritides. Other PET radiopharmaceuticals targeting inflammation and activated macrophages are becoming available and could open new frontiers in PET imaging in rheumatology. Nuclear medicine procedures can also be used therapeutically. Beta-emitting radiopharmaceuticals, such as yttrium-90, invoke localized tissue damage at the site of injection and can be used in the treatment of synovitis.

scholarly journals Confirmation of Fenfluramine Effect on 5-HT1B Receptor Binding of [11C]AZ10419369 using an Equilibrium Approach

2011 ◽  
Vol 32 (4) ◽  
pp. 685-695 ◽  
Author(s):  
Sjoerd J Finnema ◽  
Andrea Varrone ◽  
Tzung-Jeng Hwang ◽  
Christer Halldin ◽  
Lars Farde
Keyword(s):  
Specific Binding ◽  
Occipital Cortex ◽  
Serotonin Release ◽  
Binding Potential ◽  
Bolus Administration ◽  
Positron Emission ◽  
Equilibrium Approach ◽  
Induced Changes ◽  
Dose Dependent

Assessment of serotonin release in the living brain with positron emission tomography (PET) may have been hampered by the lack of suitable radioligands. We previously reported that fenfluramine caused a dose-dependent reduction in specific binding in monkeys using a classical displacement paradigm with bolus administration of [11C]AZ10419369. The aim of this study was to confirm our previous findings using an equilibrium approach in monkey. A total of 24 PET measurements were conducted using a bolus infusion protocol of [11C]AZ10419369 in three cynomolgus monkeys. Initial PET measurements were performed to assess suitable Kbol values. The fenfluramine effect on [11C]AZ10419369 binding was evaluated in a displacement and pretreatment paradigm. The effect of fenfluramine on [11C]AZ10419369 binding potential ( BPND) was dose-dependent in the displacement paradigm and confirmed in the pretreatment paradigm. After pretreatment administration of fenfluramine (5.0 mg/kg), the mean BPND of the occipital cortex decreased by 39%, from 1.38 ± 0.04 to 0.84 ± 0.09. This study confirms that the new 5-HT1B receptor radioligand [11C]AZ10419369 is sensitive to fenfluramine-induced changes in endogenous serotonin levels in vivo. The more advanced methodology is suitable for exploring the sensitivity limit to serotonin release as measured using [11C]AZ10419369 and PET.

scholarly journals On the Uniqueness of Cerebral Blood Flow Measured by the in vivo Autoradiographic Strategy and Positron Emission Tomography

1983 ◽  
Vol 3 (4) ◽  
pp. 432-441 ◽  
Author(s):  
Bernard E. Howard ◽  
Myron D. Ginsberg ◽  
William R. Hassel ◽  
Alan H. Lockwood ◽  
Philip Freed
Keyword(s):  
Positron Emission Tomography ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Regional Blood Flow ◽  
Normal Subjects ◽  
Pet Scan ◽  
Emission Tomography ◽  
Start Time ◽  
Positron Emission

Factors are examined in this report which govern the uniqueness and sensitivity of regional cerebral blood flow (rCBF), as determined by an in vivo autoradiographic strategy and positron emission tomography (PET), and a series of theorems is derived which specify conditions under which a unique relationship between cumulative cranial activity of the tracer ( C) and regional blood flow ( f) may be assured. It is demonstrated that, independent of the specific form of the arterial tracer input function, flow is a unique function of C whenever the start time ( T1) of the PET scan is coincident with the start of tracer infusion. Other theorems state that, even for nonzero T1s, a unique solution for flow may be expected, as long as the duration of the scan is sufficiently short. The implementation of this theory is illustrated using arterial tracer activity curves obtained in three normal subjects by a multiple arterial sampling procedure following the bolus i. v. infusion of 20–30 μCi of [15O]water. Based on these arterial curves, it is confirmed that the C vs. f relationship resulting from scan parameters T1 = 0 and T2 = 1.5 min (i.e., a PET scan of 90 s commencing with tracer infusion) has an excellent separation of flow values within the range of physiological interest, whereas a 90-s scan beginning at time T1 = 1.7 min results in poorer separation of flow values and loss of the monotonic relationship between C and f at higher flows. The results of this study serve to clarify the in vivo autoradiographic method for measuring rCBF in humans and help to define favorable study parameters for assuring uniqueness and sensitivity of the flow measurement.

scholarly journals Measurement of Radiotracer Concentration in Brain Gray Matter Using Positron Emission Tomography: MRI-Based Correction for Partial Volume Effects

1992 ◽  
Vol 12 (4) ◽  
pp. 571-583 ◽  
Author(s):  
Hans W. Müller-Gärtner ◽  
Jonathan M. Links ◽  
Jerry L. Prince ◽  
R. Nick Bryan ◽  
Elliot McVeigh ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Computer Simulations ◽  
Gray Matter ◽  
Emission Tomography ◽  
Tracer Concentration ◽  
Partial Volume ◽  
Partial Volume Effects ◽  
Positron Emission ◽  
Volume Effects

Accuracy in in vivo quantitation of brain function with positron emission tomography (PET) has often been limited by partial volume effects. This limitation becomes prominent in studies of aging and degenerative brain diseases where partial volume effects vary with different degrees of atrophy. The present study describes how the actual gray matter (GM) tracer concentration can be estimated using an algorithm that relates the regional fraction of GM to partial volume effects. The regional fraction of GM was determined by magnetic resonance imaging (MRI). The procedure is designated as GM PET. In computer simulations and phantom studies, the GM PET algorithm permitted a 100% recovery of the actual tracer concentration in neocortical GM and hippocampus, irrespective of the GM volume. GM PET was applied in a test case of temporal lobe epilepsy revealing an increase in radiotracer activity in GM that was undetected in the PET image before correction for partial volume effects. In computer simulations, errors in the segmentation of GM and errors in registration of PET and MRI images resulted in less than 15% inaccuracy in the GM PET image. In conclusion, GM PET permits accurate determination of the actual radiotracer concentration in human brain GM in vivo. The method differentiates whether a change in the apparent radiotracer concentration reflects solely an alteration in GM volume or rather a change in radiotracer concentration per unit volume of GM.

scholarly journals The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ellis Chika Onwordi ◽  
Thomas Whitehurst ◽  
Ayla Mansur ◽  
Ben Statton ◽  
Alaine Berry ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Healthy Volunteers ◽  
Imaging Study ◽  
Volume Ratio ◽  
Anterior Cingulate ◽  
Resonance Spectroscopy ◽  
Synaptic Density ◽  
Positron Emission

AbstractGlutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ). Forty volunteers (SCZ n = 18, HV n = 22) underwent [11C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS) imaging in the left hippocampus and anterior cingulate cortex (ACC) to index [11C]UCB-J distribution volume ratio (DVR), and creatine-scaled glutamate (Glu/Cr), glutamate and glutamine (Glx/Cr) and NAA (NAA/Cr). In healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glu/Cr, in both the hippocampus and ACC. Furthermore, in healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glx/Cr, in both the hippocampus and ACC. There were no significant relationships between [11C]UCB-J DVR and NAA/Cr in the hippocampus or ACC in healthy volunteers or patients. Therefore, an appreciable proportion of the brain 1H-MRS glutamatergic signal is related to synaptic density in healthy volunteers. This relationship is not seen in schizophrenia, which, taken with lower synaptic marker levels, is consistent with lower levels of glutamatergic terminals and/or a lower proportion of glutamatergic relative to GABAergic terminals in the ACC in schizophrenia.

scholarly journals Fully Automated Radiosynthesis of [18f]lbt999on Tracerlab Fxfn and Allinonemodules, A Pet Radiopharmaceutical for Imaging the Dopamine Transporter in Human Brain

2020 ◽  
Author(s):  
Christine Vala ◽  
Céline Mothes ◽  
Gabrielle Chicheri ◽  
Pauline Magadur ◽  
Gilles Viot ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
Industrial Production ◽  
Radiochemical Purity ◽  
Acid Methyl Ester ◽  
Molar Activity ◽  
Positron Emission ◽  
Single Use ◽  
Radiochemical Yields ◽  
Pet Radiopharmaceutical

Abstract Background:Fluorine labelled 8-((E)-4-fluoro-but-2-enyl)-3b-p-tolyl-8-aza-bicyclo[3.2.1]octane-2b-carboxylic acid methyl ester ([18F]LBT999) is a selective radioligand for in vivoneuroimaging and quantification of the dopamine transporter by Positron Emission Tomography (PET). [18F]LBT999 has been produced on a TRACERlabFXFN for the Phase I study but forPhase III and a potent industrial production transfer, production has been also implemented on AllinOne (AIO)system requiring single use cassette. Both productions methods are reported herein. Results:Automation of [18F]LBT999radiosynthesis on FXFN was carried out in 35% yield (decay-corrected) in 65 min (n=16), with a radiochemical purity higher than 99 %and a molar activity of 158GBq/µmol at the end of synthesis. The transfer on the AIO platform followed by optimizations allowed the production of [18F]LBT999 in 32.7% yield (decay-corrected) within 48 min (n=5), with a radiochemical purity better than 98% and a molar activity in average higher to 154 GBq/µmol at the end of synthesis. Quality controls of both methods met the specification for clinical application.Conclusion:Both modules allow efficient and reproducible radiosynthesis of [18F]LBT999 with good radiochemical yields and a reasonable synthesis time.The developments made on AIO as its ability to meet pharmaceutical criteria and to more easily comply with GMP requirements make this approach as the best for a potent industrial production of the [18F]LBT999 and a future wider use.

scholarly journals Cerebral serotonin release correlates with [11C]AZ10419369 PET measures of 5-HT1B receptor binding in the pig brain

2017 ◽  
Vol 38 (7) ◽  
pp. 1243-1252 ◽  
Author(s):  
Louise M Jørgensen ◽  
Pia Weikop ◽  
Claus Svarer ◽  
Ling Feng ◽  
Sune H Keller ◽  
...  
Keyword(s):  
Spatial Information ◽  
Partial Agonist ◽  
Receptor Occupancy ◽  
Serotonin Release ◽  
Serotonin Level ◽  
Imaging Data ◽  
Pig Brain ◽  
Positron Emission ◽  
Acute Changes

Positron emission tomography (PET) can, when used with appropriate radioligands, non-invasively capture temporal and spatial information about acute changes in brain neurotransmitter systems. We here evaluate the 5-HT1B receptor partial agonist PET radioligand, [11C]AZ10419369, for its sensitivity to detect changes in endogenous cerebral serotonin levels, as induced by different pharmacological challenges. To enable a direct translation of PET imaging data to changes in brain serotonin levels, we compared the [11C]AZ10419369 PET signal in the pig brain to simultaneous measurements of extracellular serotonin levels with microdialysis after various acute interventions (saline, escitalopram, fenfluramine). The interventions increased the cerebral extracellular serotonin levels to two to six times baseline, with fenfluramine being the most potent pharmacological enhancer of serotonin release. The interventions induced a varying degree of decline in [11C]AZ10419369 binding in the brain, consistent with the occupancy competition model. The observed correlation between changes in the extracellular serotonin level in the pig brain and the 5-HT1B receptor occupancy indicates that [11C]AZ10419369 binding is sensitive to changes in endogenous serotonin levels to a degree equivalent to that reported of [11C]raclopride to dopamine, a much used approach to detect in vivo change in cerebral dopamine.

scholarly journals The Progress of Label-Free Optical Imaging in Alzheimer’s Disease Screening and Diagnosis

2021 ◽  
Vol 13 ◽  
Author(s):  
Kai Liu ◽  
Jiasong Li ◽  
Raksha Raghunathan ◽  
Hong Zhao ◽  
Xuping Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Optical Imaging ◽  
Imaging Techniques ◽  
Spectroscopic Imaging ◽  
Acquisition Time ◽  
Autofluorescence Imaging ◽  
Label Free ◽  
Positron Emission

As the major neurodegenerative disease of dementia, Alzheimer’s disease (AD) has caused an enormous social and economic burden on society. Currently, AD has neither clear pathogenesis nor effective treatments. Positron emission tomography (PET) and magnetic resonance imaging (MRI) have been verified as potential tools for diagnosing and monitoring Alzheimer’s disease. However, the high costs, low spatial resolution, and long acquisition time limit their broad clinical utilization. The gold standard of AD diagnosis routinely used in research is imaging AD biomarkers with dyes or other reagents, which are unsuitable for in vivo studies owing to their potential toxicity and prolonged and costly process of the U.S. Food and Drug Administration (FDA) approval for human use. Furthermore, these exogenous reagents might bring unwarranted interference to mechanistic studies, causing unreliable results. Several label-free optical imaging techniques, such as infrared spectroscopic imaging (IRSI), Raman spectroscopic imaging (RSI), optical coherence tomography (OCT), autofluorescence imaging (AFI), optical harmonic generation imaging (OHGI), etc., have been developed to circumvent this issue and made it possible to offer an accurate and detailed analysis of AD biomarkers. In this review, we present the emerging label-free optical imaging techniques and their applications in AD, along with their potential and challenges in AD diagnosis.

scholarly journals Kinetic Analysis of Central [76Br]Bromolisuride Binding to Dopamine D2 Receptors Studied by PET

1991 ◽  
Vol 11 (6) ◽  
pp. 914-925 ◽  
Author(s):  
Jacques Delforge ◽  
Christian Loc'h ◽  
Philippe Hantraye ◽  
Oscar Stulzaft ◽  
Marina Khalili-Varasteh ◽  
...  
Keyword(s):  
Kinetic Analysis ◽  
Specific Binding ◽  
Input Function ◽  
Dissociation Rate ◽  
Nonspecific Binding ◽  
Single Experiment ◽  
Tracer Injection ◽  
Positron Emission ◽  
Dissociation Rate Constants

The in vivo kinetic analysis of dopamine D2 receptors was obtained in baboon brain using positron emission tomography (PET) and [76Br]bromolisuride ([76Br]BLIS) as radioligand. An injection of a trace amount of [76Br]BLIS was followed 3 h later by an injection of a mixture of [76Br]BLIS and BLIS in the same syringe (coinjection experiment). A third injection performed at 6 h was either an excess of unlabeled ligand (displacement experiment) or a second coinjection. This protocol allowed us to evaluate in the striatum of each animal and after a single experiment the quantity of available receptors ( B′max) and the kinetic parameters including the association and dissociation rate constants ( k+1 VR and k–1, respectively, where VR is the volume of reaction). The cerebellum data were fitted using a model without specific binding. All the parameters were estimated using nonlinear mathematical models of the ligand-receptor interactions including or not including nonspecific binding. The plasma time-concentration curve was used as an input function after correction for the metabolites. An estimate of standard errors was obtained for each PET study and for each identified parameter using the covariance matrix. The average values of B′max and Kd VR were 73 ± 11 pmol/ml tissue and 1.9 ± 0.9 pmol/ml, respectively. The nonspecific binding was identifiable in the experiment where the last injection corresponded to a second coinjection. We found that ∼6% of the striatal binding was nonspecific after a tracer injection of [76Br]-BLIS. The nonspecific binding appeared to be reversible in the striatum but irreversible in the cerebellum.

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