Imaging High-Risk Atherothrombosis Using a Novel Fibrin-Binding Positron Emission Tomography Probe

Stroke ◽  
2021 ◽  
Author(s):  
David Izquierdo-Garcia ◽  
Himashinie Diyabalanage ◽  
Ian A. Ramsay ◽  
Nicholas J. Rotile ◽  
Adam Mauskapf ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
High Risk ◽  
Ex Vivo ◽  
Standardized Uptake Value ◽  
Emission Tomography ◽  
Back Muscle ◽  
Plaque Disruption ◽  
Positron Emission ◽  
Human Carotid

Background and Purpose: High-risk atherosclerosis is an underlying cause of cardiovascular events, yet identifying the specific patient population at immediate risk is still challenging. Here, we used a rabbit model of atherosclerotic plaque rupture and human carotid endarterectomy specimens to describe the potential of molecular fibrin imaging as a tool to identify thrombotic plaques. Methods: Atherosclerotic plaques in rabbits were induced using a high-cholesterol diet and aortic balloon injury (N=13). Pharmacological triggering was used in a group of rabbits (n=9) to induce plaque disruption. Animals were grouped into thrombotic and nonthrombotic plaque groups based on gross pathology (gold standard). All animals were injected with a novel fibrin-specific probe 68 Ga-CM246 followed by positron emission tomography (PET)/magnetic resonance imaging 90 minutes later. 68 Ga-CM246 was quantified on the PET images using tissue-to-background (back muscle) ratios and standardized uptake value. Results: Both tissue-to-background (back muscle) ratios and standardized uptake value were significantly higher in the thrombotic versus nonthrombotic group ( P <0.05). Ex vivo PET and autoradiography of the abdominal aorta correlated positively with in vivo PET measurements. Plaque disruption identified by 68 Ga-CM246 PET agreed with gross pathology assessment (85%). In ex vivo surgical specimens obtained from patients undergoing elective carotid endarterectomy (N=12), 68 Ga-CM246 showed significantly higher binding to carotid plaques compared to a D-cysteine nonbinding control probe. Conclusions: We demonstrated that molecular fibrin PET imaging using 68 Ga-CM246 could be a useful tool to diagnose experimental and clinical atherothrombosis. Based on our initial results using human carotid plaque specimens, in vivo molecular imaging studies are warranted to test 68 Ga-CM246 PET as a tool to stratify risk in atherosclerotic patients.

Radiosynthesis, ex vivo and in vivo evaluation of [11C]preclamol as a partial dopamine D2 agonist radioligand for positron emission tomography

Synapse ◽  
2006 ◽  
Vol 60 (4) ◽  
pp. 314-318 ◽  
Author(s):  
Neil Vasdev ◽  
Sridhar Natesan ◽  
Laurent Galineau ◽  
Armando Garcia ◽  
Winston T. Stableford ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Ex Vivo ◽  
Emission Tomography ◽  
In Vivo Evaluation ◽  
Dopamine D2 ◽  
D2 Agonist ◽  
Positron Emission ◽  
Dopamine D2 Agonist

scholarly journals Use of Positron Emission Tomography to Study AT1 Receptor Regulation In Vivo

2001 ◽  
Vol 12 (7) ◽  
pp. 1350-1358
Author(s):  
ZSOLT SZABO ◽  
ROBERT C. SPETH ◽  
P. RANDY BROWN ◽  
LEVENTE KERENYI ◽  
PAN FU KAO ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Receptor Binding ◽  
Ex Vivo ◽  
Sodium Intake ◽  
Plasma Renin ◽  
Emission Tomography ◽  
Dietary Sodium ◽  
Compensatory Mechanism ◽  
Positron Emission

Abstract. Increased sodium intake and enhanced sodium sensitivity are implicated in the pathogenesis of hypertension and in the control of a major regulator of BP, the type 1 angiotensin receptor (AT1 receptor). An in vivo technique to study changes of renal AT1 receptors by dietary sodium was developed that uses positron emission tomography (PET). PET revealed that renal cortical AT1 receptor binding was increased in sodium-loaded compared with sodium-deprived dogs, which correlated with ex vivo estimations of AT1 receptor numbers. Plasma renin activity, angiotensin II, and aldosterone were inversely related to changes in AT1 receptor binding. These results demonstrate, for the first time in vivo, that the renal AT1 receptor is inversely related to the activity of the renin angiotensin system, which may provide a compensatory mechanism to prevent inappropriate fluctuations in arterial BP. The ability to measure AT1 receptor binding in vivo has potential significance for clinical studies of AT1 receptors, because PET is a noninvasive imaging technique that is readily applicable in humans.

scholarly journals [68Ga]ABY-028: an albumin-binding domain (ABD) protein-based imaging tracer for positron emission tomography (PET) studies of altered vascular permeability and predictions of albumin-drug conjugate transport

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Emma Jussing ◽  
Li Lu ◽  
Jonas Grafström ◽  
Tetyana Tegnebratt ◽  
Fabian Arnberg ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Vascular Permeability ◽  
Ex Vivo ◽  
Circulatory System ◽  
Binding Domain ◽  
The Body ◽  
Emission Tomography ◽  
Albumin Binding ◽  
Positron Emission

Abstract Background Albumin is commonly used as a carrier platform for drugs to extend their circulatory half-lives and influence their uptake into tissues that have altered permeability to the plasma protein. The albumin-binding domain (ABD) protein, which binds in vivo to serum albumin with high affinity, has proven to be a versatile scaffold for engineering biopharmaceuticals with a range of binding capabilities. In this study, the ABD protein equipped with a mal-DOTA chelator (denoted ABY-028) was radiolabeled with gallium-68 (68Ga). This novel radiotracer was then used together with positron emission tomography (PET) imaging to examine variations in the uptake of the ABD-albumin conjugate with variations in endothelial permeability. Results ABY-028, produced by peptide synthesis in excellent purity and stored at − 20 °C, was stable for 24 months (end of study). [68Ga]ABY-028 could be obtained with labeling yields of > 80% and approximately 95% radiochemical purity. [68Ga]ABY-028 distributed in vivo with the plasma pool, with highest radioactivity in the heart ventricles and major vessels of the body, a gradual transport over time from the circulatory system into tissues and elimination via the kidneys. Early [68Ga]ABY-028 uptake differed in xenografts with different vascular properties: mean standard uptake values (SUVmean) were initially 5 times larger in FaDu than in A431 xenografts, but the difference decreased to 3 after 1 h. Cutaneously administered, vasoactive nitroglycerin increased radioactivity in the A431 xenografts. Heterogeneity in the levels and rates of increases of radioactivity uptake was observed in sub-regions of individual MMTV-PyMT mammary tumors and in FaDu xenografts. Higher uptake early after tracer administration could be observed in lower metabolic regions. Fluctuations in the increased permeability for the tracer across the blood-brain-barrier (BBB) direct after experimentally induced stroke were monitored by PET and the increased uptake was confirmed by ex vivo phosphorimaging. Conclusions [68Ga]ABY-028 is a promising new tracer for visualization of changes in albumin uptake due to disease- and pharmacologically altered vascular permeability and their potential effects on the passive uptake of targeting therapeutics based on the ABD protein technology.

scholarly journals Mapping nephron mass in vivo using positron emission tomography

2020 ◽  
Author(s):  
Edwin J. Baldelomar ◽  
David Reichert ◽  
Kooresh I. Shoghi ◽  
Scott C Beeman ◽  
Jennifer R. Charlton ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Standardized Uptake Value ◽  
Human Kidney ◽  
Clinical Translation ◽  
Emission Tomography ◽  
Positron Emission ◽  
Pet Radiotracers ◽  
The Difference ◽  
Increased Susceptibility

Nephron number varies widely in humans. A low nephron endowment at birth or a loss of functioning nephrons is strongly linked to increased susceptibility to chronic kidney disease. In this work, we develop a contrast agent, RadioCF, to map functioning glomeruli in vivo in the kidney using positron emission tomography (PET). PET radiotracers can be detected in trace doses (<30 nmol), making them useful for rapid clinical translation. RadioCF is formed from cationic ferritin (CF) and with a radioisotope, Cu-64, incorporated into the ferritin core. We show that RadioCF binds specifically to kidney glomeruli after intravenous injection in mice, while radiolabeled non-cationic ferritin, (RadioNF), and free Cu-64 do not. We then show that RadioCF-PET can distinguish kidneys in healthy wild type (WT) mice from kidneys in mice with oligosyndactylism (Os/+), a model of congenital hypoplasia and low nephron mass. Average standardized uptake value (SUV) measured by PET 90 minutes after injection was 21% higher in WT mice than in Os/+ mice, consistent with the higher glomerular density in WT mice. The difference in peak SUV from SUV at 90 minutes correlated with glomerular density in male mice from both WT and Os/+ cohorts (R2 = 0.98). Finally, we used RadioCF-PET to map functioning glomeruli in a donated human kidney. SUV within the kidney correlated with glomerular number (R2= 0.78) measured CF-enhanced magnetic resonance imaging in the same locations. This work suggests that RadioCF-PET appears to accurately detect nephron mass and has the potential for clinical translation.

Visualization of Sigma1 Receptors in Eyes by ex vivo Autoradiography and in vivo Positron Emission Tomography

2002 ◽  
Vol 75 (6) ◽  
pp. 723-730 ◽  
Author(s):  
Wei-Fang Wang ◽  
Kiichi Ishiwata ◽  
Motohiro Kiyosawa ◽  
Kazunori Kawamura ◽  
Keiichi Oda ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Ex Vivo ◽  
Emission Tomography ◽  
Positron Emission ◽  
Ex Vivo Autoradiography

scholarly journals Analysis of 18 F-Sodium Fluoride Positron Emission Tomography Signal Sources in Atherosclerotic Minipigs Shows Specific Binding of 18 F-Sodium Fluoride to Plaque Calcifications

2021 ◽  
Author(s):  
Paula Nogales ◽  
Carlos Velasco ◽  
Adriana Mota-Cobián ◽  
Leticia González-Cintado ◽  
Rubén Avelino Mota ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Positron Emission Tomography ◽  
Sodium Fluoride ◽  
Abdominal Aorta ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Emission Tomography ◽  
Iliac Arteries ◽  
Positron Emission

Objective: 18 F-sodium fluoride ( 18 F-NaF) positron emission tomography (PET) imaging is thought to visualize active atherosclerotic plaque calcification. This is supported by the binding of 18 F-NaF to plaque calcification ex vivo, but no prior studies have examined binding of 18 F-NaF to human-like plaque in vivo. Our aim was to validate the specificity of 18 F-NaF PET for plaque calcifications in atherosclerotic minipigs. Approach and Results: Gain-of-function PCSK9 D374Y (proprotein convertase/subtilisin kexin type 9) transgenic Yucatan minipigs (n=4) were fed high-fat diet for 2.5 years to develop atherosclerosis and then subjected to 18 F-NaF PET/computed tomography imaging. The heart, aorta, and iliac arteries were immediately re-scanned ex vivo after surgical extraction. Lesions from the abdominal aorta, iliac arteries, and coronary arteries were cryo-sectioned for autoradiography. Histological plaque characteristics, PET/computed tomography signal, and autoradiography were linked through regression and co-localization analysis. Arterial 18 F-NaF PET signal had intensities comparable to clinical scans and colocalized moderately with calcification detected by computed tomography. Histological analysis showed calcification spanning from microcalcifications near lipid pools and necrotic core to more homogenous macrocalcifications. Comparison with arteries from autopsy cases confirmed the resemblance in localization and appearance with early human plaque calcification. Regression analysis in the abdominal aorta showed correlations with calcified plaque but could not rule out contributions from noncalcified plaque. This was resolved by autoradiography, which showed specific accumulation in plaque calcifications in all examined arteries. In the context of porcine abdominal aorta, 18 F-NaF PET imaging was, however, less accurate than computed tomography for detecting small calcifications. Conclusions: 18 F-NaF accumulates specifically in calcifications of atherosclerotic plaques in vivo.

scholarly journals Radiosynthesis and Biological Investigation of a Novel Fluorine-18 Labeled Benzoimidazotriazine- Based Radioligand for the Imaging of Phosphodiesterase 2A with Positron Emission Tomography

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4149
Author(s):  
Ritawidya ◽  
Wenzel ◽  
Teodoro ◽  
Toussaint ◽  
Kranz ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Specific Binding ◽  
Standardized Uptake Value ◽  
Radiochemical Yield ◽  
Biological Evaluation ◽  
Emission Tomography ◽  
Biological Investigation ◽  
Positron Emission

A specific radioligand for the imaging of cyclic nucleotide phosphodiesterase 2A (PDE2A) via positron emission tomography (PET) would be helpful for research on the physiology and disease-related changes in the expression of this enzyme in the brain. In this report, the radiosynthesis of a novel PDE2A radioligand and the subsequent biological evaluation were described. Our prospective compound 1-(2-chloro-5-methoxy phenyl)-8-(2-fluoropyridin-4-yl)-3- methylbenzo[e]imidazo[5,1-c][1,2,4]triazine, benzoimidazotriazine (BIT1) (IC50 PDE2A = 3.33 nM; 16-fold selectivity over PDE10A) was fluorine-18 labeled via aromatic nucleophilic substitution of the corresponding nitro precursor using the K[18F]F‐K2.2.2‐carbonate complex system. The new radioligand [18F]BIT1 was obtained with a high radiochemical yield (54 ± 2%, n = 3), a high radiochemical purity (≥99%), and high molar activities (155–175 GBq/μmol, n = 3). In vitro autoradiography on pig brain cryosections exhibited a heterogeneous spatial distribution of [18F]BIT1 corresponding to the known pattern of expression of PDE2A. The investigation of in vivo metabolism of [18F]BIT1 in a mouse revealed sufficient metabolic stability. PET studies in mouse exhibited a moderate brain uptake of [18F]BIT1 with a maximum standardized uptake value of ~0.7 at 5 minutes p.i. However, in vivo blocking studies revealed a non-target specific binding of [18F]BIT1. Therefore, further structural modifications are needed to improve target selectivity.

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