Contents 1. Introduction 3019 2. Challenges in the Field of Paramagnetic T 1 Agents 3021 2.1. Optimizing the Rotational Mobility 3021 2.2. Effect of τ M on the Attainable Relaxivity 3022 2.3. Increasing Relaxivity through the Increase of the Hydration of the Paramagnetic Metal Ion 3023 2.4. Nanosized Systems 3023 2.5. Mn 2+ -Complexes: An Alternative to Gd-Based Agents? 3024 2.6. Field-Dependence of Relaxivity 3024 2.7. Responsive Agents 3025 3. Challenges for T 2 Agents 3027 3.1. Iron Oxide Nanoparticles 3027 3.2. T 2 Agents: Alternatives to Iron Oxide Nanoparticles 3028 3.3. Magnetic Particle Imaging 3029 4. Challenges for CEST Agents 3029 4.1. Technical Issues 3029 4.2. Chemical Issues 3031 4.3. Biological Issues 3032 5. Challenges for Heteronuclear MR Imaging 3033 5.1. 19 F-Based Probes 3033 6. Challenges for Hyperpolarized Probes 3034 6.1. Brute Force 3034 6.2. Optical Pumping and Spin Exchange 3035 6.3. Dynamic Nuclear Polarization (DNP) 3035 6.4. para-Hydrogen Induced Polarization (PHIP) 3037 6.5. Use of Gd Contrast Agents with Hyperpolarized Substances 3038 6.6. Issues with Hyperpolarized Agents 3038 7. Concluding Remarks 3038 8. Acknowledgments 3039 9. References 3039

No abstract

Contrast in magnetic resonance imaging (MRI) arises from changes in the intensity of the proton signal of water between voxels (essentially, the 3D counterpart of pixels). Differences in intervoxel intensity can be significantly enhanced with chemicals that alter the nuclear magnetic resonance (NMR) intensity of the imaged spins; this alteration can occur by various mechanisms. Paramagnetic lanthanide(III) complexes are used in two major classes of MRI contrast agent: the well-established class of Gd-based agents and the emerging class of chemical exchange saturation transfer (CEST) agents. A Gd-based complex increases water signal by enhancing the longitudinal relaxation rate of water protons, whereas CEST agents decrease water signal as a consequence of the transfer of saturated magnetization from the exchangeable protons of the agent. In this Account, we survey recent progress in both areas, focusing on how MRI is becoming a more competitive choice among the various molecular imaging methods. Compared with other imaging modalities, MRI is set apart by its superb anatomical resolution; however, its success in molecular imaging suffers because of its intrinsic insensitivity. A relatively high concentration of molecular agents (0.01-0.1 mM) is necessary to produce a local alteration in the water signal intensity. Unfortunately, the most desirable molecules for visualization in molecular imaging are present at much lower concentrations, in the nano- or picomolar range. Therefore, augmenting the sensitivity of MRI agents is key to the development of MR-based molecular imaging applications. In principle, this task can be tackled either by increasing the sensitivity of the reporting units, through the optimization of their structural and dynamic properties, or by setting up proper amplification strategies that allow the accumulation of a huge number of imaging reporters at the site of interest. For Gd-based agents, high sensitivities can be attained by exploiting a range of nanosized carriers (micelles, liposomes, microemulsions, and the like, as well as biological structures such as apoferritin and lipoproteins) properly loaded with Gd-based chelates. Furthermore, the sensitivity of Gd-based agents can be markedly affected either by their interactions with biological structures or by their cellular localization. For CEST agents, a huge sensitivity enhancement has been obtained by using the water molecules contained in the inner cavity of liposomes as the exchangeable source of protons for magnetization transfer. Several "tricks" (for example, the use of multimeric lanthanide(III) shift reagents, changes in the shape of the liposome container, and so forth) have been devised to improve the chemical shift separation between the intraliposomal water and the "bulk" water resonances. Overall, excellent sensitivity enhancements have been obtained for both classes of agents, enabling their use in MR molecular imaging applications.

The contrast obtained in magnetic resonance imaging (MRI) relies essentially on differences in the intensity of the 1 H water signal. Therefore, the contrast can be augmented by the use of chemicals (contrast agents, CAs) able to enhance the relaxation properties of water protons. [1] Recently, a novel class of paramagnetic CAs has been proposed for MRI applications. [2,3] Such chemicals contain paramagnetically shifted mobile protons whose exchange with the bulk water is slow on the NMR timescale (j k ex j < j Dw j ). Thus, irradiation of the mobile protons of the agent determines a decrease of the 1 H water signal through the so-called chemical exchange saturation transfer (CEST) effect. [4, 5] One of the major advantages of the CEST agents relies on the possibility of designing responsive agents in which the effectiveness of the CA is not dependent on its concentration. This goal can be pursued when the CEST properties of two independent exchanging pools are monitored in the same experiment (ratiometric method). [6] This possibility has been demonstrated using a mixture of two compounds. [3] An improvement in such ratiometric methods would be obtained if the two proton-exchanging pools were parts of the same molecule (single-molecule CEST procedure). Paramagnetic [Ln(dotamGly)] À complexes (dotam ¼ 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetrazacyclododecane) would be appropriate for this purpose since they are characterized by the presence of two kinds of mobile protons, namely, the four equivalent amide protons and the two protons of the water molecule coordinated to the Ln III ion. It has been previously shown that the use of a cocktail formed by [Yb(dotamGly)] À and [Eu(dotamGly)] À allows the set-up of a ratiometric method for pH measurements by making use of the two exchanging pools provided by the amide protons of the Yb derivative and by the metal-coordinated water protons of the Eu complex, respectively. Herein we demonstrate that the paramagnetic dotamGly complexes of the lighter Ln III ions (Pr, Nd, and Eu) behave as pH-responsive ™single-molecule CEST∫ agents. The efficiency of saturation transfer (ST), once the irradiation time is sufficiently long to reach a steady-state ST value, [3] is directly related to the exchange rate of the irradiated protons (k ex ), their molar concentration (defined by the product n[C], where n is the number of irradiated protons and [C] is the molar concentration of the agent), and inversely related to the longitudinal relaxation rate of the bulk water protons during the irradiation R 1,irr [Eq. (1)].The latter parameter, in the presence of a paramagnetic Ln III complex, is mainly determined by the relaxation rate of the metal-coordinated water protons, and this is directly dependent on the intrinsic paramagnetism of the metal ion (m eff ). [7] I S and I 0 refer to the intensity of the bulk water signal when the irradiation pulse is set on-resonance (frequency n on , signal intensity I S ) and off-resonance with respect to the frequency of the bulk water prot...

A paramagnetic Yb(III) complex bearing six exchangeable amide protons, [Yb(MBDO3AM)](3+), has been investigated with the aim of developing a MRI-CEST (chemical exchange saturation transfer) contrast agent responsive to the concentration of L-lactate. The complex binds the substrate quantitatively to yield [Yb(MBDO3AM)L-lactate](2+). The exchange between the free and the L-lactate-bound complex is slow on the NMR time scale, and the resonances of their corresponding amide protons are sufficiently separated (more than 10 ppm) to allow their selective irradiation. Therefore, the CEST properties of the two forms can be independently assessed. In turn, the resulting saturation transfer to the bulk water signal is dependent on the L-lactate concentration.

The modulation of the magnetic properties along the lanthanide series allows an in-depth understanding of the determinants of ST effect and provides useful insights for the design of more efficient agents.

A multiple response: YbIII‐HPDO3A has been used for the development of a magnetic resonance imaging method that is able to assess pH value and temperature simultaneously, irrespective of the concentration of the complex (see graph). This contrast agent has potential in a clinical setting as it shows the same stability and in vivo pharmacokinetic properties as GdIII‐HPDO3A, which is already used in clinical practices under the trade name of ProHance.

Contrasting views: Entrapment of a paramagnetic shift reagent for water protons inside liposomes dramatically improves the sensitivity of chemical exchange saturation transfer agents. The chemical shift of the water entrapped within the liposomes, relative to bulk water, depends upon the nature and concentration of the shift reagent as well as on the permeability of the liposome membrane (see picture; SR=shift reagent, Ln=lanthanide ion).