Prof. Dean Sherry (UT Southwestern/UT Dallas)
Abstract:
Magnetic resonance imaging (MRI) is often considered too insensitive for molecular imaging of biological processes yet there have been many different approaches taken toward the design of metal ion-based biologically responsive MRI agents. Complexes with various lanthanide ions are most often studied largely due to their many favorable magnetic properties. Among the lanthanides, Gd3+-based T1 agents have been most widely studied but other lanthanide complexes form the basis of T2ex agents and paraCEST agents. The sensitivity of each class of agent is dictated by one simple principle, the rate of water exchange between an inner-sphere water coordination position and bulk water molecules. Over the past few years, chemists have learned how to manipulate water exchange rates in each class (T1, T2ex, paraCEST) of agent and consequently the responsiveness to these agents to biological and physiological processes has improved significantly. Several examples from each class will be described. These design feature has proven useful for detecting release of free Zn2+ ions from pancreatic b-cells and from prostate epithelial cells, both stimulated by an increase in plasma glucose. Insulin produced by pancreatic b-cells is stored in granules as a zinc complex which is released in response to high glucose. As a result, the local concentration of Zn2+ ions in the extracellular space of b-cells during insulin secretion increases to ~400 mM and this increase in local Zn2+ is readily detected by MRI. The normal human prostate has the highest levels of free Zn2+ of any tissue in man while malignant prostate cells undergo a metabolic transformation that results in less accumulation of Zn2+. A recent discovery from our lab that Zn2+ is also secreted from prostate epithelial cells in response to a sudden increase in plasma glucose offers the opportunity to distinguish malignant prostate epithelial cells from benign prostatic hyperplasia (BPH), and inflammation. Thus, one may be able to not only detect PCa with high specificity and sensitivity but also grade the aggressiveness of the PCa based upon tissue zinc content by use of a simple MRI test without the need of a tissue biopsy. If translation of such an agent to the clinic is successful, this could significantly minimize the pain and morbidity associated with detection and verification of PCa (biopsies) and the emotional stress experienced by men with diagnosed with PCa currently undergoing watchful waiting.
