| Magnetic resonance imaging is a valuable clinical imaging tool that is gaining popularity in research settings due to high resolution and non-invasive image acquisition. Chelated Gd(III) contrast agents are utilized to improve image sensitivity by decreasing the relaxation time of nearby protons, thereby producing bright contrast on MR scans. Clinical contrast agents suffer from low relaxivity (ability to produce contrast), non-specificity, and a short in vivo half-life. By modifying contrast agents to bind a protein, they can experience several major improvements including an increase in relaxivity (due to a decrease in rotational correlation time) that results in improved signal to noise. In addition they have longer in vivo lifetimes, and most importantly, targeted imaging. The goal of this work is to develop optimized protein-targeted contrast agents for versatile molecular imaging by MRI.;This dissertation describes the development of monomeric and multimeric contrast agents targeted to the versatile reporter protein, HaloTag (Promega). The synthesis of a series of four monomeric HaloTag-targeted contrast agents is described. Unexpectedly, the agents in the series displayed significantly different protein-bound relaxivities. The relaxation parameters of the protein-bound agents were investigated using several new techniques and the disparate results were found to be due to structural differences in the chelators. Two of the agents suffered from decreased hydration upon protein binding, one suffered from unoptimized water exchange, and the last optimized all relaxation parameters resulting in a six-fold increase in relaxivity upon protein binding.;To improve the versatility of this system, two HaloTag-targeted multimeric contrast agents were developed. The agents were designed to each have optimal relaxivity at a particular magnetic field strength---typical clinical fields (1.5 T) and higher research level fields (4.7--9 T). With high molecular relaxivities and options for a variety of field strengths, these multimeric agents hold promise for adaptable molecular imaging in HaloTag-expressing model organisms.;Finally, two generations of contrast agent modified embolic material were developed for imaging of tumor embolization by MRI. Direct monitoring of embolic particles may facilitate accurate determination of embolization endpoint, allow observation of non-target embolization, and improve the overall success rate of the procedure. |
