ABSTRACT
A new facile synthetic strategy was developed to prepare bifunctional monophosphinic acid Ln-DOTA derivatives, Gd-DO2AGAPNBn and Gd- DO2AGAPABn. The relaxivities of the Gd-complexes are enhanced compared to Gd-DOTA. Monophosphinic acid arm of these Gd-complexes affords enhancement of inner sphere water exchange rate due to its steric bulkiness. The different functionalities of DO2AGAPNBn were appended in trans positions and are designed to conjugate identical or different vectors according to the potential applications. The conjugation of Gd-DO2AGAPABn with E3 peptide known to target apoptosis was successfully performed and in vivo MRI allowed cell death detection in a mouse model.
Subject(s)
Contrast Media/chemistry , Heterocyclic Compounds, 1-Ring/chemistry , Multimodal Imaging , Animals , Contrast Media/chemical synthesis , Dose-Response Relationship, Drug , Female , Heterocyclic Compounds, 1-Ring/chemical synthesis , Magnetic Resonance Imaging , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
TNF- α is one of the most abundant cytokines produced in many inflammatory and autoimmune conditions such as multiple sclerosis, chronic hepatitis C, or neurodegenerative diseases. These pathologies remain difficult to diagnose and consequently difficult to treat. The aim of this work is to offer a new diagnostic tool by seeking new molecular probes for medical imaging. The target-specific part of the probe consists here of heptameric peptides selected by the phage display technology for their affinity for TNF- α . Several affinity tests allowed isolating 2 peptides that showed the best binding capacity to TNF- α . Finally, the best peptide was synthesized in both linear and cyclic forms and tested on the histological sections of concanavalin-A-(ConA-)treated mice liver. In this well-known hepatitis mouse model, the best results were obtained with the cyclic form of peptide 2, which allowed for the staining of inflamed areas in the liver. The cyclic form of peptide 2 (2C) was, thus, covalently linked to iron oxide nanoparticles (magnetic resonance imaging (MRI) contrast agent) and tested in the ConA-induced hepatitis mouse model. The vectorized nanoparticles allowed for the detection of inflammation as well as of the free peptide. These ex vivo results suggest that phage display-selected peptides can direct imaging contrast agents to inflammatory areas.
ABSTRACT
In area CA1 of hippocampal slices, a single 1-sec train of 100-Hz stimulation generally triggers a short-lasting long-term potentiation (S-LTP) of 1-2 h. Here, we found that when such a train was applied 45 min after application of the small conductance Ca(2+)-activated K(+ )(SK) channel blocker apamin, it induced a long-lasting LTP (L-LTP) of several hours, instead of an S-LTP. Apamin-induced SK channel blockage is known to resist washing. Nevertheless, the aforementioned effect is not a mere delayed effect; it is metaplastic. Indeed, when a single train was delivered to the Schaffer's collaterals during apamin application, it induced an S-LTP, like in the control situation. At the moment of this LTP induction (15th min of apamin application), the SK channel blockage was nevertheless complete. Indeed, at that time, under the influence of apamin, the amplitude of the series of field excitatory postsynaptic potentials (fEPSPs) triggered by a stimulation train was increased. We found that the metaplastic effect of apamin on LTP was crucially dependent on the NO-synthase pathway, whereas the efficacy of the NMDA receptors was not modified at the time of its occurrence. We also found that apamin produced an increase in paired-pulse facilitation not during, but after, the application of the drug. Finally, we found that the induction of each of these two metaplastic phenomena was mediated by NMDA receptors. A speculative unitary hypothesis to explain these phenomena is proposed.
