High-Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging

The desire to improve and expand the scope of clinical magnetic resonance imaging (MRI) has prompted the search for contrast agents of higher efficiency. The development of better agents requires consideration of the fundamental coordination chemistry of the gadolinium(III) ion and the parameters that affect its efficacy as a proton relaxation agent. In optimizing each parameter, other practical issues such as solubility and in vivo toxicity must also be addressed, making the attainment of safe, high-relaxivity agents a challenging goal. Here we present recent advances in the field, with an emphasis on the hydroxypyridinone family of Gd{sup III} chelates

High Relaxivity Gadolinium Hydroxypyridonate-Viral Capsid Conjugates: Nano-sized MRI Contrast Agents

High relaxivity macromolecular contrast agents based on the conjugation of gadolinium chelates to the interior and exterior surfaces of MS2 viral capsids are assessed. The proton nuclear magnetic relaxation dispersion (NMRD) profiles of the conjugates show up to a five-fold increase in relaxivity, leading to a peak relaxivity (per Gd{sup 3+} ion) of 41.6 mM{sup -1}s{sup -1} at 30 MHz for the internally modified capsids. Modification of the exterior was achieved through conjugation to flexible lysines, while internal modification was accomplished by conjugation to relatively rigid tyrosines. Higher relaxivities were obtained for the internally modified capsids, showing that (1) there is facile diffusion of water to the interior of capsids and (2) the rigidity of the linker attaching the complex to the macromolecule is important for obtaining high relaxivity enhancements. The viral capsid conjugated gadolinium hydroxypyridonate complexes appear to possess two inner-sphere water molecules (q = 2) and the NMRD fittings highlight the differences in the local motion for the internal ({tau}{sub RI} = 440 ps) and external ({tau}{sub RI} = 310 ps) conjugates. These results indicate that there are significant advantages of using the internal surface of the capsids for contrast agent attachment, leaving the exterior surface available for the installation of tissue targeting groups

Gd-HOPO Based High Relaxivity MRI Contrast Agents

Tris-bidentate HOPO-based ligands developed in our laboratory were designed to complement the coordination preferences of Gd{sup 3+}, especially its oxophilicity. The HOPO ligands provide a hexadentate coordination environment for Gd{sup 3+} in which all he donor atoms are oxygen. Because Gd{sup 3+} favors eight or nine coordination, this design provides two to three open sites for inner-sphere water molecules. These water molecules rapidly exchange with bulk solution, hence affecting the relaxation rates of bulk water olecules. The parameters affecting the efficiency of these contrast agents have been tuned to improve contrast while still maintaining a high thermodynamic stability for Gd{sup 3+} binding. The Gd- HOPO-based contrast agents surpass current commercially available agents ecause of a higher number of inner-sphere water molecules, rapid exchange of inner-sphere water molecules via an associative mechanism, and a long electronic relaxation time. The contrast enhancement provided by these agents is at least twice that of commercial contrast gents, which are based on polyaminocarboxylate ligands

Smart “lanthano” proteins for phospholipid sensing

Metal-ion-mediated interactions between calcium-binding peripheral proteins and membrane phospholipids is a key feature of multiple cell signaling processes. The molecular basis for the interaction involves the displacement of inner-sphere water molecules on calcium ions by phosphate groups of the phospholipids. On the basis of this fundamental mechanism, we have devised a novel “turn-on” optical sensing strategy for anionic phospholipids by using a lanthanide reconstituted protein. The “lanthano” protein turns on selectively in the presence of a crucial signaling phospholipid, phosphatidylserine, by affording a 6 times enhancement in lanthanide luminescence. The “turn-on” sensing strategy was distinctly validated by direct evidence for the water-displacement mechanism via lifetime measurements

A zebrafish model of manganism reveals reversible and treatable symptoms that are independent of neurotoxicity

Manganese (manganese ion; referred to as Mn) is essential for neuronal function, yet it is toxic at high concentrations. Environmental and occupational exposure to high concentrations of Mn causes manganism, a well-defined movement disorder in humans, with symptoms resembling Parkinson’s disease (PD). However, manganism is distinct from PD and the neural basis of its pathology is poorly understood. To address this issue, we generated a zebrafish model of manganism by incubating larvae in rearing medium containing Mn. We find that Mn-treated zebrafish larvae exhibit specific postural and locomotor defects. Larvae begin to float on their sides, show a curved spine and swim in circles. We discovered that treatment with Mn causes postural defects by interfering with mechanotransduction at the neuromasts. Furthermore, we find that the circling locomotion could be caused by long-duration bursting in the motor neurons, which can lead to long-duration tail bends in the Mn-treated larvae. Mn-treated larvae also exhibited fewer startle movements. Additionally, we show that the intensity of tyrosine hydroxylase immunoreactivity is reversibly reduced after Mn-treatment. This led us to propose that reduced dopamine neuromodulation drives the changes in startle movements. To test this, when we supplied an external source of dopamine to Mn-treated larvae, the larvae exhibited a normal number of startle swims. Taken together, these results indicate that Mn interferes with neuronal function at the sensory, motor and modulatory levels, and open avenues for therapeutically targeted studies on the zebrafish model of manganism

Smart “Lanthano” Proteins for Phospholipid Sensing

Metal-ion-mediated interactions between calcium-binding peripheral proteins and membrane phospholipids is a key feature of multiple cell signaling processes. The molecular basis for the interaction involves the displacement of inner-sphere water molecules on calcium ions by phosphate groups of the phospholipids. On the basis of this fundamental mechanism, we have devised a novel “turn-on” optical sensing strategy for anionic phospholipids by using a lanthanide reconstituted protein. The “lanthano” protein turns on selectively in the presence of a crucial signaling phospholipid, phosphatidylserine, by affording a 6 times enhancement in lanthanide luminescence. The “turn-on” sensing strategy was distinctly validated by direct evidence for the water-displacement mechanism via lifetime measurements

A Sensitive Water-Soluble Reversible Optical Probe for Hg²⁺ Detection

We report the serendipitous discovery of an optical mercury sensor while trying to develop a water-soluble manganese probe. The sensor is based on a pentaaza macrocycle conjugated to a hemicyanine dye. The pentaaza macrocycle earlier designed in our group was used to develop photoinduced electron transfer (PET)-based “turn-on” fluorescent sensors for manganese. In an attempt to increase the water-solubility of the manganese sensors we changed the dye from BODIPY to hemicyanine. The resultant molecule <b>qHCM</b> afforded a distinct reversible change in the absorption features and a concomitant visible color change upon binding to Hg²⁺ ions, leading to a highly water-soluble mercury sensor with a 10 ppb detection limit. The molecule acts as a reversible “ON–OFF” fluorescent sensor for Hg²⁺ with a 35 times decrease in the emission intensity in the presence of 1 equiv of Hg²⁺ ions. We have demonstrated the applicability of the probe for detecting Hg²⁺ ions in living cells and in live zebrafish larvae using confocal fluorescence microscopy with visible excitation. High selectivity and sensitivity toward Hg²⁺ detection make <b>qHCM</b> an attractive probe for detecting Hg²⁺ in contaminated water sources, which is a major environmental toxicity concern. We have scrutinized the altered metal-ion selectivity of the probe using density functional theory (DFT) and time-dependent DFT calculations, which show that a PET-based metal-sensing scheme is not operational in <b>qHCM</b>. ¹H NMR studies and DFT calculations indicate that Hg²⁺ ions coordinate to oxygen-donor atoms from both the chromophore and macrocycle, leading to sensitive mercury detection