ConspectusMagnetic resonance imaging (MRI) has become increasingly popular in molecular imaging and clinical radiology because it is non-invasive and capable of producing three-dimensional representations of opaque organisms with high spatial and temporal resolution. While approximately 35% of all clinical MR scans utilize contrast media, a primary limitation of MR imaging is the low sensitivity to detect contrast agents requiring high concentrations of agent for enhanced signal intensity (0.1-0.6 mM). 1 A number of strategies have been employed to amplify the observed in vivo signal of MR contrast agents. Approaches include attachment of Gd(III) chelates to polymers, proteins and particles, encapsulation into micelles and caged structures, and targeting to receptors. While each of these approaches has yielded significant increases in the relaxivity of MR contrast agents (and therefore sensitivity), all of these classes of complexes possess intrinsic background signal and function solely as anatomical reporters due to their constitutive activity.In order to reduce the background signal and simultaneously create probes that are modulated by biochemical events, caged complexes were designed to coordinatively saturate the paramagnetic ion. Coupled with amplification strategies, these agents represent a means to selectively modulate the observed MR signal and function as in vivo biochemical reporters. For example, to create an in vivo MR assay of enzymatic activities and secondary messengers, agents have been designed and synthesized with removable protection groups that largely prevent access of water to a paramagnetic center. By limiting the access of bulk water (q-modulation) the unprocessed agent is designed to be an ineffective contrast agent, and hence serves as a reliable marker for regions of enzyme activity or secondary messengers.In this Account we describe our results toward designing new classes of MR agents that are i. responsive to in vivo physiological or biochemical events ii. cell-permeable to increase local concentration, and iii. attached to large molecules or are synthesized with multiply labeled conjugates for signal amplification. Magnetic Resonance ImagingImaging with nuclear magnetic resonance (NMR) spectroscopy was first introduced by the pioneering work of Lauterbur in 1973. 2 MRI exploits the differences in the relaxation rates of nuclear spins due to an applied magnetic field. MR detects the electromagnetic radiation emitted from the transition of higher energy nuclei to a lower energy level. While nuclei with a spin quantum number of I = ½ such as 1 H, 13 C, 19 F and 31 P are used, the majority of current MR technology is based on 1 H nuclei. The NMR signal is relatively low compared to other tmeade@northwestern.edu. spectroscopic methods, however due to the large number of protons in a typical sample, detection is possible. Current MR images are acquired using magnetic field strengths from 1.5 to 7 Tesla in clinical applications, and as high as 19T for high-resolution molecular imaging....

Zinc(II) plays a vital role in normal cellular function as an essential component of numerous enzymes, transcription factors, and synaptic vesicles. While zinc can be linked to a variety of physiological processes, the mechanisms of its cellular actions are less discernible. Here, we have synthesized and tested a Zn(II)-activated magnetic resonance imaging (MRI) contrast agent in which the coordination geometry of the complex rearranges upon binding of Zn(II). In the absence of Zn(II) water is restricted from binding to a chelated Gd(III) ion by coordinating acetate arms resulting in a low relaxivity of 2.33 mM ؊1 ⅐s ؊1 at 60 MHz. Upon addition of Zn(II) the relaxivity of the Gd(III)-Zn(II) complex increases to 5.07 mM ؊1 ⅐s ؊1 and is consistent with one water molecule bound to Gd(III). These results were confirmed by nuclear magnetic relaxation dispersion analysis. There was no observed change in relaxivity of the Gd(III) complex when physiologically competing cations Ca(II) and Mg(II) were added. A competitive binding assay gave a dissociation constant of 2.38 ؋ 10 ؊4 M for the Gd(III)-Zn(II) complex. In vitro magnetic resonance images confirm that Zn(II) concentrations as low as 100 M can be detected by using this contrast agent. biological molecular imaging ͉ zinc sensing ͉ gadolinium Z inc(II) plays a critical role in cellular physiology and is involved in structural stability, catalytic activity, and signal transduction processes (1-3). While a great deal is known about the biochemistry of Zn(II) in relation to metalloproteins, far less is understood about the specific mechanisms of its cellular physiology and distribution because it is tightly bound to zincbinding ligands (4). To understand the specific functions of Zn(II), research has focused on the development of Zn(II) fluorescent probes (5, 6). These Zn(II) probes are changing our understanding of the biological function of this important ion in cell and tissue culture experiments.Our goal has been to noninvasively image Zn(II) activity in whole organisms, and we have focused on developing Zn(II) magnetic resonance (MR) contrast agents. Unlike light-based microscopy, MRI can provide three-dimensional images without the limitations of light scattering and photobleaching (7,8). MRI takes advantage of the most abundant molecule in biological tissues, water. In the presence of a magnetic field the magnetic moments of the protons in water molecules orient themselves along the magnetic field. An applied radiofrequency pulse inverts the magnetization vector, and reorientation to the original magnetic field direction occurs with a characteristic time constant. This process of realignment characterized by T 1 is called longitudinal or spin-lattice relaxation, and it is the dominant factor in producing contrast in a T 1 -weighted MR image. While intrinsic contrast between organs can be observed by using MRI, resolution and sensitivity improve greatly with the use of contrast agents such as Gd(III) chelates. The efficacy of these complexes to decrease the T 1 o...

We report on the mechanism of a series of Zn II -activated magnetic resonance contrast agents that modulate the access of water to a paramagnetic Gd III ion to create an increase in relaxivity upon binding of Zn II . In the absence and presence of Zn II , the coordination at the Gd III center is modulated by appended Zn II binding groups. These groups were systematically varied to optimize the change in coordination upon Zn II binding. We observe that at least one appended aminoacetate must be present as a coordinating group to bind Gd III and effectively inhibit access of water. At least two binding groups are required to efficiently bind Zn II , creating an unsaturated complex and allowing access of water. 13 C isotopic labeling of the acetate binding groups for NMR spectroscopy provides evidence of a change in the metal coordination of these groups upon the addition of Zn II supporting our proposed mechanism of activation as presented.

Bio-assembly strategies may allow formation of high-density nano-electronic architectures possessing unique electronic properties. These bio-nanomaterial hybrids should exhibit bio- compatibility and bio-viability. Therefore, contingencies of maintaining tertiary structure in the presence of nanometer-sized particles are a potential fatal flaw in bio-scaffolded assemblies. In this manuscript we investigate the assembly of bio-scaffolded nanomaterial constructs, specifically polypeptides, while probing the issue of bio-compatibility and viability by TEM imaging.

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