Paramagnetic Complexes as High Field Contrast Agents

With the advent of high-field whole body magnets (3-9.4 T) and animal systems (up to 21 T), with the potential for increased sensitivity, it will be important to translate these technological improvements directly into enhanced molecular and cellular images. Among the lanthanide ions, Gd is known as the best low-field T1 relaxation agent because of its long electronic relaxation time. Complexes with other paramagnetic lanthanides (III) have been commonly used as shift agents in NMR spectroscopy or as susceptibility agents in MRI (Arteaga et al., 1999; Beache et al., 1998; Dubois et al., 2005; Haraldseth et al., 1996; Johnson et al., 2000; Villringer et al., 1988). While Gd does not increase water relaxivity at magnetic field strengths above 4T, other lanthanide complexes have been shown to increase their relaxivity quadratically with field strength (Bulte et al., 1998; Caravan et al., 2001; Kellar et al., 1998; Vander Elst et al., 2002a,b). This field dependence is illustrated in Figure 6.5 for Dysprosium-DTPA-BBMA in 2% agarose imaged from 4.7 to 21 T. For select lanthanide ions [Dy(III), Pr(III), Sm(III), Ho(III), Er(III), and Yb(III)], this increase in relaxivity at high fields is due to very short electronic relation times that result in a large static magnetic moment, referred to as Curie relaxation (Bulte et al., 1998; Caravan et al., 2001; Vander Elst et al., 2002a). It had previously been suggested by Aime et al. that the predicted reduction of T2 with field strength can be used in high-field NMR and as negative contrast agent for MRI (Bulte et al., 1998; Kellar et al., 1998; Vander Elst et al., 2002a).

Another class of contrast agents that stand to directly benefit from ultra-high magnetic fields are chemical exchange saturation transfer (CEST) contrast agents (Aime et al., 2002a,b, 2005a; Gillies et al., 2004; Snoussi et al., 2003; Terreno et al., 2004; Trokowski et al., 2004; Ward, 2000; Ward and Balaban 2000; Woessner et al., 2005; Zhang et al., 2003a,b; Zhou et al., 2004). CEST agents typically contain an exchangeable pool of protons that can be used to transfer magnetization to bulk water. If the conditions are optimal, the saturation of a small pool of exchangeable protons will result in a measurable decrease in the 40-55 molar tissue water signal typically used to image. Despite resulting in a decrease in signal intensity similar to SPIO contrast agents, CEST images have the advantage that they can be turned on and off for different lanthanide (iii) paramagnetic chelates (PARACEST agents) through the use of frequency selective pre-saturation pulses. PARACEST agents are particularly useful due to

Dy-DTPA-BBMA

Figure 6.5. Experimentally determined increase in rx and r2 that occurs with Dy-DTPA-BBMA with increasing magnetic field between 4.7 and 21 T in 2 % agarose based on spin-echo images.

Magnetic Field (Tesla) Magnetic Field (Tesla)

Figure 6.5. Experimentally determined increase in rx and r2 that occurs with Dy-DTPA-BBMA with increasing magnetic field between 4.7 and 21 T in 2 % agarose based on spin-echo images.

their large chemical shifts and long life times of bound water, which can result in a more efficient transfer of magnetization to bulk water increasing contrast. It has been predicted that most LnDOTA-4AmCE complexes should function as PARACEST agents at 11.75 T, but only a few (Eu3+, Tb3+, Dy3+, and Ho3+) will be useable at low fields (1.5 T) (Zhang et al., 2003a). On the other hand, some of the potentially most effective PARACEST agents, such as those based on Yb3+, may not be usable below 11 T. It has also been predicted that PARACEST agents will likely become more efficient at higher B0 fields. Block equation modeling has predicted that when the bound water pool of a PARACEST agent (500 ppm and exchange time (iM) of 3 ^s) is completely saturated, then 5 % of the bulk water signal will be eliminated by ~10 ^M of the agent. This corresponds to a concentration that is well below the detection limit of a low molecular weight Gd3+-based contrast agent with a r1 of 4-5 mM-1s-1 (Zhang et al., 2003a). Moreover, similar to the substantial increase in relaxivity of Gd3+-based agents by conjugation to a polymer or formation of a nanoaggregates, it may be possible to extend the lower detection limit into the submicromolar range. PARACEST contrast agents also operate at specific RF irradiation frequencies such that contrast in different cell populations can be turned on and off using different irradiation pulses. Moreover, PARACEST contrast is not generated based on T and T2* differences and will not obscure or be complicated by underlying tissue anatomy, hopefully increasing their cell specificity. Since PARACEST is extremely sensitive to water exchange, it will provide an ideal mechanism for activatable contrast agents but again water comparmentation within the cellular milieu (endosome vs the cytoplasm) may lead to differing amount of PARACEST contrast. PARACEST agents have been used to image changes in temperature (Hekmatyar et al., 2005; Terreno et al., 2004), glucose (Trokowski et al., 2004; Zhang et al., 2003b), pH (Aime et al., 2002a,b; Gillies et al., 2004; Ward and Balaban, 2000), and liposomes (Aime et al., 2005b).

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