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 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 Improved in vivo PET imaging of the adenosine A2A receptor in the brain using [18F]FLUDA, a deuterated radiotracer with high metabolic stability

2021 ◽  
Author(s):  
Thu Hang Lai ◽  
Magali Toussaint ◽  
Rodrigo Teodoro ◽  
Sladjana Dukić-Stefanović ◽  
Daniel Gündel ◽  
...  
Keyword(s):  
Specific Binding ◽  
Radiochemical Yield ◽  
Toxicity Study ◽  
In Vivo Evaluation ◽  
One Pot ◽  
Specific Binding Ratio ◽  
Mri Studies ◽  
The Brain

Abstract Purpose The adenosine A2A receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A2A receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A2A receptor radiotracer and report herein the preclinical evaluation of [18F]FLUDA, a deuterated isotopologue of [18F]FESCH. Methods [18F]FLUDA was synthesized by a two-step one-pot approach and evaluated in vitro by autoradiographic studies as well as in vivo by metabolism and dynamic PET/MRI studies in mice and piglets under baseline and blocking conditions. A single-dose toxicity study was performed in rats. Results [18F]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72–180 GBq/μmol. Autoradiography proved A2A receptor–specific accumulation of [18F]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [18F]FLUDA compared to that of [18F]FESCH, resulting in the absence of brain-penetrant radiometabolites. Furthermore, the radiometabolites detected in piglets are expected to have a low tendency for brain penetration. PET/MRI studies confirmed high specific binding of [18F]FLUDA towards striatal A2A receptor with a maximum specific-to-non-specific binding ratio in mice of 8.3. The toxicity study revealed no adverse effects of FLUDA up to 30 μg/kg, ~ 4000-fold the dose applied in human PET studies using [18F]FLUDA. Conclusions The new radiotracer [18F]FLUDA is suitable to detect the availability of the A2A receptor in the brain with high target specificity. It is regarded ready for human application.

scholarly journals PET Imaging of [11C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2289
Author(s):  
Naresh Damuka ◽  
Paul Czoty ◽  
Ashley Davis ◽  
Michael Nader ◽  
Susan Nader ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Neurological Disorders ◽  
Healthy Male ◽  
Time Activity ◽  
Positron Emission ◽  
Pet Ct ◽  
Scan Data ◽  
The Brain ◽  
Human Primate

Dysregulation of microtubules is commonly associated with several psychiatric and neurological disorders, including addiction and Alzheimer’s disease. Imaging of microtubules in vivo using positron emission tomography (PET) could provide valuable information on their role in the development of disease pathogenesis and aid in improving therapeutic regimens. We developed [11C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain. The aim of the present study was to assess the reproducibility of [11C]MPC-6827 PET imaging in non-human primate brains. Two dynamic 0–120 min PET/CT imaging scans were performed in each of four healthy male cynomolgus monkeys approximately one week apart. Time activity curves (TACs) and standard uptake values (SUVs) were determined for whole brains and specific regions of the brains and compared between the “test” and “retest” data. [11C]MPC-6827 showed excellent brain uptake with good pharmacokinetics in non-human primate brains, with significant correlation between the test and retest scan data (r = 0.77, p = 0.023). These initial evaluations demonstrate the high translational potential of [11C]MPC-6827 to image microtubules in the brain in vivo in monkey models of neurological and psychiatric diseases.

scholarly journals Odor-Driven Activity in the Olfactory Cortex of an In Vitro Isolated Guinea Pig Whole Brain With Olfactory Epithelium

2007 ◽  
Vol 97 (1) ◽  
pp. 670-679 ◽  
Author(s):  
Takahiro Ishikawa ◽  
Takaaki Sato ◽  
Akira Shimizu ◽  
Ken-Ichiro Tsutsui ◽  
Marco de Curtis ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Olfactory Epithelium ◽  
Afferent Input ◽  
Initial Component ◽  
Induced Response ◽  
Activity Data ◽  
Olfactory Neural Network ◽  
The Brain

We developed a new technique to isolate a whole guinea pig brain with an intact olfactory epithelium (OE) that enables us to access the ventral surface of the brain including olfactory areas with ease during natural odor stimulation. We applied odorants to OE and confirmed that odor-induced local field potentials (LFPs) could be induced in olfactory areas. In the olfactory bulb (OB) and the piriform cortex (PC), odor-induced LFPs consisted of a phasic initial component followed by a fast activity oscillation in the beta range (20 Hz). To understand the neural mechanisms of odor-induced responses especially in the anterior PC, we analyzed odor-induced LFPs, together with unit activity data. We confirmed that the initial component of odor-induced response has a characteristic temporal pattern, generated by a relatively weak direct afferent input, followed by an intra-cortical associative response, which was associated with a phasic inhibition. The beta oscillation might be formed by the repetition of these network activities. These electrophysiological data were consistent with the results of previous studies that used slice or in vivo preparations, suggesting that the olfactory neural network and activities of the brain are preserved in our new in vitro preparation. This study provides the basis for clarifying the sequence of neural activities underlying odor information processing in the brain in vitro following natural olfactory stimulation.

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 Permeability of the windows of the brain: feasibility of dynamic contrast-enhanced MRI of the circumventricular organs

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Inge C. M. Verheggen ◽  
Joost J. A. de Jong ◽  
Martin P. J. van Boxtel ◽  
Alida A. Postma ◽  
Frans R. J. Verhey ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Gray Matter ◽  
Circumventricular Organs ◽  
Brain Barrier ◽  
Dce Mri ◽  
Dynamic Contrast Enhanced ◽  
Blood Brain ◽  
Contrast Enhanced ◽  
The Brain

Abstract Background Circumventricular organs (CVOs) are small structures without a blood–brain barrier surrounding the brain ventricles that serve homeostasic functions and facilitate communication between the blood, cerebrospinal fluid and brain. Secretory CVOs release peptides and sensory CVOs regulate signal transmission. However, pathogens may enter the brain through the CVOs and trigger neuroinflammation and neurodegeneration. We investigated the feasibility of dynamic contrast-enhanced (DCE) MRI to assess the CVO permeability characteristics in vivo, and expected significant contrast uptake in these regions, due to blood–brain barrier absence. Methods Twenty healthy, middle-aged to older males underwent brain DCE MRI. Pharmacokinetic modeling was applied to contrast concentration time-courses of CVOs, and in reference to white and gray matter. We investigated whether a significant and positive transfer from blood to brain could be measured in the CVOs, and whether this differed between secretory and sensory CVOs or from normal-appearing brain matter. Results In both the secretory and sensory CVOs, the transfer constants were significantly positive, and all secretory CVOs had significantly higher transfer than each sensory CVO. The transfer constants in both the secretory and sensory CVOs were higher than in the white and gray matter. Conclusions Current measurements confirm the often-held assumption of highly permeable CVOs, of which the secretory types have the strongest blood-to-brain transfer. The current study suggests that DCE MRI could be a promising technique to further assess the function of the CVOs and how pathogens can potentially enter the brain via these structures. Trial registration: Netherlands Trial Register number: NL6358, date of registration: 2017-03-24

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 Permeability of the windows of the brain: Feasibility of dynamic contrast-enhanced MRI of the circumventricular organs

2020 ◽  
Author(s):  
Inge C.M. Verheggen ◽  
Joost J.A. de Jong ◽  
Martin P.J. van Boxtel ◽  
Alida A. Postma ◽  
Frans R.J. Verhey ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Gray Matter ◽  
Circumventricular Organs ◽  
Brain Barrier ◽  
Dce Mri ◽  
Dynamic Contrast Enhanced ◽  
Blood Brain ◽  
Contrast Enhanced ◽  
The Brain

Abstract Background: Circumventricular organs (CVOs) are small structures without a blood-brain barrier surrounding the brain ventricles that serve homeostasic functions and facilitate communication between the blood, cerebrospinal fluid and brain. Secretory CVOs release peptides and sensory CVOs regulate signal transmission. However, pathogens may enter the brain through the CVOs and trigger neuroinflammation and neurodegeneration. We investigated the feasibility of dynamic contrast-enhanced (DCE) MRI to assess the CVO permeability characteristics in vivo, and expected significant contrast uptake in these regions, due to blood-brain barrier absence.Methods: Twenty healthy, middle-aged to older males underwent brain DCE MRI. Pharmacokinetic modeling was applied to contrast concentration time-courses of CVOs, and in reference to white and gray matter. We investigated whether a significant and positive transfer from blood to brain could be measured in the CVOs, and whether this differed between secretory and sensory CVOs or from normal-appearing brain matter.Results: In both the secretory and sensory CVOs, the transfer constants were significantly positive, and all secretory CVOs had significantly higher transfer than each sensory CVO. The transfer constants in both the secretory and sensory CVOs were higher than in the white and gray matter.Conclusions: Current measurements confirm the often-held assumption of highly permeable CVOs, of which the secretory types have the strongest blood-to-brain transfer. The current study suggests that DCE MRI could be a promising technique to further assess the function of the CVOs and how pathogens can potentially enter the brain via these structures.Trial registration: Netherlands Trial Register number: NL6358, date of registration: 2017-03-24

In vivo measurements of pulmonary angiotensin-converting enzyme kinetics. II. Implementation and application

1995 ◽  
Vol 78 (3) ◽  
pp. 1169-1178 ◽  
Author(s):  
D. P. Schuster ◽  
T. J. McCarthy ◽  
M. J. Welch ◽  
S. Holmberg ◽  
P. Sandiford ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Regional Blood Flow ◽  
Water Concentration ◽  
Converting Enzyme ◽  
Activity Data ◽  
Time Activity ◽  
Positron Emission ◽  
Left And Right ◽  
The Mean

We measured pulmonary angiotensin-converting enzyme (ACE) kinetics with fluorine-18 captopril and positron emission tomographic (PET) imaging in five control dogs and in five dogs after 20–30 min of left caudal lobe (LCL) hypoxic ventilation. Time-activity data obtained with PET were interpreted with a compartmental receptor model relating changes in tissue and blood activity to one another within the region. In control dogs, the mean ratio of regional blood flow (measured by PET) between left and right dorsal lung regions was 0.90 +/- 0.16 (SD) vs. 0.54 +/- 0.24 (P < 0.05) in LCL hypoxic dogs. In control dogs, the amount of perfused unbound enzyme normalized to regional extravascular water concentration (Bmax/EVLW) averaged 13.3 +/- 8.9 x 10(-6) mmol ACE/ml EVLW; the ratio of regional values between the left and right sides was 1.02 +/- 0.18. In the LCL hypoxic dogs, Bmax/EVLW was 9.7 +/- 11.3 x 10(-6) mmol/ml hypoxic lung region and the ratio was 0.47 +/- 0.31 (P < 0.05). In control dogs, the coefficient of variation for Bmax/EVLW among regions was only 19 +/- 10%, although the between-dog variation was greater (64 +/- 4%). We conclude that this completely noninvasive method appears to be a promising approach for evaluating the expression of pulmonary ACE in vivo.

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