19F-based Contrast Agents
The feasibility of 19F MRI was firstly demonstrated in
1977, few years after the advent of 1H MRI. Even if
this technique is still mostly exploited at the preclinical
level, various clinical trials are ongoing to evaluate the safety
and potentiality of fluorinated probes. 19F MRI is
based on the naturally occurring stable fluorine isotope 19F
(100% natural abundance), bearing a spin of ½, and a
gyromagnetic ratio of 40.08 MHz/T (slightly lower than the 42.58
MHz/T of 1H), resulting in 83% of the sensitivity of 1H. One of
the greatest advantage of 19F MRI is the almost
complete absence of endogenous signal, thus allowing the
detection and exact quantification of administered fluorinated
compounds. However, to spatially locate the signal unambiguously,
the 19F acquisition has to be overlaid to the1H MR
image (Figure 1).
The 19F spectroscopic signature extends to a range of
more than 200 ppm, thus allowing the unequivocal and simultaneous
identification of different 19F-containing compounds. Moreover,
it is worth mentioning thatthe chemical shift of 19F
is sensitive to the molecular environment of its nucleus, due to
the seven outer-shell electrons of 19F atom. Developed probes are
generally chemically and biologically inertand,in order to obtain
a strong resonance peak, they must contain a high number of
magnetically equivalent fluorine atoms. In addition, favorable
relaxation properties are needed, in order to achieve relatively
long echo times.
Among the most diffuse and promising fluorinated probes, perfluorocarbon (PFC) based nanosystems can be cited. These systems are basically nanoparticles or nanoemulsions made up of perfluorurated compounds, molecules similar to common organic compounds, with all the hydrogen atoms replaced by fluorine. These systems are mainly exploited for the ex-vivo or in-vivo labeling of immune system cells (e.g. dendritic cells, monocytes, macrophages), to visualize inflamed areas and spatio-temporally track the course of the inflammatory processes, in both qualitative and quantitative way (Figure 2). Recently, the use of PFCs has been extended also to stem cell transplantation tracking.
Other appealing 19F MRI probes, are responsive
compounds, designed to be silent in physiological conditions, but
MR active in presence of specific enzymes (e.g. esterase,
caspase-3, β-galactosidase). In addition, many fluorinated
compounds capable of detecting changes in oxygen, Na+,
Ca2+ and Mg2+ concentrations in biological
tissues have been developed. A specific attention has been
devoted to the design of pH sensitive fluorinated compounds, that
must have a pKa value in the physiological range, good
sensitivity and specificity as well as low toxicity, a large
chemical shift range and a sufficient intracellular uptake to
provide a detectable signal.
19F MRI can be also exploited to monitor metabolism of fluorinated drugs, such as 5-fluorouracil, floxuridine, fluoexetine. However, in order to monitor drug biodistribution and the formation of fluorinated metabolic byproducts, consistent dosage of these compounds must be administered. 19F containing compounds can be further employed for lung functional MRI. Basically, fluorinated gases, such as fluoropropane (C3F8), hexafluoride (SF6), tetrafluoromethane (CF4) or hexafluoroethane (C2F6), can be regarded as a safe and low-cost alternative to hyper-polarized gases, currently employed for lung fMRI. Finally, in the last few years, numerous fluorinated polymers have been employed in implant materials, detectable by 19F MRI, with the great advantage of the absence of susceptibility artifacts.
In our group, the research in the field of 19F-MRI contrast agents is mainly focused on two different systems: i) perfluorocarbon-based nanosystems for tracking immune cells in inflammatory processes (mainly in CNS); and ii) fluorinated small molecules to target specific markers of Alzheimer s Disease.