Coordination Complexes for the Development of Zn(II)-Activated MR Imaging ProbesPublic Deposited
My thesis focuses on the design and synthesis of lanthanide coordination complexes as Zn(II)-responsive magnetic resonance imaging (MRI) contrast agents. These agents produce an increase in MR intensity upon binding of Zn(II) through water modulation to Gd(III) chelates. To this end, several Zn(II)-responsive contrast agents have been synthesized and studied in detail to investigate their ability to be activated in the presence of Zn(II), as well as their mechanism. MRI has become a powerful tool for molecular imaging because of its ability to provide three-dimensional images of opaque organisms without the use of ionizing radiation. 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. Recently, a new class of biologically activated MR contrast agents has been developed in which a change in the relaxivity of the agent is observed upon a biological signal. The research presented in this thesis expands on this new class of agents. I have designed the first example of a Gd(III)-based MRI contrast agent in which an increase in MR intensity is observed in the presence of Zn(II). In the absence of Zn(II), this agent creates a coordinatively saturated Gd(III) complex with no water access to produce a dark MR contrast. In the presence of Zn(II), a coordination change of the Gd(III) chelate occurs upon the binding of Zn(II), allowing access of water and hence a bright MR image. This agent is selective for Zn(II) as there is no change in relaxivity in the presence of Ca(II) or Mg(II) and it binds Zn(II) in concentrations relevant for the study of Zn(II) release from synaptic nerves. Further investigation of this Zn(II)-activated agent included the synthesis of a series of agents with varied lengths of the carbon chain between the Zn(II)-binding groups and the Gd(III) chleate and with varied Zn(II)-binding groups. The relaxation enhancement of these agents as well as their mechanism of activation is presented. This work improves our understanding of biologically responsive MRI contrast agents and will allow for the development of a variety of ion-responsive contrast agents.