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Significance The duration of cerebral ischemia is a key factor in determining the severity of brain damage and the course of action. Thus, an accurate and timely observation of the ischemic process is highly critical. Here we present a molecular neuroimaging approach that enables direct detection and real-time visualization of transient cerebral ischemia. The method relies on high-resolution observation of extracellular calcium alterations associated with the spatiotemporal dynamics of cerebral ischemia, using a selective molecular MRI probe. The rapid detection of calcium fluctuations in healthy and disease states will not only lead to essential insights for successful treatment and recovery of ischemic brain tissue but will also improve our understanding of the underlying neurobiology of neurological and psychiatric disorders., Cerebral ischemia is one of the leading causes of mortality and disability in infants and adults and its timely diagnosis is essential for an efficient treatment. We present a methodology for fast detection and real-time monitoring of fluctuations of calcium ions associated with focal ischemia using a molecular functional MRI approach. We used a dinuclear paramagnetic gadolinium(III) complex chelate that changes MR image contrast through its reversible interaction with extracellular calcium ions, while applying a remote transient middle cerebral artery occlusion as a model for ischemic stroke. Our method sensitively recognizes the onset and follows the dynamics of the ischemic core and penumbra with submillimeter spatial and second-scale temporal resolution, thus paving the way for noninvasive monitoring and development of targeted treatment strategies for cerebral ischemia.

We present a detailed study of the lanthanide(III) complexes with cyclen-based ligands containing phenylacetamide pendants that incorporate CF3 group(s) at different distances from the metal ion. The complexes exhibit square-antiprismatic coordination in solution, as demonstrated by analysis of the Yb3+-induced paramagnetic shifts and the X-ray structure of the [YbL3] complex. Luminescence lifetime measurements and a detailed 1H and 17O relaxometric characterization confirmed the presence of an inner-sphere H2O molecule. The Tm3+ complexes provide chemical-exchange saturation-transfer response upon saturation at the frequency of the amide protons. A 19F relaxation study provided accurate estimates of the Ln···F distances that were used to rationalize the efficiency of the complexes as 19F magnetic resonance imaging (MRI) probes, which was tested in vitro using MRI phantom studies.

We present two novel octadentate cyclen-based ligands bearing one (L1 ) or two (L2 ) phenylacetamide pendants with two CF3 groups either at positions 3 and 5 (L1 ) or 4 (L2 ). The corresponding Gd3+ complexes possess one coordinated water molecule, as confirmed by luminescence lifetime measurements on the EuIII and TbIII analogues. A detailed 1 H and 17 O relaxometric characterization has revealed the parameters that govern the relaxivities of these complexes. The water-exchange rate of the mono-amide derivative GdL1 (kex298 =1.52×106 s-1 ) is faster than that determined for the bis-amide complex GdL2 (kex298 =0.73×106 s-1 ). 1 H and 19 F NMR studies have indicated that the complexes are present in solution almost exclusively as the square-antiprismatic (SAP) isomers. 19 F NMR relaxation studies indicated Gd⋅⋅⋅F distances of 7.4±0.1 and 9.1±0.1 A for GdL1 and GdL2 , respectively. Phantom MRI studies revealed the favorable properties of GdL2 as a dual 1 H/19 F magnetic resonance imaging (MRI) probe, whereas the shorter Gd⋅⋅⋅F distance of GdL1 reduces the signal-to-noise ratio due to the very short transverse relaxation time of the 19 F NMR signal.

We present a detailed study of the lanthanide(III) complexes with cyclen-based ligands containing phenylacetamide pendants that incorporate CF

Reinforced cross-bridged Ni2+-cyclam complexes were functionalised with pendant arms containing both amide protons and CF3 groups that lead to a dual 1H/19F response. The resulting complexes possess very high inertness favourable for MRI applications. The paramagnetism of the Ni2+ ion shifts the amide resonance 56 ppm away from bulk water favouring the chemical exchange saturation transfer (CEST) effect and shortening the acquisition times in 19F magnetic resonance imaging (MRI) experiments, thus enhancing the signal-to-noise ratios compared to the fluorinated diamagnetic reference.

Reinforced cross-bridged Ni2+-cyclam complexes were functionalised with pendant arms containing both amide protons and CF3 groups that lead to a dual 1H/19F response. The resulting complexes possess very high inertness favourable for MRI applications. The paramagnetism of the Ni2+ ion shifts the amide resonance 56 ppm away from bulk water favouring the chemical exchange saturation transfer (CEST) effect and shortening the acquisition times in 19F magnetic resonance imaging (MRI) experiments, thus enhancing the signal-to-noise ratios compared to the fluorinated diamagnetic reference.

We present two novel octadentate cyclen-based ligands bearing one (L

Paramagnetic complexes of gadolinium(III) with acyclic or macrocyclic chelates are the most commonly used contrast agents (CAs) for magnetic resonance imaging (MRI). Their purpose is to enhance the relaxation rate of water protons in tissue, thus increasing the MR image contrast and the specificity of the MRI measurements. Current clinically approved contrast agents are low molecular weight molecules that are rapidly cleared from the body. The use of dendrimers as carriers of paramagnetic chelators can play an important role in the future development of more efficient MRI contrast agents. Specifically, the increase in local concentration of the paramagnetic species results in a higher signal contrast. Furthermore, this CA provides a longer tissue retention time due to its high molecular weight and size. Here, we demonstrate a convenient procedure for the preparation of macromolecular MRI contrast agents based on poly(amidoamine) (PAMAM) dendrimers with monomacrocyclic DOTA-type chelators (DOTA – 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate). The chelating unit was appended by exploiting the reactivity of the isothiocyanate (NCS) group towards the amine surface groups of the PAMAM dendrimer to form thiourea bridges. Dendrimeric products were purified and analyzed by means of nuclear magnetic resonance spectroscopy, mass spectrometry, and elemental analysis. Finally, high resolution MR images were recorded and the signal contrasts obtained from the prepared dendrimeric and the commercially available monomeric agents were compared.

Paramagnetic complexes of gadolinium(III) with acyclic or macrocyclic chelates are the most commonly used contrast agents (CAs) for magnetic resonance imaging (MRI). Their purpose is to enhance the relaxation rate of water protons in tissue, thus increasing the MR image contrast and the specificity of the MRI measurements. Current clinically approved contrast agents are low molecular weight molecules that are rapidly cleared from the body. The use of dendrimers as carriers of paramagnetic chelators can play an important role in the future development of more efficient MRI contrast agents. Specifically, the increase in local concentration of the paramagnetic species results in a higher signal contrast. Furthermore, this CA provides a longer tissue retention time due to its high molecular weight and size. Here, we demonstrate a convenient procedure for the preparation of macromolecular MRI contrast agents based on poly(amidoamine) (PAMAM) dendrimers with monomacrocyclic DOTA-type chelators (DOTA – 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate). The chelating unit was appended by exploiting the reactivity of the isothiocyanate (NCS) group towards the amine surface groups of the PAMAM dendrimer to form thiourea bridges. Dendrimeric products were purified and analyzed by means of nuclear magnetic resonance spectroscopy, mass spectrometry, and elemental analysis. Finally, high resolution MR images were recorded and the signal contrasts obtained from the prepared dendrimeric and the commercially available monomeric agents were compared.

Bioresponsive MRI contrast agents hold great potential for non-invasive tracking of essential biological processes. Consequently, a number of MR sensors for several imaging protocols have been developed, attempting to produce the maximal signal difference for a given event. Here we introduce an approach which could substantially improve the detection of physiological events with fast kinetics. We developed a nanosized, calcium-sensitive dendrimeric probe that changes longitudinal and transverse relaxation times with different magnitudes. The change in their ratio is rapidly recorded by means of a balanced steady-state free precession (bSSFP) imaging protocol. The employed methodology results in an almost four times greater signal gain per unit of time as compared to conventional T1-weighted imaging with small sized contrast agents. Furthermore, it is suitable for high resolution functional MRI at high magnetic fields. This methodology could evolve into a valuable tool for rapid monitoring of various biological events.

[Abstract] The preparation of a paramagnetic chelator that serves as a platform for multicontrast MRI, and can be utilized either as a T1-weighted, paraCEST or 19F MRI contrast agent is reported. Its europium(III) complex exhibits an extremely slow water exchange rate which is optimal for the use in CEST MRI. The potential of this platform was demonstrated through a series of MRI studies on tube phantoms and animals. Ministerio de Economía y Competitividad; CTQ2013-43243-P Ministerio de Economía y Competitividad; CTQ2015-71211-REDT