Fluorescently detectable magnetic resonance imaging agents
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Figure 1.
Gd(rhoda-DOTA) (1). Magnetic Resonance Imaging Agents Bioconjugate Chem., Vol.
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Bioconjugate Chem. 1998, 9, 242−249
Fluorescently Detectable Magnetic Resonance Imaging Agents
Martina M. Huber, Andrea B. Staubli, Karen Kustedjo, Mike H. B. Gray, John Shih, Scott E. Fraser, ¨ Russell E. Jacobs,* and Thomas J. Meade*
Division of Biology and Beckman Institute, California Institute of Technology, Pasadena, California 91125.
Received August 13, 1997; Revised Manuscript Received December 12, 1997
This report describes the synthesis, characterization, and in vivo testing of several bifunctional contrastenhancing agents for optical and magnetic resonance imaging (MRI) of experimental animals. These new agents integrate the advantages of both techniques since they can be visualized simultaneously by light and MRI microscopy. Employing this strategy allows the same biological structures of a specimen to be studied at dramatically different resolutions and depths. The complexes possess a metal chelator for binding a paramagnetic ion, gadolinium (Gd3+), and a covalently attached fluorescent dye. The first class of complexes are low-molecular weight species that are composed of the macrocyclic tetraamine 1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid (DOTA) as the metal-chelating ligand coupled to tetramethylrhodamine. The second class of MRI-enhancing agents are composed of high-molecular weight polymers that are membrane impermeable and once injected into a cell or cells are trapped inside. These complexes possess multiple copies of both the metal-chelatordiethylenetriaminepentaacetic acid (DTPA) and the tetramethylrhodamine attached to a macromolecular framework of either poly(D-lysine) (pdl) or dextran. Images acquired of single cells after injection with these bifunctional agents enabled us to follow the relative motions and reorganizations of different cell layers during amphibian gastrulation and neurulation in Xenopus laevis embryos.
INTRODUCTION
In recent years, two imaging techniques have emerged that have had a major impact upon basic and clinical science: computer-enhanced light microscopy imaging and nuclear magnetic resonance imaging (1-3). Unlike previous approaches that required the processing of fixed tissue samples, both these techniques permit aspects of a living, intact organism to be imaged. With imaging of the organism in defined physiological states, a more realistic picture of developmental processes has begun to emerge. Computer-enhanced light microscopy permits highresolution imaging to be accomplished in imperfect preparations, such as whole tissues and organisms. The use of fluorescent indicator dyes visualized with a video or confocal microscope has resulted in several classes of novel experiments. For example, individual cells have been injected with membrane impermeable dyes (e.g., fluorescent dextrans) so that the only cells that are labeled are the original cell and its progeny (1). MRI offers the potential of true three-dimensional imaging of biological structures and processes at cellular resolution (≈10 µm) (4-7). Typically, the image is based upon the NMR signal from the protons of water where the signal intensity in a given volume element is a function of the water concentration and relaxation times (T1 and T2). The paramagnetic ion gadolinium (Gd3+) is used in MRI agents to decrease the local T1 of water protons and therefore provide increased contrast. The long electron spin relaxation time and high magnetic moment of Gd3+ make it an efficient perturbant of T1. Through chelation of the Gd3+ aqua ion using various ligands, its toxic effects can be minimized (8-10). While significant results have been obtained employing these techniques, each suffers from inherent constraints.
* To whom correspondence should be addressed.
Light microscopy is limited by optical aberrations and light scattering to the outer 100-300 µm of a specimen. MRI microscopy provides a solution to this limitation by rendering three-dimensional images of opaque specimens, but sacrifices resolution by at least 10-20-fold compared to that of light microscopy. There are a significant number of MRI contrast agents that have been developed for clinical use because they enhance the local image intensity of organs and tissues. However, there are very few examples of agents that have been specifically designed for imaging experimental animals. Therefore, we have prepared a series of bifunctional contrast-enhancing agents that are designed to integrate the advantages of both techniques. We report the synthesis and in vivo testing of a class of agents that are simultaneously detectable by fluorescence and MRI microscopy, thereby permitting multimodal imaging of experimental animals. The design of these bifunctional contrast agents included the lanthanide chelators DTPA and DOTA, which are known to form lanthanide complexes with high stability and selectivity (9, 11, 12). Conjugation of the fluorescent functionality, tetramethylrhodamine, was achieved either through coupling to the carboxylic acid group of DTPA or by functionalizing the DOTA macrocycle (Figures 1-3) (13-17). The first class of complexes includes Gd[p-(aminobenzyl)DOTA]-tetramethylrhodamine[Gd(rhoda-DOTA)]. This agent carries the macrocyclic tetraamine DOTA linked to the fluorochrome in a 1:1 complex and may be used to investigate membrane permeability, fusion, gap-junctional communication, and lesions. The second class includes membrane impermeable agents, such as Gd(DTPA)-tetramethylrhodamine-hydroxypropylpoly(Dlysine) (GRIP) and Gd(DTPA)-tetramethylrhodamineaminedextran (GRID). These agents are based on a polymeric scaffold (i.e., pdl and dextran, respectively), carrying several tetramethylrhodamine molecules and Gd(DTPA) complexes.
S1043-1802(97)00153-5 CCC: $15.00 © 1998 American Chemical Society Published on Web 02/27/1998
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