Responsive Probes for [sup(19)]F MRS/MRI

In 1985, McFarland and coworkers performed the first in vivo 19F MRI studies in rats [6]. Since then, a continuous development has taken place in the field of 19F MRI/MRS, constantly broadening the range of applications (e.g., monitoring of drug metabolism, cell tracking, plaque detection, sensing microenvironmental changes, etc.). Historically, (per)fluorinated molecules (e.g., perfluorocarbons and highly fluorous gases) have been used for 19F MRI/MRS, however, in recent years new 19F probes have been developed. There have been several promising reports on fluorinated micelles, dendrimers, hyperbranched polymers, as well as responsive and multimodal probes. These fluorinated agents are generally categorized into two groups: (a) targeted and (b) responsive depending on their mode of action. Accordingly, targeted 19F-reporters function by accumulating at the site of interest via binding to specific targets, for instance cell surface epitopes, or are used for tracking of macrophages, immune and stem cells [3, 7]. Whereas for targeted agents the detected signal is dependent basically on their local concentration, for responsive 19F probes a designated modulation of the fluorine signal takes place in situ only in response to specific stimuli in the local biochemical environment. Hence, responsive agents have the potential for high specificity and may provide deeper insights into biochemical processes of interest. Accordingly, several promising 19F agents have been reported that proved to be responsive to key physiological processes and diagnostically relevant parameters such as enzymatic activity, changes in metal ion concentration, pH, and pO2 [5].In this chapter, we aim to provide a brief overview on the recent developments in responsive 19F reporters, the mechanisms

underlying their “responsiveness,” as well as the obstacles related to detection sensitivity and efficient utilization of these agents in vivo. 5.2  Response MechanismsResponsive 19F probes primarily function by alternating their 19F chemical shift and/or relaxation rates (R1 = 1/T1 and R2 = 1/T2) via stimuli driven reversible (e.g., ion sensing) or irreversible (e.g., sensing of enzymatic activity) changes in molecular structure (Fig. 5.1). In some responsive probes, inter-actions with the biological marker of interest induce alterations of the relaxation parameters, albeit without changing the structure of the fluorinated agent (e.g., pO2 mapping by perfluorocarbons).