[Frontiers in Bioscience 13, 1733-1752, January 1, 2008] 1733 An overview of responsive MRI contrast agents for molecular imaging Byunghee Yoo 1 , Mark D. Pagel 1 1 Case Center for Imaging Research and Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Ave. Cleveland, Ohio TABLE OF CONTENTS 1. Abstract 2. Introduction 3. MRI contrast mechanisms 4. Exogenous MRI contrast agents 5. Responsive MRI contrast agents 5.1. Molecular imaging of proteins 5.1.1. Contrast agents that bind to proteins 5.1.2. Contrast agents that are catalyzed by enzymes 5.2. Molecular imaging of nucleic acids 5.3. Molecular imaging of metabolites 5.4. Molecular imaging of oxygen 5.5. Molecular imaging of metal ions 5.6. Molecular imaging of pH 5.7. Molecular imaging of temperature 6. Future Directions 7. Acknowledgements 8. References 1. ABSTRACT This review focuses on MR contrast agents that are responsive to a change in physiological environment. The “response” mechanisms are dependent on 6 physicochemical phenomena, including the accessibility of water to the agent, rotational tumbling time, proton exchange rate, electron spin state, MR frequency, or local field inhomogenieties caused by the agent. These phenomena can be affected by the physiological environment, including changes in concentrations or activities of proteins, enzymes, nucleic acids, metabolites, oxygen and metal ions, and changes in pH and temperature. A total of 52 examples are presented, which demonstrate the variety and creativity of different approaches used to create responsive MRI contrast agents. 2. INTRODUCTION During the last 30 years, Magnetic Resonance Imaging (MRI) has developed from an intriguing research project to an essential diagnostic method in the armamentarium of clinical radiologists. An estimated 26.6 million MRI examinations were performed annually in 2006, with a 3% annual increase in the number of MRI exams since 2003 (1). The growth of MRI is partly driven by the broad variety of clinical examinations that exploit many types of MRI contrast mechanisms in endogenous tissues. Different image contrast generated by different soft tissues can be used to assess anatomy at excellent spatial resolution that is typically approaches or exceeds 1 mm. Different image contrast can also assess physiological function, such as the function of the cardiopulmonary