Refine
Has Fulltext
- yes (16) (remove)
Is part of the Bibliography
- yes (16) (remove)
Document Type
- Journal article (16)
Language
- English (16)
Keywords
- positron emission tomography (3)
- kinetics (2)
- natural products (2)
- norepinephrine transporter (2)
- sympathetic nervous system (2)
- AD mouse modele (1)
- Alzheimer's diseas (1)
- Alzheimer's disease (1)
- Alzheimer’s disease (1)
- Alzheimer′s disease (1)
- Eriodictyon californicum (1)
- FV45 (1)
- Flavonoids (1)
- G-protein coupled receptor (1)
- In vivo studies (1)
- Microglia (1)
- Mitsunobu (1)
- Natural product hybrids (1)
- PET (1)
- Phenolic acids (1)
- Positronen-Emissions-Tomografie (1)
- SPECT (1)
- T-shaped π-π stacking (1)
- T-shaped π–π stacking (1)
- amber light (1)
- amyloid beta (1)
- amyloid-β (Aβ) (1)
- angiotensin II type 1 receptor (1)
- azobenzenes (1)
- bioisosterism (1)
- biophysics (1)
- butyrylcholinesterase (1)
- carbamate (1)
- cardiac innervation imaging (1)
- cardiac neurohormonal system (1)
- chiral resolution (1)
- circular dichroism (1)
- decafluoroazobezene (1)
- dehydration (1)
- enzyme kinetics (1)
- enzymes (1)
- flavonoid (1)
- flavonoids (1)
- fluorescent ligands (1)
- fluorescent probes (1)
- fluorine-18 (1)
- heart failure (1)
- homodimerization (1)
- hydnocarpin (1)
- hydrolysis (1)
- imaging (1)
- microscopy (1)
- molecular mechanics (1)
- natural product hybrids (1)
- neuroprotectivity (1)
- nonhuman primates (1)
- nuclear cardiology (1)
- opioid ligands (1)
- opioid receptors (1)
- oxytosis/ferroptosis (1)
- peptide stapling (1)
- perfluoroarylation (1)
- photocontrol (1)
- photopharmacology (1)
- quantum mechanics (1)
- radiotracer (1)
- radiotracer kinetics (1)
- radiotracers (1)
- renin-angiotensin system (1)
- replica-exchange molecular dynamics (1)
- silybin (1)
- single-molecule microscopy (1)
- sterubin (1)
- structure–activity relationships (1)
- tacrine (1)
- valsartan (1)
Institute
- Institut für Pharmazie und Lebensmittelchemie (16)
- Klinik und Poliklinik für Nuklearmedizin (6)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (1)
- Institut für Anorganische Chemie (1)
- Institut für Organische Chemie (1)
- Institut für Pharmakologie und Toxikologie (1)
- Institut für Physikalische und Theoretische Chemie (1)
- Lehrstuhl für Tissue Engineering und Regenerative Medizin (1)
Sonstige beteiligte Institutionen
EU-Project number / Contract (GA) number
- 701983 (1)
Opioid receptors (ORs) are classified among the oldest and best investigated drug targets due to their fundamental role in the treatment of pain and related disorders. ORs are divided in three conventional subtypes (μ, κ, δ) and the non‐classical nocicepetin receptor. All ORs are family A G protein‐coupled receptors (GPCRs), and are located on the cell surface. Modern biophysical methods use light to investigate physiological processes at organismal, cellular and subcellular level. Many of these methods rely on fluorescent ligands, thus highlighting their importance. This review addresses the advancements in the development of opioid fluorescent ligands and their use in biological, pharmacological and imaging applications.
μ‐Opioid receptors (μ‐ORs) play a critical role in the modulation of pain and mediate the effects of the most powerful analgesic drugs. Despite extensive efforts, it remains insufficiently understood how μ‐ORs produce specific effects in living cells. We developed new fluorescent ligands based on the μ‐OR antagonist E‐p‐nitrocinnamoylamino‐dihydrocodeinone (CACO), that display high affinity, long residence time and pronounced selectivity. Using these ligands, we achieved single‐molecule imaging of μ‐ORs on the surface of living cells at physiological expression levels. Our results reveal a high heterogeneity in the diffusion of μ‐ORs, with a relevant immobile fraction. Using a pair of fluorescent ligands of different color, we provide evidence that μ‐ORs interact with each other to form short‐lived homodimers on the plasma membrane. This approach provides a new strategy to investigate μ‐OR pharmacology at single‐molecule level.
Background: Radiolabeled agents that are substrates for the norepinephrine transporter (NET) can be used to quantify cardiac sympathetic nervous conditions and have been demonstrated to identify high-risk congestive heart failure (HF) patients prone to arrhythmic events. We aimed to fully characterize the kinetic profile of the novel \(^{18}\)F-labeled NET probe AF78 for PET imaging of the cardiac sympathetic nervous system (SNS) among various species.
Methods: \(^{18}\)F-AF78 was compared to norepinephrine (NE) and established SNS radiotracers by employing in vitro cell assays, followed by an in vivo PET imaging approach with healthy rats, rabbits and nonhuman primates (NHPs). Additionally, chase protocols were performed in NHPs with NET inhibitor desipramine (DMI) and the NE releasing stimulator tyramine (TYR) to investigate retention kinetics in cardiac SNS.
Results: Relative to other SNS radiotracers, 18F-AF78 showed higher transport affinity via NET in a cell-based competitive uptake assay (IC\(^{50}\) 0.42 ± 0.14 µM), almost identical to that of NE (IC\(^{50}\), 0.50 ± 0.16 µM, n.s.). In rabbits and NHPs, initial cardiac uptake was significantly reduced by NET inhibition. Furthermore, cardiac tracer retention was not affected by a DMI chase protocol but was markedly reduced by intermittent TYR chase, thereby suggesting that \(^{18}\)F-AF78 is stored and can be released via the synaptic vesicular turnover process. Computational modeling hypothesized the formation of a T-shaped π-π stacking at the binding site, suggesting a rationale for the high affinity of \(^{18}\)F-AF78.
Conclusion: \(^{18}\)F-AF78 demonstrated high in vitro NET affinity and advantageous in vivo radiotracer kinetics across various species, indicating that \(^{18}\)F-AF78 is an SNS imaging agent with strong potential to guide specific interventions in cardiovascular medicine.
Heart failure is one of the growing causes of death especially in developed countries due to longer life expectancy. Although many pharmacological and instrumental therapeutic approaches have been introduced for prevention and treatment of heart failure, there are still limitations and challenges. Nuclear cardiology has experienced rapid growth in the last few decades, in particular the application of single photon emission computed tomography (SPECT) and positron emission tomography (PET), which allow non-invasive functional assessment of cardiac condition including neurohormonal systems involved in heart failure; its application has dramatically improved the capacity for fundamental research and clinical diagnosis. In this article, we review the current status of applying radionuclide technology in non-invasive imaging of neurohormonal system in the heart, especially focusing on the tracers that are currently available. A short discussion about disadvantages and perspectives is also included.
Renin–angiotensin system (RAS) plays an important role in the regulation of blood pressure and hormonal balance. Using positron emission tomography (PET) technology, it is possible to monitor the physiological and pathological distribution of angiotensin II type 1 receptors (AT\(_1\)), which reflects the functionality of RAS. A new \(^{18}\)F-labeled PET tracer derived from the clinically used AT\(_1\) antagonist valsartan showing the least possible chemical alteration from the valsartan structure has been designed and synthesized with several strategies, which can be applied for the syntheses of further derivatives. Radioligand binding study showed that the cold reference FV45 (K\(_i\) 14.6 nM) has almost equivalent binding affinity as its lead valsartan (K\(_i\) 11.8 nM) and angiotensin II (K\(_i\) 1.7 nM). Successful radiolabeling of FV45 in a one-pot radiofluorination followed by the deprotection procedure with 21.8 ± 8.5% radiochemical yield and >99% radiochemical purity (n = 5) enabled a distribution study in rats and opened a path to straightforward large-scale production. A fast and clear kidney uptake could be observed, and this renal uptake could be selectively blocked by pretreatment with AT\(_1\)-selective antagonist valsartan. Overall, as the first \(^{18}\)F-labeled PET tracer based on a derivation from clinically used drug valsartan with almost identical chemical structure, [\(^{18}\)F]FV45 will be a new tool for assessing the RAS function by visualizing AT\(_i\) receptor distributions and providing further information regarding cardiovascular system malfunction as well as possible applications in inflammation research and cancer diagnosis.
Amber Light Control of Peptide Secondary Structure by a Perfluoroaromatic Azobenzene Photoswitch
(2023)
The incorporation of photoswitches into the molecular structure of peptides and proteins enables their dynamic photocontrol in complex biological systems. Here, a perfluorinated azobenzene derivative triggered by amber light was site‐specifically conjugated to cysteines in a helical peptide by perfluoroarylation chemistry. In response to the photoisomerization (trans→cis) of the conjugated azobenzene with amber light, the secondary structure of the peptide was modulated from a disorganized into an amphiphilic helical structure.