First‐row transition metal (TM) complexes are of interest as members of a relatively new class of coordination complexes that produce MRI contrast through CEST (chemical‐exchange saturation transfer). CEST reduces the intensity of the water protons upon exchange of a selectively magnetically saturated proton with the water proton pool. Paramagnetic TM complexes produce large paramagnetically shifted protons, which facilitates CEST signal intensity by avoiding tissue background signal (paraCEST agents) and also allowing for faster proton‐exchange rates. TM paraCEST agents have certain advantages over lanthanide paraCEST agents including the possibility of tuning oxidation and spin states to allow for the development of responsive agents. Moreover, the covalent bonding character of the TM ions bestows large through‐bond contributions to the hyperfine shifts of protons, which is beneficial for paraCEST agents. New applications include the development of TM water proton shift reagents (SRs) for improvement of sensitivity through incorporation into supramolecular assemblies. Liposomes with encapsulated and amphiphilic SRs produce lipoCEST, and cells loaded with SRs produce cellCEST. This article summarizes TM paraCEST agents and SRs and highlights new research directions.

Paramagnetic liposomes containing Fe­(III) complexes were prepared by incorporation of mononuclear (Fe­(L1) or Fe­(L3)) or dinuclear (Fe2(L2)) coordination complexes of 1,4,7-triazacyclononane macrocycles containing 2-hydroxypropyl pendant groups. Two different types of paramagnetic liposomes were prepared. The first type, LipoA, has the mononuclear Fe­(L1) complex loaded into the internal aqueous core. The second type, LipoB, has the amphiphilic Fe­(L3) complex inserted into the liposomal bilayer and the internal aqueous core loaded with either Fe­(L1) (LipoB1) or Fe2(L2) (LipoB2). LipoA enhances both T1 and T2 water proton relaxation rates. Treatment of LipoA with osmotic gradients to produce a nonspherical liposome produces a liposome with a chemical exchange saturation transfer effect as shown by an asymmetry analysis but only at high osmolarity. LipoB1, which contains an amphiphilic complex in the liposomal bilayer, produced a broadened Z-spectrum upon treatment of the liposome with osmotic gradients. The r 1 relaxivity of LipoB1 and LipoB2 were higher than the r 1 relaxivity of LipoA on a per Fe basis, suggesting an important contribution from the amphiphilic Fe­(III) center. The r 1 relaxivities of paramagnetic liposomes are relatively constant over a range of magnetic field strengths (1.4–9.4 T), with the ratio of r 2/r 1 substantially increasing at high field strengths. MRI studies of LipoB1 in mice showed prolonged contrast enhancement in blood compared to the clinically employed Gd­(DOTA), which was injected at a 2-fold higher dose per metal than the Fe­(III)-loaded liposomes.

No abstract