scholarly journals Development and preclinical evaluation of novel fluorinated ammonium salts for PET myocardial perfusion imaging

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ofer Shamni ◽  
Hilbert Grievink ◽  
Netanel Kolevzon ◽  
Seweryn Krajewski ◽  
Lukasz Steczek ◽  
...  
Keyword(s):  
Ammonium Salt ◽  
Ex Vivo ◽  
Small Animal ◽  
Underlying Mechanism ◽  
Ammonium Salts ◽  
Quinolinium Salt ◽  
Organ Uptake ◽  
Major Route ◽  
Pet Myocardial Perfusion Imaging

AbstractWe previously presented the radiolabeled ammonium salt [11C]-dimethyl diphenylammonium trifluoromethanesulfonate ([11C]DMDPA) as a potential novel PET-MPI agent. The current study aimed to increase the clinical applicability of PET-MPI by designing and synthesizing fluorinated ammonium salt derivatives. Four fluorinated DMDPA derivatives and two quinolinium salt analogs were radiolabeled. The dynamic distribution in vivo, following injection of each derivative into male SD rats, was evaluated using small-animal dedicated PET/CT. Organ uptake after injection of [18F]fluoroethylquinolinium acetate ([18F]FEtQ) was examined ex vivo. Four fluorinated DMDPA derivatives were synthesized, two were labeled with fluorine-18: [18F]fluoroethyl-methyldiphenylammonium trifluoromethanesulfonate ([18F]FEMDPA) and [18F]fluorobuthyl-methyldiphenylammonium trifluoromethanesulfonate ([18F]FBMDPA). The other two were labeled using carbon-11: [11C]methyl-(3-fluorophenyl)-methylphenylammonium trifluoromethanesulfonate ([11C]3-F-DMDPA) and [11C]methyl-(4-fluorophenyl)-methylphenylammonium trifluoromethanesulfonate ([11C]4-F-DMDPA). All four DMDPA derivatives exhibited significantly lower heart/liver radioactivity uptake ratios (0.6, 0.4, 0.7 and 0.6, respectively) compared to that of [11C]DMDPA (1.2). Conversely, the two radiolabeled quinolinium salt derivatives, [11C]methylquinolinium iodide ([11C]MeQ) and [18F]FEtQ demonstrated improved heart/liver ratios (2.0 and 1.3, respectively) with clear visualization of the left ventricle myocardium. Renal clearance was the major route of elimination. Among the fluorinated quaternary ammonium salts tested, [18F]FEtQ yielded the best images. Further studies are in progress to elucidate the underlying mechanism of its cardiac uptake.

scholarly journals In VivoVisualization of Heterogeneous Intratumoral Distribution of Hypoxia-Inducible Factor-1αActivity by the Fusion of High-Resolution SPECT and Morphological Imaging Tests

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Hirofumi Fujii ◽  
Masayuki Yamaguchi ◽  
Kazumasa Inoue ◽  
Yasuko Mutou ◽  
Masashi Ueda ◽  
...  
Keyword(s):  
High Resolution ◽  
Ex Vivo ◽  
Hypoxia Inducible Factor ◽  
Chimeric Protein ◽  
Small Animal ◽  
Ct Scanner ◽  
Heterogeneous Distribution ◽  
Fusion Images ◽  
Intratumoral Distribution

Purpose. We aimed to clearly visualize heterogeneous distribution of hypoxia-inducible factor 1α(HIF) activity in tumor tissuesin vivo.Methods. We synthesized of125I-IPOS, a125I labeled chimeric protein probe, that would visualize HIF activity. The biodistribution of125I-IPOS in FM3A tumor-bearing mice was evaluated. Then, the intratumoral localization of this probe was observed by autoradiography, and it was compared with histopathological findings. The distribution of125I-IPOS in tumors was imaged by a small animal SPECT/CT scanner. The obtainedin vivoSPECT-CT fusion images were compared withex vivoimages of excised tumors. Fusion imaging with MRI was also examined.Results.125I-IPOS well accumulated in FM3A tumors. The intratumoral distribution of125I-IPOS by autoradiography was quite heterogeneous, and it partially overlapped with that of pimonidazole. High-resolution SPECT-CT fusion images successfully demonstrated the heterogeneity of125I-IPOS distribution inside tumors. SPECT-MRI fusion images could give more detailed information about the intratumoral distribution of125I-IPOS.Conclusion. High-resolution SPECT images successfully demonstrated heterogeneous intratumoral distribution of125I-IPOS. SPECT-CT fusion images, more favorably SPECT-MRI fusion images, would be useful to understand the features of heterogeneous intratumoral expression of HIF activityin vivo.

scholarly journals In Vivo Imaging of Peripheral Benzodiazepine Receptors in Mouse Lungs: A Biomarker of Inflammation

2005 ◽  
Vol 4 (4) ◽  
pp. 7290.2005.05133 ◽  
Author(s):  
Matthew J. Hardwick ◽  
Ming-Kai Chen ◽  
Kwamena Baidoo ◽  
Martin G. Pomper ◽  
Tomás R. Guilarte
Keyword(s):  
In Vivo Imaging ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
Imaging Techniques ◽  
Benzodiazepine Receptors ◽  
Small Animal ◽  
Small Animal Pet ◽  
Planar Imaging ◽  
Peripheral Benzodiazepine Receptors

The ability to visualize the immune response with radioligands targeted to immune cells will enhance our understanding of cellular responses in inflammatory diseases. Peripheral benzodiazepine receptors (PBR) are present in monocytes and neutrophils as well as in lung tissue. We used lipopolysaccharide (LPS) as a model of inflammation to assess whether the PBR could be used as a noninvasive marker of inflammation in the lungs. Planar imaging of mice administrated 10 or 30 mg/kg LPS showed increased [123I]-( R)-PK11195 radioactivity in the thorax 2 days after LPS treatment relative to control. Following imaging, lungs from control and LPS-treated mice were harvested for ex vivo gamma counting and showed significantly increased radioactivity above control levels. The specificity of the PBR response was determined using a blocking dose of nonradioactive PK11195 given 30 min prior to radiotracer injection. Static planar images of the thorax of nonradioactive PK11195 pretreated animals showed a significantly lower level of radiotracer accumulation in control and in LPS-treated animals ( p < .05). These data show that LPS induces specific increases in PBR ligand binding in the lungs. We also used in vivo small-animal PET studies to demonstrate increased [11C]-( R)-PK11195 accumulation in the lungs of LPS-treated mice. This study suggests that measuring PBR expression using in vivo imaging techniques may be a useful biomarker to image lung inflammation.

scholarly journals Functional Calsequestrin-1 Is Expressed in the Heart and Its Deficiency Is Causally Related to Malignant Hyperthermia-Like Arrhythmia

Circulation ◽  
2021 ◽  
Author(s):  
Zhipeng Sun ◽  
Luqi Wang ◽  
Lu Han ◽  
Yue Wang ◽  
Yuan Zhou ◽  
...  
Keyword(s):  
Heart Rate ◽  
Ventricular Tachycardia ◽  
Malignant Hyperthermia ◽  
Ex Vivo ◽  
Heat Stroke ◽  
Time Lapse ◽  
Underlying Mechanism ◽  
Neonatal Rat ◽  
Polymorphic Ventricular Tachycardia

Background: Calsequestrins (Casqs), comprising the Casq1 and Casq2 isoforms, buffer Ca 2+ and regulate its release in the sarcoplasmic reticulum (SR) of skeletal and cardiac muscle, respectively. Human inherited diseases associated with mutations in CASQ1 or CASQ2 include malignant hyperthermia/environmental heat stroke (MH/EHS) and catecholaminergic polymorphic ventricular tachycardia. However, patients with an MH/EHS event often suffer from arrhythmia for which the underlying mechanism remains unknown. Methods: Working hearts from conventional ( Casq1 -KO) and cardiac-specific ( Casq1 -CKO) Casq1 knockout mice were monitored in vivo and ex vivo by electrocardiogram and electrical mapping, respectively. MH was induced by 2% isoflurane and treated intraperitoneally with dantrolene. Time-lapse imaging was used to monitor intracellular Ca 2+ activity in isolated mouse cardiomyocytes or neonatal rat ventricular myocytes (NRVMs) with knockdown, over-expression or truncation of the Casq1 gene. Conformational change in both Casqs was determined by crosslinking Western blot analysis. Results: Like MH/EHS patients, Casq1 -KO and Casq1 -CKO mice had faster basal heart rate, and ventricular tachycardia upon exposure to 2% isoflurane, which could be relieved by dantrolene. Basal sinus tachycardia and ventricular ectopic electrical triggering also occurred in Casq1 -KO hearts ex vivo . Accordingly, the ventricular cardiomyocytes from Casq1 -CKO mice displayed dantrolene-sensitive increased Ca 2+ waves and diastole premature Ca 2+ transients/oscillations upon isoflurane. NRVMs with Casq1-knockdown had enhanced spontaneous Ca2+ sparks/transients upon isoflurane, while cells over-expressing Casq1 exhibited decreased Ca2+ sparks/transients that were absent in cells with truncation of 9 amino acids at the C-terminus of Casq1. Structural evaluation showed that most of the Casq1 protein was present as a polymer and physically interacted with RyR2 in the ventricular SR. The Casq1 isoform was also expressed in human myocardium. Mechanistically, exposure to 2% isoflurane or heating at 41ºC induced Casq1 oligomerization in mouse ventricular and skeletal muscle tissues, leading to a reduced Casq1/RyR2 interaction and increased RyR2 activity in the ventricle. Conclusions: Casq1 is expressed in the heart, where it regulates SR Ca 2+ release and heart rate. Casq1 deficiency independently causes MH/EHS-like ventricular arrhythmia by trigger-induced Casq1 oligomerization and a relief of its inhibitory effect on RyR2-mediated Ca 2+ release, thus revealing a new inherited arrhythmia and a novel mechanism for MH/EHS arrhythmogenesis.

Abstract 1767: Feasibility of In Vivo Cardiac Stem Cell Tracking, by SPECT and PET Imaging, Using the Sodium-iodide Symporter as Reporter Gene

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
John Terrovitis ◽  
Keng Fai Kwok ◽  
Riikka Läutamaki ◽  
James M Engles ◽  
Andreas S Barth ◽  
...  
Keyword(s):  
Stem Cell ◽  
Reporter Gene ◽  
Cell Tracking ◽  
Ex Vivo ◽  
Small Animal ◽  
Cell Labeling ◽  
Sodium Iodide Symporter ◽  
Cell Injection

Background. Stem cells offer the promise of cardiac repair. Stem cell labeling is a prerequisite to tracking cell fate in vivo . Aim. To develop a reporter gene that permits in vivo stem cell labeling. We examined the sodium-iodide symporter (NIS), a protein that is not expressed in the heart, but promotes cellular uptake of 99m Tc or 124 I, thus permitting cell tracking by SPECT or PET imaging, respectively. Methods. The human NIS gene ( h NIS) was expressed in rat cardiac derived stem cells (rCDCs) using lentivirus driven by the CAG or CMV promoter. NIS function in transduced cells was confirmed by in vitro 99m Tc uptake. Eleven rats were injected with 1 or 2 million rCDCs intramyocardially immediately after LAD ligation; 6 with CMV-NIS and 5 with CAG-NIS cells. Dual isotope SPECT imaging was performed on a small animal SPECT/CT system, using 99m Tc for cell detection and 201 Tl for myocardial delineation, 24 hrs after cell injection. PET was performed on a small animal PET scanner using 124 I for cell tracking and 13 NH 3 for myocardial delineation, 48hrs after cell injection. Contrast Ratio (CR) was defined as [(signal in the cells)-(signal in blood pool)]/signal in blood pool. High resolution ex vivo SPECT scans of explanted hearts (n=3) were obtained to confirm that in vivo signal was derived from the cell injection site. The presence of h NIS mRNA was confirmed in injected hearts after animal sacrifice (n=2), by real-time RT-PCR. Results. NIS expression in rCDCs did not affect cell viability/proliferation (p=0.718, ctr vs NIS). In vitro 99m Tc uptake was 6.0±0.9% vs 0.07±0.05, without and with perchlorate (specific NIS blocker), respectively. NIS-transduced rCDCs were easily visualized as spots of 99m Tc or 124 I uptake within a perfusion deficit in the SPECT and PET images. CR was considerably higher when cells were transduced by the CMV-NIS virus in comparison to the CAG-NIS virus (70±40% vs 28±29%, p=0.085). Ex vivo small animal SPECT imaging confirmed that in vivo 99m Tc signals were localized to the injection sites. PCR confirmed the presence of h NIS mRNA in injected hearts. Conclusion. NIS expression allows non invasive in vivo stem cell tracking in the myocardium, using both SPECT and PET. This reporter gene has great potential for translation in future clinical applications.

Abstract 401: Experimental Aneurysm in Rats Excluded by Stent Graft: A New Model to Assess the Impact of Endovascular Aneurysm Repair on the Pathophysiology of Abdominal Aortic Aneurysm.

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Martin Rouer ◽  
Martin Rouer ◽  
Jean-Marc Alsac ◽  
Jean-Baptiste Michel
Keyword(s):  
Experimental Model ◽  
Ex Vivo ◽  
Endovascular Aneurysm Repair ◽  
Small Animal ◽  
Normal Diet ◽  
Biological Study ◽  
Experimental Aneurysm ◽  
Midline Laparotomy ◽  
The Impact

Introduction Biological study of the impact of endovascular aortic repair (EVAR) on pathophysiology of aortic abdominal aneurysms (AAA) can only be performed indirectly in humans, by imaging or search for peripheral biomarkers in the circulating blood. Therefore biological mechanism’s modifications into the aneurismal wall related to its endovascular exclusion are still to be elucidated, and small animal models should bring a valuable help in this field. We describe a new experimental model of stentgraft implantation for the exclusion of AAA in rats. Methods Aneurysms were induced as previously described by intra-aortic elastase injection in Wistar rats, or by aortic decellularized xenograft transplantation in Lewis rats. At least 15 days later, the midline laparotomy was reopened, and 3mm covered stentgraft were inserted and deployed in the AAA to obtain its exclusion. The patency of the graft and the AAA exclusion could be assessed by a global arteriogram through the carotid artery. After closure of the laparotomy, the rats were awakened and returned to a normal diet. Results This experimental model of AAA exclusion by a stentgraft allows many in vivo and ex vivo studies of the pathophysiology of AAA after EVAR. Histological modifications of the aortic wall and the intra-luminal thrombus could be assessed. The impact of EVAR on the adventitial immuno-inflammatory activity could be studied by different imaging such as MRI, scintigraphy or PET-scan. In situ biological and enzymatic activities could be evaluated to better understand the local mechanisms leading to AAA shrinkage or expansion after EVAR. Conclusion Exclusion by stentgraft of experimental AAA in rats is the first described model of EVAR in small animals. It is feasible and reproducible for both elastase and xenograft experimental AAA models. This model will definitely help to a better analysis and understanding of the impact of stentgrafting on biological mechanisms in the aneurismal wall, that lead to EVAR success with shrinkage of aneurismal sac or EVAR failure with its continuing expansion.

scholarly journals Single-cell resolution in high-resolution synchrotron X-ray CT imaging with gold nanoparticles

2013 ◽  
Vol 21 (1) ◽  
pp. 242-250 ◽  
Author(s):  
Elisabeth Schültke ◽  
Ralf Menk ◽  
Bernd Pinzer ◽  
Alberto Astolfo ◽  
Marco Stampanoni ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Single Cell ◽  
Brain Tumour ◽  
Ex Vivo ◽  
Small Animal ◽  
C6 Glioma Cells ◽  
X Ray ◽  
Local Tomography ◽  
The Brain

Gold nanoparticles are excellent intracellular markers in X-ray imaging. Having shown previously the suitability of gold nanoparticles to detect small groups of cells with the synchrotron-based computed tomography (CT) technique bothex vivoandin vivo, it is now demonstrated that even single-cell resolution can be obtained in the brain at leastex vivo. Working in a small animal model of malignant brain tumour, the image quality obtained with different imaging modalities was compared. To generate the brain tumour, 1 × 105C6 glioma cells were loaded with gold nanoparticles and implanted in the right cerebral hemisphere of an adult rat. Raw data were acquired with absorption X-ray CT followed by a local tomography technique based on synchrotron X-ray absorption yielding single-cell resolution. The reconstructed synchrotron X-ray images were compared with images obtained by small animal magnetic resonance imaging. The presence of gold nanoparticles in the tumour tissue was verified in histological sections.

scholarly journals Citrulline directly modulates muscle protein synthesis via the PI3K/MAPK/4E-BP1 pathway in a malnourished state: evidence from in vivo, ex vivo, and in vitro studies

2017 ◽  
Vol 312 (1) ◽  
pp. E27-E36 ◽  
Author(s):  
Servane Le Plénier ◽  
Arthur Goron ◽  
Athanassia Sotiropoulos ◽  
Eliane Archambault ◽  
Chantal Guihenneuc ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Ex Vivo ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Fold Increase ◽  
Underlying Mechanism ◽  
Muscle Homeostasis

Citrulline (CIT) is an endogenous amino acid produced by the intestine. Recent literature has consistently shown CIT to be an activator of muscle protein synthesis (MPS). However, the underlying mechanism is still unknown. Our working hypothesis was that CIT might regulate muscle homeostasis directly through the mTORC1/PI3K/MAPK pathways. Because CIT undergoes both interorgan and intraorgan trafficking and metabolism, we combined three approaches: in vivo, ex vivo, and in vitro. Using a model of malnourished aged rats, CIT supplementation activated the phosphorylation of S6K1 and 4E-BP1 in muscle. Interestingly, the increase in S6K1 phosphorylation was positively correlated ( P < 0.05) with plasma CIT concentration. In a model of isolated incubated skeletal muscle from malnourished rats, CIT enhanced MPS (from 30 to 80% CIT vs. Ctrl, P < 0.05), and the CIT effect was abolished in the presence of wortmannin, rapamycin, and PD-98059. In vitro, on myotubes in culture, CIT led to a 2.5-fold increase in S6K1 phosphorylation and a 1.5-fold increase in 4E-BP1 phosphorylation. Both rapamycin and PD-98059 inhibited the CIT effect on S6K1, whereas only LY-294002 inhibited the CIT effect on both S6K1 and 4E-BP1. These findings show that CIT is a signaling agent for muscle homeostasis, suggesting a new role of the intestine in muscle mass control.

scholarly journals A Semi Rigid Novel Hydroxamate AMPED-Based Ligand for 89Zr PET Imaging

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5819
Author(s):  
Lisa Russelli ◽  
Francesco De Rose ◽  
Loredana Leone ◽  
Sybille Reder ◽  
Markus Schwaiger ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Ex Vivo ◽  
Small Animal ◽  
Biologically Active ◽  
Small Animal Pet ◽  
Organ Distribution ◽  
Complexing Agent ◽  
Distribution Studies

In this work, we designed, developed, characterized, and investigated a new chelator and its bifunctional derivative for 89Zr labeling and PET-imaging. In a preliminary study, we synthesized two hexadentate chelators named AAZTHAS and AAZTHAG, based on the seven-membered heterocycle AMPED (6-amino-6-methylperhydro-1,4-diazepine) with the aim to increase the rigidity of the 89Zr complex by using N-methyl-N-(hydroxy)succinamide or N-methyl-N-(hydroxy)glutaramide pendant arms attached to the cyclic structure. N-methylhydroxamate groups are the donor groups chosen to efficiently coordinate 89Zr. After in vitro stability tests, we selected the chelator with longer arms, AAZTHAG, as the best complexing agent for 89Zr presenting a stability of 86.4 ± 5.5% in human serum (HS) for at least 72 h. Small animal PET/CT static scans acquired at different time points (up to 24 h) and ex vivo organ distribution studies were then carried out in healthy nude mice (n = 3) to investigate the stability and biodistribution in vivo of this new 89Zr-based complex. High stability in vivo, with low accumulation of free 89Zr in bones and kidneys, was measured. Furthermore, an activated ester functionalized version of AAZTHAG was synthesized to allow the conjugation with biomolecules such as antibodies. The bifunctional chelator was then conjugated to the human anti-HER2 monoclonal antibody Trastuzumab (Tz) as a proof of principle test of conjugation to biologically active molecules. The final 89Zr labeled compound was characterized via radio-HPLC and SDS-PAGE followed by autoradiography, and its stability in different solutions was assessed for at least 4 days.

The Cole Relaxation Frequency as a Parameter to Identify Cancer in Lung Tissue: Preliminary Animal and ex vivo Patient Studies (Preprint)

2021 ◽  
Author(s):  
Les Bogdanowicz ◽  
Onur Fidaner ◽  
Donato Ceres ◽  
Alex Grycuk ◽  
David Demos
Keyword(s):  
Lung Cancer ◽  
Ex Vivo ◽  
Human Subjects ◽  
Small Animal ◽  
Relaxation Frequency ◽  
Normal Tissues ◽  
Electrical Bioimpedance ◽  
Benign Nodules ◽  
Porcine Lungs

UNSTRUCTURED Lung cancer is the world’s leading cause of cancer deaths, and diagnosis remains challenging. Lung cancer starts as small nodules; early and accurate diagnosis allows timely surgical resection of malignant nodules while avoiding unnecessary surgery in patients with benign nodules. The Cole Relaxation Frequency (CRF) is a derived electrical bioimpedance signature, which may be utilized to distinguish cancerous tissues from normal tissues. Here we show that CRF allows for diagnosis of cancer in human subjects, based on evaluation of 60 specimens obtained from 30 patients. We observed clear discrimination of CRF values in tumor and distant normal tissues, resulting in a high degree of sensitivity (97%) and specificity (87%) in cancer diagnosis. Furthermore, we tested 20 xenograft small animal model specimens, observing a similar separation of CRF values as in the human in-vivo measurements. We also obtained CRF measurements in pressurized and unpressurized lungs by implanting tumors into ex-vivo porcine lungs. CRF measurements align with previous tests in human and small animal models.

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