scholarly journals Kinetic Evaluation of Positron-Emitting Muscarinic Receptor Ligands Employing Direct Intracarotid Injection

1996 ◽  
Vol 16 (6) ◽  
pp. 1280-1287 ◽  
Author(s):  
A. Buck ◽  
G. K. Mulholland ◽  
S. M. Papadopoulos ◽  
R. A. Koeppe ◽  
K. A. Frey
Keyword(s):  
Carotid Artery ◽  
Specific Activity ◽  
Specific Binding ◽  
Distribution Volume ◽  
External Carotid ◽  
Receptor Ligands ◽  
Kinetic Evaluation ◽  
Time Activity ◽  
Indwelling Catheters

The development and characterization of new receptor ligands for in vivo binding assays are often both lengthy and expensive. It is therefore desirable to predict the suitability of a ligand early in the process of its evaluation. In the present study, compartmental analysis following intracarotid ligand injection in the monkey is used to evaluate the in vivo kinetics of the muscarinic cholinergic receptor antagonists [11C]tropanyl benzilate ([11C]TRB) and [11C] N-methylpiperidyl benzilate ([11C]NMPB). Animals were implanted with chronic subcutaneous access ports and indwelling catheters with tips located in the common carotid artery, just proximal to its bifurcation. The external carotid artery was ligated to ensure selective tracer delivery through the internal carotid artery to the brain. Positron emission tomography was used to measure brain tissue time–activity curves following tracer injections. CBF was estimated from the clearance of [15O]H2O, and receptor ligand distributions were analyzed according to a physiologic model consisting of an intravascular compartment and nonspecific plus free and receptor-bound tissue ligand compartments. In [11C]TRB studies, marked reductions in the forward ligand-receptor binding rate and in both the total and the specific binding tissue-to-plasma volumes of ligand distribution were observed after scopolamine receptor blockade or with low administered specific activity. Conversely, neither the distribution volume of the nonspecific plus free ligand compartment nor the rate of ligand dissociation from receptor sites was affected. In [11C]NMPB studies, tissue compartments describing specific binding and nonsaturable components could not be reliably separated. The receptor-related term in this case, the total tissue-to-plasma distribution volume, demonstrated reduction after low specific activity ligand injection. Comparison of the two ligands suggests that NMPB interacts more rapidly with the receptors and has a lower apparent volume of distribution than does TRB. Thus, NMPB may be the more suitable ligand if accurate estimates of binding dissociation rate are limited by temporal constraints or if simplified, one-tissue-compartment analyses are used. The carotid injection method appears promising for the initial evaluation of ligand kinetics, permitting physiologic compartmental analyses without measurement of input functions or chromatography of blood samples.

scholarly journals Brain Uptake of the Acid Metabolites of F-18—Labeled WAY 100635 Analogs

2003 ◽  
Vol 23 (2) ◽  
pp. 249-260 ◽  
Author(s):  
Richard E. Carson ◽  
Yanjun Wu ◽  
Lixin Lang ◽  
Ying Ma ◽  
Margaret G. Der ◽  
...  
Keyword(s):  
Gray Matter ◽  
Specific Binding ◽  
Additional Term ◽  
Free Fraction ◽  
Brain Uptake ◽  
Activity Data ◽  
Time Activity ◽  
Arterial Blood ◽  
The Brain

The 5-HT1A ligands [F]FPWAY and [18F]FCWAY are metabolized in vivo to [18F]fluorobenzoic acid (FB) and [18F]fluorocyclohexanecarboxylic acid (FC), respectively. To quantify the penetration of these acids into the brain, dynamic positron emission tomography studies were performed in rhesus monkeys with [18F]FB and [18F]FC. High-performance liquid chromatography analysis of arterial blood samples showed no metabolites for [18F]FB, whereas [18F]FC was rapidly metabolized to [18F]fluoride. A model with one tissue compartment and vascular radioactivity was used to analyze gray matter time-activity curves. For [18F]FC, an additional term was added to account for [18F]fluoride skull spillover into the brain; this term accounted for 70% to 90% of the measured radioactivity concentration at 90 minutes. For [18F]FB, mean gray matter parameters were as follows: K1, 10 ± 3 μL · min−1 · mL−1; distribution volume V, 0.052 ± 0.006 (mL/mL). For [18F]FC, the values were as follows: K1, 15 ± 4 μL · min−1 · mL−1; V, 0.29 ± 0.06 mL/mL. The V values were consistent with a physiologic model that included brain-to-blood pH difference and the plasma free fraction of the acid. Simulations based on [18F]FCWAY human data showed that [18F]FC uptake produces significant biases in V estimates in regions with low specific binding. These results can be used to correct the tissue [18F]FCWAY time-activity data for brain uptake of [18F]FC using the measured [18F]FC input function.

scholarly journals Kinetic Modeling of [11C]Raclopride: Combined PET-Microdialysis Studies

1997 ◽  
Vol 17 (9) ◽  
pp. 932-942 ◽  
Author(s):  
Christopher J. Endres ◽  
Bhaskar S. Kolachana ◽  
Richard C. Saunders ◽  
Tom Su ◽  
Daniel Weinberger ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Specific Binding ◽  
Compartment Model ◽  
Emission Tomography ◽  
Extended Model ◽  
Simulation Studies ◽  
Time Activity ◽  
Endogenous Dopamine ◽  
Positron Emission

The in vivo binding of D2 receptor ligands can be affected by agents that alter the concentration of endogenous dopamine. To define a more explicit relation between dopamine and D2 receptor binding, the conventional compartment model for reversible ligands has been extended to account for a time-varying dopamine pulse. This model was tested with [11C]raclopride positron emission tomography and dopamine microdialysis data that were acquired simultaneously in rhesus monkeys. The microdialysis data were incorporated into the model assuming a proportional relation to synaptic dopamine. Positron emission tomography studies used a bolus-plus-infusion tracer delivery with amphetamine given at 40 minutes to induce dopamine release. The extended model described the entire striatal time–activity curve, including the decrease in radioactivity concentration after an amphetamine-induced dopamine pulse. Based on these results, simulation studies were performed using the extended model. The simulation studies showed that the percent decrease in specific binding after amphetamine measured with the bolus-plus-infusion protocol correlates well with the integral of the postamphetamine dopamine pulse. This suggests that changes in specific binding observed in studies in humans can be interpreted as being linearly proportional to the integral of the amphetamine-induced dopamine pulse.

scholarly journals Comparison of two PET radioligands, [11C]FPEB and [11C]SP203, for quantification of metabotropic glutamate receptor 5 in human brain

2016 ◽  
Vol 37 (7) ◽  
pp. 2458-2470 ◽  
Author(s):  
Talakad G Lohith ◽  
Tetsuya Tsujikawa ◽  
Fabrice G Siméon ◽  
Mattia Veronese ◽  
Sami S Zoghbi ◽  
...  
Keyword(s):  
Human Brain ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Specific Activity ◽  
Specific Binding ◽  
Distribution Volume ◽  
Whole Body ◽  
Reference Region ◽  
Metabotropic Glutamate Receptor 5 ◽  
Metabotropic Glutamate

Of the two 18F-labeled PET ligands currently available to image metabotropic glutamate receptor 5 (mGluR5), [18F]FPEB is reportedly superior because [18F]SP203 undergoes glutathionlyation, generating [18F]-fluoride ion that accumulates in brain and skull. To allow multiple PET studies on the same day with lower radiation exposure, we prepared [11C]FPEB and [11C]SP203 from [11C]hydrogen cyanide and compared their abilities to accurately quantify mGluR5 in human brain, especially as regards radiometabolite accumulation. Genomic plot was used to estimate the ratio of specific-to-nondisplaceable uptake ( BPND) without using a receptor blocking drug. Both tracers quantified mGluR5; however [11C]SP203, like [18F]SP203, had radiometabolite accumulation in brain, as evidenced by increased distribution volume ( VT) over the scan period. Absolute VT values were ∼30% lower for 11C-labeled compared with 18F-labeled radioligands, likely caused by the lower specific activities (and high receptor occupancies) of the 11C radioligands. The genomic plot indicated ∼60% specific binding in cerebellum, which makes it inappropriate as a reference region. Whole-body scans performed in healthy subjects demonstrated a low radiation burden typical for 11C-ligands. Thus, the evidence suggests that [11C]FPEB is superior to [11C]SP203. If prepared in higher specific activity, [11C]FPEB would presumably be as effective as [18F]FPEB for quantifying mGluR5 in human brain.

High non-specific binding of the β1-selective radioligand 2-125I-ICI-H

2003 ◽  
Vol 42 (04) ◽  
pp. 173-180 ◽  
Author(s):  
M. P. Law ◽  
K. Kopka ◽  
St. Wagner ◽  
S. Luthra ◽  
V. W. Pike ◽  
...  
Keyword(s):  
Specific Activity ◽  
Single Photon ◽  
Specific Binding ◽  
Photon Emission ◽  
Radiochemical Yield ◽  
Emission Computed Tomography ◽  
Biodistribution Studies ◽  
Positron Emission

Summary: Aim: As results of cardiac biopsies suggest, myocardial β1-adrenoceptor density is reduced in patients with chronic heart failure. However, changes in cardiac β2-adrenoceptors vary. With suitable radiopharmaceuticals single photon emission computed tomography (SPECT) and positron emission tomography (PET) offer the opportunity to assess β-adrenoceptors non-invasively. Among the novel racemic analogues of the established β1-selective adrenoceptor antagonist ICI 89.406 the iodinated 2-I-ICI-H showed high affinity and selectivity to β1-adrenoceptors in murine ventricular membranes. The aim of this study was its evaluation as a putative sub-type selective β1-adrenergic radioligand in cardiac imaging. Methods: Competition studies in vitro and in vivo were used to investigate the kinetics of 2-I-ICI-H binding to cardiac β-adrenoceptors in mice and rats. In addition, the radiosynthesis of 2-125I-ICI-H from the silylated precursor 2-SiMe3-ICI-H was established. The specific activity was 80 GBq/µmol, the radiochemical yield ranged from 70 to 80%. Results: The unlabelled compound 2-I-ICI-H showed high β1-selectivity and -affinity in the in vitro competition studies. In vivo biodistribution studies apparently showed low affinity to cardiac β-adrenoceptors. The radiolabelled counterpart 2-125I-ICI-H showed a high degree of non-specific binding in vitro and no specific binding to cardiac β1-adrenoceptors in vivo. Conclusion: Because of its high non-specific binding 2-125I-ICI-H is no suitable radiotracer for imaging in vivo.

scholarly journals Parametric methods for [18F]flortaucipir PET

2018 ◽  
Vol 40 (2) ◽  
pp. 365-373 ◽  
Author(s):  
Sandeep SV Golla ◽  
Emma E Wolters ◽  
Tessa Timmers ◽  
Rik Ossenkoppele ◽  
Chris WJ van der Weijden ◽  
...  
Keyword(s):  
Specific Binding ◽  
Volume Ratio ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Distribution Volume ◽  
Binding Potential ◽  
Parametric Images ◽  
Distribution Volume Ratio ◽  
Pet Scans

[18F]Flortaucipir is a PET tau tracer used to visualize tau binding in Alzheimer’s disease (AD) in vivo. The present study evaluated the performance of several methods to obtain parametric images of [18F]flortaucipir. One hundred and thirty minutes dynamic PET scans were performed in 10 AD patients and 10 controls. Parametric images were generated using different linearization and basis function approaches. Regional binding potential (BPND) and volume of distribution (VT) values obtained from the parametric images were compared with corresponding values derived using the reversible two-tissue compartment model (2T4k_VB). Performance of SUVr parametric images was assessed by comparing values with distribution volume ratio (DVR) and SRTM-derived BPND estimates obtained using non-linear regression (NLR). Spectral analysis (SA) ( r2 = 0.92; slope = 0.99) derived VT correlated well with NLR-derived VT. RPM ( r2 = 0.95; slope = 0.98) derived BPND correlated well with NLR-derived DVR. Although SUVr80–100 min correlated well with NLR-derived DVR ( r2 = 0.91; slope = 1.09), bias in SUVr appeared to depend on uptake time and underlying level of specific binding. In conclusion, RPM and SA provide parametric images comparable to the NLR estimates. Individual SUVr values are biased compared with DVR and this bias requires further study in a larger dataset in order to understand its consequences.

scholarly journals Measurement of hemodynamics in human carotid artery using ultrasound and computational fluid dynamics

2002 ◽  
Vol 92 (3) ◽  
pp. 957-961 ◽  
Author(s):  
Mirian J. Starmans-Kool ◽  
Alice V. Stanton ◽  
Shunzhi Zhao ◽  
X. Yun Xu ◽  
Simon A. M. Thom ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Shear Stress ◽  
Carotid Artery ◽  
External Carotid Artery ◽  
External Carotid ◽  
Cyclic Variation ◽  
Carotid Arterial ◽  
Human Carotid

The objective of the study was to investigate the feasibility of using computational fluid dynamic modeling (CFD) with noninvasive ultrasound measurements to determine time-variant three-dimensional (3D) carotid arterial hemodynamics in humans in vivo. The effects of hyperoxia and hypoxic hypercapnia on carotid artery local hemodynamics were examined by use of this approach. Six normotensive volunteers followed a double-blind randomized crossover design. Blood pressure, heart rate, and carotid blood flow were measured while subjects breathed normal air, a mixture of 5% CO2 and 15% O2 (hypoxic hypercapnia), and 100% O2 (hyperoxia). Carotid artery geometry was reconstructed on the basis of B-mode ultrasound images by using purpose-built image processing software. Time-variant 3D carotid hemodynamics were estimated by using finite volume-based CFD. Systemic blood pressure was not significantly affected by hyperoxia or hypoxic hypercapnia, but heart rate decreased significantly with hyperoxia. There was an increase in diastolic flow velocity in the external carotid artery after hypoxic hypercapnia, but otherwise carotid blood flow velocities did not change significantly. Compared with normal air, hyperoxic conditions were associated with a decrease in the width of the region of flow separation in the external carotid artery. During hyperoxia, there was also an increase in the minimum and a decrease in maximum shear stress in the bifurcation and hence a reduction in cyclic variation in shear stress. Hypoxic hypercapnia was associated with a reduced duration of flow separation in the external carotid artery and an increase in the minimum shear stress without affecting the cyclic variation in shear stress. This study demonstrates the feasibility of using noninvasive ultrasound techniques in conjunction with CFD to describe time-variant 3D hemodynamics in the human carotid arterial bifurcation in vivo.

scholarly journals Accuracy and reliability of [11C]PBR28 specific binding estimated without the use of a reference region

2018 ◽  
Author(s):  
Pontus Plaven-Sigray ◽  
Martin Schain ◽  
Francesca Zanderigo ◽  
Ilan Rabiner ◽  
Roger Gunn ◽  
...  
Keyword(s):  
Outcome Measure ◽  
Specific Binding ◽  
Distribution Volume ◽  
Translocator Protein ◽  
Simultaneous Estimation ◽  
Reference Region ◽  
Simulation Experiments ◽  
Time Activity ◽  
Healthy Humans ◽  
Specific Distribution

[11C]PBR28 is a positron emission tomography radioligand used to estimate the expression of 18kDa translocator protein (TSPO). TSPO is expressed on glial cells and can function as a marker for immune activation. Since TSPO is expressed throughout the brain, no true reference region exists. For this reason, an arterial input function is required for accurate quantification of [11C]PBR28 binding and the most common outcome measure is the total distribution volume (VT). Notably, VT reflects both specific binding and non-displaceable binding (VND). Therefore, estimates of specific binding, such as binding potentials (e.g., BPND) and specific distribution volume (VS) should theoretically be more sensitive to underlying differences in TSPO expression. It is unknown, however, if unbiased and accurate estimates of these measures are obtainable for [11C]PBR28.The Simultaneous Estimation (SIME) method uses time-activity-curves from multiple brain regions with the aim to obtain a brain-wide estimate of VND, which can subsequently be used to improve the estimation of BPND and VS. In this study we evaluated the accuracy of SIME-derived VND, and the reliability of resulting estimates of specific binding for [11C]PBR28, using a combination of simulation experiments and in vivo studies in healthy humans.The simulation experiments showed that VND values estimated using SIME were both precise and accurate. Data from a pharmacological competition challenge showed that SIME provided VND values that were on average 19% lower than those obtained using the Lassen plot, but similar to values obtained using the Likelihood-Estimation of Occupancy technique. Test-retest data showed that SIME-derived VS values exhibited good reliability and precision, while larger variability was observed in SIME-derived BPND values.The results support the use of SIME for quantifying specific binding of [11C]PB28, and suggest that VS can be used in preference to, or as a complement to the conventional outcome measure VT. Additional studies in patient cohorts are warranted.

scholarly journals A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: synthesis and preclinical characterization of [18F]SDM-16

2021 ◽  
Author(s):  
Chao Zheng ◽  
Daniel Holden ◽  
Ming-Qiang Zheng ◽  
Richard Pracitto ◽  
Kyle C. Wilcox ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Nonhuman Primate ◽  
Specific Binding ◽  
Volume Of Distribution ◽  
Time Activity ◽  
Pet Tracers ◽  
Arterial Blood ◽  
Brain Pet ◽  
Pet Tracer

Abstract Purpose To quantify the synaptic vesicle glycoprotein 2A (SV2A) changes in the whole central nervous system (CNS) under pathophysiological conditions, a high affinity SV2A PET radiotracer with improved in vivo stability is desirable to minimize the potential confounding effect of radiometabolites. The aim of this study was to develop such a PET tracer based on the molecular scaffold of UCB-A, and evaluate its pharmacokinetics, in vivo stability, specific binding, and nonspecific binding signals in nonhuman primate brains, in comparison with [11C]UCB-A, [11C]UCB-J, and [18F]SynVesT-1. Methods The racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolidin-2-one) and its two enantiomers were synthesized and assayed for in vitro binding affinities to human SV2A. We synthesized the enantiopure [18F]SDM-16 using the corresponding enantiopure arylstannane precursor. Nonhuman primate brain PET scans were performed on FOCUS 220 scanners. Arterial blood was drawn for the measurement of plasma free fraction (fP), radiometabolite analysis, and construction of the plasma input function. Regional time-activity curves (TACs) were fitted with the one-tissue compartment (1TC) model to obtain the volume of distribution (VT). Nondisplaceable binding potential (BPND) was calculated using either the nondisplaceable volume of distribution (VND) or the centrum semiovale (CS) as the reference region. Results SDM-16 was synthesized in 3 steps with 44% overall yield and has the highest affinity (Ki = 0.9 nM) to human SV2A among all reported SV2A ligands. [18F]SDM-16 was prepared in about 20% decay-corrected radiochemical yield within 90 min, with greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in monkey brains and was metabolically more stable than the other SV2A PET tracers. The fP of [18F]SDM-16 was 69%, which was higher than those of [11C]UCB-J (46%), [18F]SynVesT-1 (43%), [18F]SynVesT-2 (41%), and [18F]UCB-H (43%). The TACs were well described with the 1TC. The averaged test–retest variability (TRV) was 7 ± 3%, and averaged absolute TRV (aTRV) was 14 ± 7% for the analyzed brain regions. Conclusion We have successfully synthesized a novel SV2A PET tracer [18F]SDM-16, which has the highest SV2A binding affinity and metabolical stability among published SV2A PET tracers. The [18F]SDM-16 brain PET images showed superb contrast between gray matter and white matter. Moreover, [18F]SDM-16 showed high specific and reversible binding in the NHP brains, allowing for the reliable and sensitive quantification of SV2A, and has potential applications in the visualization and quantification of SV2A beyond the brain.

Tissue distribution of radioiodinated FAUC113

2006 ◽  
Vol 45 (01) ◽  
pp. 41-48 ◽  
Author(s):  
C. Hocke ◽  
S. Löber ◽  
H. Hübner ◽  
P. Gmeiner ◽  
T. Kuwert ◽  
...  
Keyword(s):  
Frontal Cortex ◽  
Rat Brain ◽  
Specific Activity ◽  
Ex Vivo ◽  
Specific Binding ◽  
Receptor Subtype ◽  
Subtype Selectivity ◽  
Selective Ligand

Summary Aim: Disturbances of the D4 receptor subtype have been implicated in the genesis of a broad range of psychiatric disorders. In order to assess the suitability of a radioiodinated analogue of the D4-selective ligand FAUC 113 for tracer studies in vivo, we investigated the in-vivo stability, biodistribution and brain-uptake of 7-131I-FAUC 113 in Sprague-Dawley rats. Methods: Radiolabelling was carried out with high radiochemical yield and specific activity. After intravenous injection, blood and tissue samples, taken at designated time intervals, were collected for analysis. Analyses of metabolites were performed by radiohplc and radio-tlc. For in-vivo evaluation, sagittal cryo-sections of the rat brain were investigated by in-vitro and exvivo autoradiography on a μ-Imager system. Results: 7-131I-FAUC 113 was rapidly cleared from blood. Highest uptake was observed in kidney (0.603±0.047% ID/g, n=4) and liver (0.357±0.070% ID/g, n=4) at 10 min p.i.; 7-131I-FAUC 113 displayed rapid uptake (0.21-0.26% ID/g) and fast clearance in various brain regions consistent with the determined logP-value of 2.36±0.15 (n=4). In-vivo stability of 7-131I-FAUC 113 was confirmed in the frontal cortex (>95%). Ex-vivo autoradiography revealed a frontal cortex-to-cerebellum ratio of 1.57±0.13 at 10 min p.i. (n=6). Coinjection with L-750667 could not suppress any putative specific binding of 7-131I-FAUC 113. In-vitro autoradiography using authentic 7-iodo-FAUC 113 or L-750667 failed to cause significant displacement of the radioligand. Conclusions: Radioiodinated FAUC 113 does not allow imaging of D4 receptors in the rat brain in vivo nor in vitro. Further work should aim at the development of selective dopamine D4 radioligands with improved tracer characteristics, such as receptor affinity and subtype selectivity, specific activity or blood-brainbarrier permeability.

scholarly journals Comparison of high and low molar activity TSPO tracer [18F]F-DPA in a mouse model of Alzheimer’s disease

2019 ◽  
Vol 40 (5) ◽  
pp. 1012-1020 ◽  
Author(s):  
Thomas Keller ◽  
Francisco R López-Picón ◽  
Anna Krzyczmonik ◽  
Sarita Forsback ◽  
Jatta S Takkinen ◽  
...  
Keyword(s):  
Mouse Model ◽  
Specific Binding ◽  
Translocator Protein ◽  
Wild Type ◽  
Time Activity ◽  
Molar Activity ◽  
Model Of Alzheimer’S Disease ◽  
Standardized Uptake Values ◽  
High Level

[18F]F-DPA, a novel translocator protein 18 kDa (TSPO)-specific radioligand for imaging neuroinflammation, has to date been synthesized with low to moderate molar activities (Am’s). In certain cases, low Am can skew the estimation of specific binding. The high proportion of the non-radioactive component can reduce the apparent-specific binding by competitively binding to receptors. We developed a nucleophilic synthesis of [18F]F-DPA resulting in high Am (990 ± 150 GBq/µmol) and performed in vivo comparison with low Am (9.0 ± 2.9 GBq/µmol) [18F]F-DPA in the same APP/PS1-21 and wild-type mice (injected masses: 0.34 ± 0.13 µg/kg and 38 ± 15 µg/kg, respectively). The high level of microgliosis in the APP/PS1-21 mouse model enables good differentiation between diseased and healthy animals and serves better to distinguish the effect of differing Am on specific binding. The differing injected masses affect the washout profile and shape of the time–activity curves. Ratios of standardized uptake values obtained with high and low Am [18F]F-DPA demonstrate that there is a 1.5-fold higher uptake of radioactivity in the brains of APP/PS1-21 animals when imaging is carried out with high Am [18F]F-DPA. The differences between APP/PS1-21 and wild-type animals showed higher significance when high Am was used.

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