Double agents and secret agents: the emerging fields of exogenous chemical exchange saturation transfer and T₂-exchange magnetic resonance imaging contrast agents for molecular imaging

Figures & data

Figure 1 The mechanism of chemical exchange saturation transfer (CEST).

Notes: (A) Exchangeable protons are saturated with a radiofrequency pulse. (B) Saturated protons are exchanged between the CEST agents and the bulk water. (C) The bulk water loses part of its net MR signal due to the exchange of saturated protons. (D) Water signals are collected with a range of radiofrequencies. Direct saturation of bulk water is set as the reference (0 ppm). (E) Connecting the signals of bulk water generates a Z-spectrum.
Abbreviation: MR, magnetic resonance.

Figure 2 ParaCEST agents that detect enzyme activity.

Notes: Agents have been designed that detect (A) caspase-3, (B) urokinase plasminogen activator, (C) cathepsin D, (D) transglutaminase, (E) β-galactosidase, and (F) esterase.
Abbreviation: ParaCEST, paramagnetic chemical exchange saturation transfer.

Figure 3 Responsive CEST agents.

Notes: (A) Deamination of cytosine by deaminase enzyme. Other agents can detect (B and C) DNA, (D) glucose, (E) lactate, (F) methyl phosphate, and (G) nitric oxide.
Abbreviation: CEST, chemical exchange saturation transfer.

Figure 4 ParaCEST agents that detect ions, redox state, and temperature.

Notes: Agents have been designed that detect (A) Zn²⁺, (B) Ca²⁺, and (C–E) redox conditions. (F–H) Other agents can measure temperature.
Abbreviation: ParaCEST, paramagnetic chemical exchange saturation transfer.

Figure 5 CEST agents that measure pH include (A) Yb-DOTAM-Gly-X, (B) Ln-DOTAM-Gly, (C) Yb(III)-HPDO3A, (D) Co(II)-complex, (E) iopamidol, (F) iopromide, (G) iobitridol, (H) and Tm-DOTAM-Gly-Lys. (I) Deprotonation of a Eu(III) complex changes the coordination around the Eu³⁺ ion, which changes the CEST effect of this agent.

Abbreviation: CEST, chemical exchange saturation transfer.

Figure 6 The mechanism of the T_2ex process.

Notes: (A) T₂ is measured by rotating the net magnetization into the transverse plane by an excitation pulse, then components of the net magnetization evolve to defocus, and then a 180° pulse causes these components to refocus. (B) The chemical exchange of protons with different phases causes cancelation of net magnetization, creating a shorter T₂ relaxation time constant for the bulk water due to T_2ex.
Abbreviation: T_2ex, T₂ exchange.

Figure 7 The dependence of T_2ex on environmental conditions.

Notes: (A) An increase in temperature increases relaxivities on the rising side of Swift–Connick plot (shown by the white arrow), while an increase in temperature decreases relaxivities on the falling side of the Swift–Connick plot (shown by the gray arrow). (B) Triangles show relaxivities due to exchange of a proton with the same chemical shift and chemical exchange rate in three different magnetic fields. The chemical structures of (C) Dy-DOTAM-(Gly)x complexes, (D) Eu(III) complexes, and (E) Tm-DO3A-oAA show similar features that lead to T_2ex relaxation.
Abbreviation: T_2ex, T₂ exchange.