Exchange of water molecules between the frequency-shifted inner-sphere of a paramagnetic lanthanide ion and aqueous solvent can shorten the T(2) of bulk water protons. The magnitude of the line-broadening T(2) exchange (T(2exch)) is determined by the lanthanide concentration, the chemical shift of the exchanging water molecule, and the rate of water exchange between the two pools. A large T(2exch) contribution to the water linewidth was initially observed in experiments involving Eu(3+)-based paramagnetic chemical exchange saturation transfer agents in vivo at 9.4 T. Further in vitro and in vivo experiments using six different Eu(3+) complexes having water exchange rates ranging from zero (no exchange) to 5 × 10(6) s(-1) (fast exchange) were performed. The results showed that the exchange relaxivity (r(2exch)) is small for complexes having either very fast or very slow exchange, but reaches a well-defined maximum for complexes with intermediate water exchange rates. These experimental results were verified by Bloch simulations for two site exchange. This new class of T(2exch) agent could prove useful in the design of responsive MRI contrast agents for molecular imaging of biological processes.
[Show abstract][Hide abstract] ABSTRACT: Chemical exchange saturation transfer (CEST) is a new approach for generating magnetic resonance imaging (MRI) contrast that allows monitoring of protein properties in vivo. In this method, a radiofrequency pulse is used to saturate the magnetization of specific protons on a target molecule, which is then transferred to water protons via chemical exchange and detected using MRI. One advantage of CEST imaging is that the magnetizations of different protons can be specifically saturated at different resonance frequencies. This enables the detection of multiple targets simultaneously in living tissue. We present here a CEST MRI approach for detecting the activity of cytosine deaminase (CDase), an enzyme that catalyzes the deamination of cytosine to uracil. Our findings suggest that metabolism of two substrates of the enzyme, cytosine and 5-fluorocytosine (5FC), can be detected using saturation pulses targeted specifically to protons at +2 ppm and +2.4 ppm (with respect to water), respectively. Indeed, after deamination by recombinant CDase, the CEST contrast disappears. In addition, expression of the enzyme in three different cell lines exhibiting different expression levels of CDase shows good agreement with the CDase activity measured with CEST MRI. Consequently, CDase activity was imaged with high-resolution CEST MRI. These data demonstrate the ability to detect enzyme activity based on proton exchange. Consequently, CEST MRI has the potential to follow the kinetics of multiple enzymes in real time in living tissue.
Journal of the American Chemical Society 09/2011; 133(41):16326-9. DOI:10.1021/ja204701x · 12.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chemical exchange saturation transfer (CEST) MRI enables measurement of dilute CEST agents and microenvironment properties such as pH and temperature, holding great promise for in vivo applications. However, because of confounding concomitant radio frequency (RF) irradiation and relaxation effects, the CEST-weighted MRI contrast may not fully characterize the underlying CEST phenomenon. We postulated that the accuracy of quantitative CEST MRI could be improved if the experimental factors (labeling efficiency and RF spillover effect) were estimated and taken into account. Specifically, the experimental factor was evaluated as a function of exchange rate and CEST agent concentration ratio, which remained relatively constant for intermediate RF irradiation power levels. Hence, the experimental factors can be calculated based on the reasonably estimated exchange rate and labile proton concentration ratio, which significantly improved quantification. The simulation was confirmed with creatine phantoms of serially varied concentration titrated to the same pH, whose reverse exchange rate (k(ws)) was found to be linearly correlated with the concentration. In summary, the proposed solution provides simplified yet reasonably accurate quantification of the underlying CEST system, which may help guide the ongoing development of quantitative CEST MRI.
[Show abstract][Hide abstract] ABSTRACT: The exchange of water molecules between the inner sphere of a paramagnetic chemical exchange saturation transfer (PARACEST) contrast agent and bulk water can shorten the bulk water T(2) through the T(2) -exchange (T(2ex) ) mechanism. The line-broadening T(2ex) effect is proportional to the agent concentration, the chemical shift of the exchanging water molecule, and is highly dependent on the water molecule exchange rate. A significant T(2ex) contribution to the bulk water linewidth can make the regions of agent uptake appear dark when imaging with conventional sequences like gradient-echo and fast spin-echo. The minimum echo times for these sequences (1-10 ms) are not fast enough to capture signal from the regions of shortened T(2) . This makes "Off" (saturation at -Δω) minus "On" (saturation at +Δω) imaging of PARACEST agents difficult, because the regions of uptake are dark in both images. It is shown here that the loss of bulk water signal due to T(2ex) can be reclaimed using the ultrashort echo times (<10 μs) achieved with the sweep imaging with Fourier transform pulse sequence. Modification of the sweep imaging with Fourier transform sequence for PARACEST imaging is first discussed, followed by parameter optimization using in vitro experiments. In vivo PARACEST studies comparing fast spin-echo to sweep imaging with Fourier transform were performed using EuDOTA-(gly) 4- uptake in healthy mouse kidneys. The results show that the negative contrast caused by T(2ex) can be overcome using the ultrashort echo time achieved with sweep imaging with Fourier transform, thereby enabling fast and sensitive in vivo PARACEST imaging.
Magnetic Resonance in Medicine 09/2012; 68(3):816-21. DOI:10.1002/mrm.23302 · 3.57 Impact Factor
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