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 ◽  
Binding Potential ◽  
Time Activity ◽  
Peripheral Tissues ◽  
High Affinity ◽  
Arterial Blood ◽  
Pet Tracer

Purpose: To investigate the synaptic vesicle glycoprotein 2A (SV2A) expression in the whole central nervous system and peripheral tissues, a metabolically stable SV2A radiotracer is desirable to minimize a potential confounding effect of radiometabolites. The aim of this study was to develop and evaluate a metabolically stable SV2A radiotracer, [18F]SDM-16, in nonhuman primate brains. Methods: The racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolidin-2-one ) was synthesized and assayed for in vitro SV2A binding affinity. We synthesized the enantiopure [18F]SDM-16 using the corresponding arylstannane precursor. Nonhuman primate brain PET was performed on a FOCUS 220 system. Arterial blood was drawn for metabolite analysis and construction of plasma input function. Regional time-activity curves (TACs) were evaluated with the one-tissue compartment (1TC) model to obtain the volume of distribution (VT). Binding potential (BPND) was calculated using either the nondisplaceable volume of distribution (VND) or the centrum semiovale (CS) as the reference region. Results: Racemic SDM-16 was synthesized in 3 steps with 44% overall yield and has high affinity (Ki = 3.7 nM) to human SV2A. [18F]SDM-16 was prepared in greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in brain and was metabolically more stable than other SV2A PET tracers. The plasma free fraction (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 -9%, and averaged absolute TRV (aTRV) was 10% for all analyzed brain regions. Conclusion: We have successfully synthesized a metabolically stable and high affinity SV2A PET tracer, [18F]SDM-16, which showed high specific and reversible binding in the NHP brain. [18F]SDM-16 may have potential application in the visualization and quantification of SV2A beyond the brain.

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 ◽  
Binding Potential ◽  
Time Activity ◽  
Peripheral Tissues ◽  
High Affinity ◽  
Arterial Blood ◽  
Pet Tracer

Abstract PurposeTo investigate the synaptic vesicle glycoprotein 2A (SV2A) expression in the whole central nervous system and peripheral tissues, a metabolically stable SV2A radiotracer is desirable to minimize a potential confounding effect of radiometabolites. The aim of this study was to develop and evaluate a metabolically stable SV2A radiotracer, [18 F]SDM-16, in nonhuman primate brains. MethodsThe racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1yl)methyl)pyrrolidin-2-one) was synthesized and assayed for in vitro SV2A binding affinity. We synthesized the enantiopure [18F]SDM-16 using the corresponding arylstannane precursor. Nonhuman primate brain PET was performed on a FOCUS 220 system. Arterial blood was drawn for metabolite analysis and construction of plasma input function. Regional time-activity curves (TACs) were evaluated with the one-tissue compartment (1TC) model to obtain the volume of distribution (VT). Binding potential (BPND) was calculated using either the nondisplaceable volume of distribution (VND) or the centrum semiovale (CS) as the reference region. ResultsRacemic SDM-16 was synthesized in 3 steps with 44% overall yield and has high affinity (K i = 3.7 nM) to human SV2A. [18F]SDM-16 was prepared in greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in brain and was metabolically more stable than other SV2A PET tracers. The plasma free fraction (fP) of [ 18 F]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 -9±8%, and averaged absolute TRV (aTRV) was 10±7% for all analyzed brain regions. ConclusionWe have successfully synthesized a metabolically stable and high affinity SV2A PET tracer, [18F]SDM-16, which showed high specific and reversible binding in the NHP brain. [18F]SDM-16 may have potential application in the visualization and quantification of SV2A beyond the brain.

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.

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 Quantification of Ligand PET Studies using a Reference Region with a Displaceable Fraction: Application to Occupancy Studies with [11C]-DASB as an Example

2011 ◽  
Vol 32 (1) ◽  
pp. 70-80 ◽  
Author(s):  
Federico E Turkheimer ◽  
Sudhakar Selvaraj ◽  
Rainer Hinz ◽  
Venkatesha Murthy ◽  
Zubin Bhagwagar ◽  
...  
Keyword(s):  
Specific Binding ◽  
Normal Subjects ◽  
Volume Of Distribution ◽  
Binding Potential ◽  
Accurate Estimation ◽  
Data Sets ◽  
Reference Region ◽  
Reference Tissue ◽  
Positron Emission ◽  
Definition Of

This paper aims to build novel methodology for the use of a reference region with specific binding for the quantification of brain studies with radioligands and positron emission tomography (PET). In particular: (1) we introduce a definition of binding potential BPD = DVR–1 where DVR is the volume of distribution relative to a reference tissue that contains ligand in specifically bound form, (2) we validate a numerical methodology, rank-shaping regularization of exponential spectral analysis (RS-ESA), for the calculation of BPD that can cope with a reference region with specific bound ligand, (3) we demonstrate the use of RS-ESA for the accurate estimation of drug occupancies with the use of correction factors to account for the specific binding in the reference. [11C]-DASB with cerebellum as a reference was chosen as an example to validate the methodology. Two data sets were used; four normal subjects scanned after infusion of citalopram or placebo and further six test—retest data sets. In the drug occupancy study, the use of RS-ESA with cerebellar input plus corrections produced estimates of occupancy very close the ones obtained with plasma input. Test-retest results demonstrated a tight linear relationship between BPD calculated either with plasma or with a reference input and high reproducibility.

scholarly journals Kinetic Analysis of the 5-HT2A Ligand [11C]MDL 100,907

2000 ◽  
Vol 20 (6) ◽  
pp. 899-909 ◽  
Author(s):  
Hiroshi Watabe ◽  
Michael A. Channing ◽  
Margaret G. Der ◽  
H. Richard Adams ◽  
Elaine Jagoda ◽  
...  
Keyword(s):  
Kinetic Analysis ◽  
Specific Binding ◽  
Compartment Model ◽  
Input Function ◽  
Brain Regions ◽  
Time Activity ◽  
Tissue Compartment ◽  
Arterial Blood ◽  
Fixed Parameter ◽  
Mdl 100,907

The goal of this study was to develop a suitable kinetic analysis method for quantification of 5-HT2A receptor parameters with [11C]MDL 100,907. Twelve control studies and four preblocking studies (400 nmol/kg unlabeled MDL 100,907) were performed in isoflurane-anesthetized rhesus monkeys. The plasma input function was determined from arterial blood samples with metabolite measurements by extraction in ethyl acetate. The preblocking studies showed that a two-tissue compartment model was necessary to fit the time activity curves of all brain regions including the cerebellum—in other words, the need for two compartments is not proof of specific binding. Therefore, a three-tissue compartment model was used to analyze the control studies, with three parameters fixed based on the preblocking data. Reliable fits of control data could be obtained only if no more than three parameters were allowed to vary. For routine use of [11C]MDL 100,907, several simplified methods were evaluated. A two-tissue (2T‘) compartment with one fixed parameter was the most reliable compartmental approach; a one-compartment model failed to fit the data adequately. The Logan graphical approach was also tested and produced comparable results to the 2T’ model. However, a simulation study showed that Logan analysis produced a larger bias at higher noise levels. Thus, the 2T' model is the best choice for analysis of [11C]MDL 100,907 studies.

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 Serotonin 5HT2 Receptor Imaging in the Human Brain Using Positron Emission Tomography and a New Radioligand, [18F]Altanserin: Results in Young Normal Controls

1995 ◽  
Vol 15 (5) ◽  
pp. 787-797 ◽  
Author(s):  
B. Sadzot ◽  
C. Lemaire ◽  
P. Maquet ◽  
E. Salmon ◽  
A. Plenevaux ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
High Specific Activity ◽  
Emission Tomography ◽  
Binding Potential ◽  
Receptor Imaging ◽  
Time Activity ◽  
Arterial Blood ◽  
Positron Emission

Changes in serotonin-2 receptors have been demonstrated in brain autopsy material from patients with various neurodegenerative and affective disorders. It would be desirable to locate a ligand for the study of these receptors in vivo with positron emission tomography (PET). Altanserin is a 4-benzoylpiperidine derivative with a high affinity and selectivity for S2 receptors in vitro. Dynamic PET studies were carried out in nine normal volunteers with high-specific activity (376–1,680 mCi/μmol) [18F]altanserin. Arterial blood samples were obtained and the plasma time–activity curves were corrected for the presence of labeled metabolites. Thirty minutes after injection, selective retention of the radioligand was observed in cortical areas, while the cerebellum, caudate, and thalamus had low radioactivity levels. Specific binding reached a plateau between 30 and 65 min postinjection at 1.8% of the injected dose/L of brain and then decreased, indicating the reversibility of the binding. The total/nonspecific binding ratio reached 2.6 for times between 50 and 70 min postinjection. The graphical analysis proposed by Logan et al. allowed us to estimate the binding potential ( Bmax/ KD). Pretreatment with ketanserin was given to three volunteers and brain activity remained uniformly low. An additional study in one volunteer showed that [18F]altanserin can be displaced from the receptors by large doses of ketanserin. At the end of the study, unchanged altanserin was 57% of the total plasma activity. These results suggest that [18F]altanserin is selective for S2 receptors in vivo as it is in vitro. They indicate that [18F]altanserin is suitable for imaging and quantifying S2 receptors with PET in humans.

scholarly journals Development of a Tracer Kinetic Plasma Input Model for (R)-[11C]PK11195 Brain Studies

2005 ◽  
Vol 25 (7) ◽  
pp. 842-851 ◽  
Author(s):  
Marc A Kropholler ◽  
Ronald Boellaard ◽  
Alie Schuitemaker ◽  
Bart NM van Berckel ◽  
Gert Luurtsema ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Benzodiazepine Receptor ◽  
Compartment Model ◽  
Input Function ◽  
Volume Of Distribution ◽  
Binding Potential ◽  
Arterial Blood ◽  
Tracer Kinetic ◽  
Input Model

(R)-[11C]PK11195 ([1-(2-chlorophenyl)- N-methyl- N-(1-methylpropyl]-3-isoquinoline carboxamide) is a ligand for the peripheral benzodiazepine receptor, which, in the brain, is mainly expressed on activated microglia. Using both clinical studies and Monte Carlo simulations, the aim of this study was to determine which tracer kinetic plasma input model best describes (R)-[11C]PK11195 kinetics. Dynamic positron emission tomography (PET) scans were performed on 13 subjects while radioactivity in arterial blood was monitored online. Discrete blood samples were taken to generate a metabolite corrected plasma input function. One-tissue, two-tissue irreversible, and two-tissue reversible compartment models, with and without fixing K1/ k2 ratio, k4 or blood volume to whole cortex values, were fitted to the data. The effects of fixing parameters to incorrect values were investigated by varying them over a physiologic range and determining accuracy and reproducibility of binding potential and volume of distribution using Monte Carlo simulations. Clinical data showed that a two-tissue reversible compartment model was optimal for analyzing (R)-[11C]PK11195 PET brain studies. Simulations showed that fixing the K1/ k2 ratio of this model provided the optimal trade-off between accuracy and reproducibility. It was concluded that a two-tissue reversible compartment model with K1/ k2 fixed to whole cortex value is optimal for analyzing (R)-[11C]PK11195 PET brain studies.

scholarly journals 11C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than 11C-(R)-PK11195

2017 ◽  
Vol 38 (3) ◽  
pp. 393-403 ◽  
Author(s):  
Masato Kobayashi ◽  
Teresa Jiang ◽  
Sanjay Telu ◽  
Sami S Zoghbi ◽  
Roger N Gunn ◽  
...  
Keyword(s):  
Second Generation ◽  
Specific Binding ◽  
Translocator Protein ◽  
Emission Tomography ◽  
Binding Potential ◽  
Arterial Blood ◽  
Plot Analysis ◽  
Positron Emission ◽  
Translocator Protein 18 Kda ◽  
Pet Scans

Positron emission tomography (PET) radioligands for translocator protein 18 kDa (TSPO) are widely used to measure neuroinflammation, but controversy exists whether second-generation radioligands are superior to the prototypical agent 11C-( R)-PK11195 in human imaging. This study sought to quantitatively measure the “signal to background” ratio (assessed as binding potential ( BPND)) of 11C-( R)-PK11195 compared to one of the most promising second-generation radioligands, 11C-DPA-713. Healthy subjects had dynamic PET scans and arterial blood measurements of radioligand after injection of either 11C-( R)-PK11195 (16 subjects) or 11C-DPA-713 (22 subjects). To measure the amount of specific binding, a subset of these subjects was scanned after administration of the TSPO blocking drug XBD173 (30–90 mg PO). 11C-DPA-713 showed a significant sensitivity to genotype in brain, whereas 11C-( R)-PK11195 did not. Lassen occupancy plot analysis revealed that the specific binding of 11C-DPA-713 was much greater than that of 11C-( R)-PK11195. The BPND in high-affinity binders was about 10-fold higher for 11C-DPA-713 (7.3) than for 11C-( R)-PK11195 (0.75). Although the high specific binding of 11C-DPA-713 suggests it is an ideal ligand to measure TSPO, we also found that its distribution volume increased over time, consistent with the accumulation of radiometabolites in brain.

scholarly journals Astroglial tracer BU99008 detects multiple binding sites in Alzheimer’s disease brain

2021 ◽  
Author(s):  
Amit Kumar ◽  
Niina A. Koistinen ◽  
Mona-Lisa Malarte ◽  
Inger Nennesmo ◽  
Martin Ingelsson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Binding Sites ◽  
Specific Binding ◽  
Brain Regions ◽  
Binding Studies ◽  
Reactive Astrogliosis ◽  
High Affinity ◽  
Pet Tracer ◽  
Multiple Binding

AbstractWith reactive astrogliosis being established as one of the hallmarks of Alzheimer’s disease (AD), there is high interest in developing novel positron emission tomography (PET) tracers to detect early astrocyte reactivity. BU99008, a novel astrocytic PET ligand targeting imidazoline-2 binding sites (I2BS) on astrocytes, might be a suitable candidate. Here we demonstrate for the first time that BU99008 could visualise reactive astrogliosis in postmortem AD brains and propose a multiple binding site [Super-high-affinity (SH), High-affinity (HA) and Low-affinity (LA)] model for BU99008, I2BS specific ligands (2-BFI and BU224) and deprenyl in AD and control (CN) brains. The proportion (%) and affinities of these sites varied significantly between the BU99008, 2-BFI, BU224 and deprenyl in AD and CN brains. Regional binding studies demonstrated significantly higher 3H-BU99008 binding in AD brain regions compared to CN. Comparative autoradiography studies reinforced these findings, showing higher specific binding for 3H-BU99008 than 3H-Deprenyl in sporadic AD brain compared to CN, implying that they might have different targets. The data clearly shows that BU99008 could detect I2BS expressing reactive astrocytes with good selectivity and specificity and hence be a potential attractive clinical astrocytic PET tracer for gaining further insight into the role of reactive astrogliosis in AD.

Sign in / Sign up

Export Citation Format

Share Document