The expression and function of endothelin (ET) receptors are abnormal in cardiovascular diseases, tumor progression, and tumor metastasis. A previously reported promising radioligand for positron ...emission tomography (PET) based on the non-peptide ETA receptor antagonist PD 156707 showed specific binding to target receptors in the myocardium but high accumulation in bile and intestine, probably because of its high lipophilicity. In this study we describe the synthesis of a series of fluorinated derivatives with hydrophilic building blocks. All compounds were evaluated as high affinity ETA receptor ligands (16, 17, 23−26, K i = 1.4−7.9 nM) with high subtype selectivity over the ETB receptor. 18F3-Benzo1,3dioxol-5-yl-4-{3-1-(2-{2-2-(2-fluoroethoxy)ethoxyethoxy}ethyl)-1H-1,2,3triazol-4-ylmethoxy-4,5-dimethoxybenzyl}-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one (18F17) was synthesized as one of the radioligands of this series that possesses a higher hydrophilicity and an excellent stability in human serum. Improved clearance properties and specific uptake in target organs have been confirmed by biodistribution studies and small animal PET imaging.
Although the objectives of the
Energiewende
(energy transition) are broadly accepted in Germany, the practical ways of achieving them remain highly contentious. In particular, the question of whether ...and how security of supply can be guaranteed over the course of this profound transformation of the energy system is currently the subject of controversy in the scientific and public debate. Recently, calls for additional payments to power plant operators for providing generation capacity have grown increasingly loud. But the introduction of capacity payments of this sort could have far-reaching consequences for the future organisation of Germany’s electricity supply. Therefore, the political decision on this issue - which is scheduled for this year - should not be made without a sound scientific analysis.
Basically, measures aimed at guaranteeing security of supply must address the possible causes of capacity shortages as broadly as possible. When designing such measures, besides security of supply, additional objectives such as cost-effectiveness and the environmental and social acceptability of electricity supply should also be taken into account. Capacity payments only partially meet these requirements. Moreover, once introduced, they are difficult to adapt, or revise even, to suit changing framework conditions. This is particularly problematic in view of the current lack of clear evidence for future security of supply problems. Therefore, introducing capacity payments at this point in time would not appear to be constructive. It would make more sense to introduce instead a mix of measures which would strengthen the electricity market, create conditions for feeding in electricity from renewable energy sources as and when required, and set incentives for the expansion of grid capacity, storage systems and demand side management. Should security of supply still appear uncertain under these changed framework conditions, the introduction of a strategic reserve, which would be held by the regulatory authority or the transmission system operator, is recommended - not, however, the creation of an entirely new, additional market segment in the form of a capacity market.
Background
The “back-translation” of clinically available protocols to measure myocardial perfusion to preclinical imaging in mouse models of human disease is attractive for basic biomedical ...research. With respect to single-photon emission computed tomography (SPECT) approaches, clinical myocardial perfusion imaging protocols are established with different
99m
Tc-labeled perfusion tracers; however, studies evaluating and optimizing protocols for these tracers in high-resolution pinhole SPECT in mice are lacking. This study aims at evaluating two clinically available
99m
Tc-labeled myocardial perfusion tracers (
99m
Tc-sestamibi vs.
99m
Tc-Tetrofosmin) in mice using four different imaging protocols.
Methods
Adult C57BL/6 male mice were injected with
99m
Tc-sestamibi (MIBI) or
99m
Tc-Tetrofosmin (TETRO) (4 MBq/g body weight) either intravenously through the tail vein (
n
= 5) or retroorbitally (
n
= 5) or intraperitoneally (i.p.) under anesthesia (
n
= 3) or i.p. in an awake state (
n
= 3) at rest. Immediately after injection, a multi-frame single-photon emission computed tomography/computed tomography (SPECT/CT) acquisition was initiated with six subsequent time frames of 10 min each. Reconstructed images of the different protocols were assessed and compared by visual analysis by experts and by time-activity-curves generated from regions-of-interest for various organs (normalized uptake values).
Results
Visually assessing overall image quality, the best image quality was found for MIBI for both intravenous injection protocols, whereas TETRO only had comparable image quality after retroorbital injections. These results were confirmed by quantitative analysis where left ventricular (LV) uptake of MIBI after tail vein injections was found significantly higher for all time points accompanied with a significantly slower washout of 16% for MIBI vs. 33% for TETRO (
p
= 0.009) from 10 to 60 min post injection (PI). Interestingly, LV washout from 10 to 60 min PI was significantly higher for TETRO when applied by tail vein injections when compared to retroorbital injections (22%,
p
= 0.008). However, liver uptake was significant and comparable for both tracers at all time points. Radioactivity concentration in the lungs was negligible for all time points and both tracers.
Conclusion
Intravenous MIBI injection (both tail vein and retroorbital) results in the best image quality for assessing myocardial perfusion of the murine heart by SPECT/CT. TETRO has a comparable image quality only for the retroorbital injection route.
Abstract
Background
Increased central venous pressure is inherent in Fontan circulation but not strongly related to Fontan complication. Abnormalities of the lymphatic circulation may play a crucial ...role in early Fontan complications.
Methods
This was a retrospective, single-center study of patients undergoing Fontan operation from 2008 to 2015. The primary outcome was significant early Fontan complication defined as secondary in-hospital treatment due to peripheral edema, ascites, pleural effusions, protein-losing enteropathy, or plastic bronchitis. All patients received T2-weighted magnetic resonance images to assess abdominal and thoracic lymphatic perfusion pattern 6 months after Fontan completion with respect to localization, distribution, and extension of lymphatic perfusion pattern (type 1–4) and with application of an area score (0–12 points).
Results
Nine out of 42 patients developed early Fontan complication. Patients with complication had longer chest tube drainage (mean 28 interquartile range IQR: 13–60 vs. 13 IQR: 2–22 days,
p
= 0.01) and more often obstructions in the Fontan circuit 6 months after surgery (56 vs. 15%,
p
= 0.02). Twelve patients showed little or no abnormalities of lymphatic perfusion (lymphatic perfusion pattern type 1). Most frequently magnetic resonance imaging showed lymphatic congestion in the supraclavicular region (24/42 patients). Paramesenteric lymphatic congestion was observed in eight patients. Patients with early Fontan complications presented with higher lymphatic area score (6 min–max: 2–10 vs. 2 min–max: 0–8),
p
= 0.001) and greater distribution and extension of thoracic lymphatic congestion (type 3–4:
n
= 5/9 vs.
n
= 1/33,
p
= 0.001).
Conclusion
Early Fontan complication is related to hemodynamic factors such as circuit obstruction and to the occurrence and extent of lymphatic congestion.
Molecular imaging allows the noninvasive assessment of cancer progression and response to therapy. The aim of this study was to investigate molecular and cellular determinants of ...3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET and diffusion-weighted (DW) MR imaging in lung carcinoma xenografts.
Four lung cancer cell lines (A549, HTB56, EBC1, and H1975) were subcutaneously implanted in nude mice, and growth was followed by caliper measurements. Glucose uptake and tumor proliferation were determined by (18)F-FDG and (18)F-FLT PET, respectively. T2-weighted MR imaging was performed, and the apparent diffusion coefficient (ADC) was determined by DW MR imaging as an indicator of cell death. Imaging findings were correlated to histology with markers for tumor proliferation (Ki67, 5-bromo-2'-deoxyuridine BrdU) and cell death (caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling). The expression of human equilibrative nucleoside transporter 1 (hENT1), thymidine kinase 1 (TK1), thymidylate synthase, and thymidine phosphorylase (TP) were analyzed by Western blot and immunohistochemistry. Thymidine levels were determined by liquid chromatography-mass spectrometry.
Xenografts varied with respect to in vivo growth rates. MR imaging and PET revealed intratumoral heterogeneities, which were confirmed by histology. (18)F-FLT uptake differed significantly between tumor lines, with A549 and H1975 demonstrating the highest radiotracer accumulation (A549, 8.5 ± 3.2; HTB56, 4.4 ± 0.7; EBC1, 4.4 ± 1.2; and H1975, 12.1 ± 3.5 maximal percentage injected dose per milliliter). In contrast, differences in (18)F-FDG uptake were only marginal. No clear relationship between (18)F-FLT accumulation and immunohistochemical markers for tumor proliferation (Ki67, BrdU) as well as hENT1, TK1, or TS expression was detected. However, TP was highly expressed in A549 and H1975 xenografts, which was accompanied by low tumor thymidine concentrations, suggesting that tumor thymidine levels influence (18)F-FLT uptake in the tumor models investigated. MR imaging revealed higher ADC values within proliferative regions of H1975 and A549 tumors than in HTB56 and EBC1. These ADC values were negatively correlated with cell density but not directly related to cell death.
A direct relationship of (18)F-FLT with proliferation or ADC with cell death might be complicated by the interplay of multiple processes at the cellular and physiologic levels in untreated tumors. This issue must be considered when using these imaging modalities in preclinical or clinical settings.
Molecular imaging allows the noninvasive assessment of cancer progression and response to therapy. The aim of this study was to investigate molecular and cellular determinants of ...3'-deoxy-3'-...F-fluorothymidine (...F-FLT) PET and diffusion-weighted (DW) MR imaging in lung carcinoma xenografts. Four lung cancer cell lines (A549, HTB56, EBC1, and H1975) were subcutaneously implanted in nude mice, and growth was followed by caliper measurements. Glucose uptake and tumor proliferation were determined by ...F-FDG and ...F-FLT PET, respectively. T2-weighted MR imaging was performed, and the apparent diffusion coefficient (ADC) was determined by DW MR imaging as an indicator of cell death. Imaging findings were correlated to histology with markers for tumor proliferation (Ki67, 5-bromo-2'-deoxyuridine BrdU) and cell death (caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling). The expression of human equilibrative nucleoside transporter 1 (hENT1), thymidine kinase 1 (TK1), thymidylate synthase, and thymidine phosphorylase (TP) were analyzed by Western blot and immunohistochemistry. Thymidine levels were determined by liquid chromatography-mass spectrometry. Xenografts varied with respect to in vivo growth rates. MR imaging and PET revealed intratumoral heterogeneities, which were confirmed by histology. ...F-FLT uptake differed significantly between tumor lines, with A549 and H1975 demonstrating the highest radiotracer accumulation (A549, 8.5 ± 3.2; HTB56, 4.4 ± 0.7; EBC1, 4.4 ± 1.2; and H1975, 12.1 ± 3.5 maximal percentage injected dose per milliliter). In contrast, differences in ...F-FDG uptake were only marginal. No clear relationship between ...F-FLT accumulation and immunohistochemical markers for tumor proliferation (Ki67, BrdU) as well as hENT1, TK1, or TS expression was detected. However, TP was highly expressed in A549 and H1975 xenografts, which was accompanied by low tumor thymidine concentrations, suggesting that tumor thymidine levels influence ...F-FLT uptake in the tumor models investigated. MR imaging revealed higher ADC values within proliferative regions of H1975 and A549 tumors than in HTB56 and EBC1. These ADC values were negatively correlated with cell density but not directly related to cell death. A direct relationship of ...F-FLT with proliferation or ADC with cell death might be complicated by the interplay of multiple processes at the cellular and physiologic levels in untreated tumors. This issue must be considered when using these imaging modalities in preclinical or clinical settings. (ProQuest: ... denotes formulae/symbols omitted.)
Today, non-invasive imaging techniques are significantly contributing to the understanding of molecular processes
in vivo. Positron emission tomography (PET) is a scintigraphic medical imaging ...modality that uses radiolabelled molecules (tracers), provides quantitative tomographic images and allows non-invasive assessment of the biodistribution of radioactive substances
in vivo. The assessment of pathological glucose metabolism is the clinically best-established application of PET today; however, a multitude of different tracers are available to assess diverse physiological processes. The growing interest in pre-clinical imaging studies, in biological and medical basic research, as well as in pharmaceutical research, has fostered the recent growth in small-animal PET. Small-animal PET can be applied to enable the transfer from molecular findings in vitro to
in vivo applications in humans, from bench to bed side.
PDF
