Mn(II) complexes of phenylenediamine based macrocyclic ligands as T₁-MRI contrast agents

The Mn(II) complexes are emerging as alternative T₁-MRI contrast agents (CAs) to the currently available Gd-based CAs. The complexes [Mn(L1)] 1 and [Mn(L2)] 2 of o-phenylenediamine based macrocyclic ligands are reported as T₁-CAs for MRI applications. The high spin state of the Mn(II) complexes (S = 5/2) is confirmed by EPR spectra. The complexes showed an irreversible Mn(II)/Mn(III) redox potential at pH 7.28, which became more and less positive at the acidic and alkaline pHs, respectively. The species [MnL], [Mn(LH_-1), and [Mn(LH_-2) are persisted in solution. Complex 1 is inert towards Ca(II), Mg(II), and Zn(II), whereas complex 2 is inert for Ca(II) and Mg(II) and labile under Zn(II) and Cu(II) ions. Complex 1 showed an r₁-relaxivity of 3.27 and 2.32 mM^-1 s^-1 at 1.41 T, 25, and 37 °C respectively via inner-sphere water relaxation, which is lower than that of 2 (r₁, 5.56, and 4.19 mM^-1 s^-1) at pH 7.28 and 1.41 T. The Mn(II) complexes showed a 2-8% enhancement of r₁-relaxivity while lowering the pH to acidic, which corresponds to the release of free Mn(II) ions. In contrast, the r₁-relaxivity is dropped to 52% and 20% for 1 and 2 respectively under alkaline pH due to the deprotonation of inner-sphere water. Phantom images obtained on Bruker 'BIOSPEC' 47/40 animal research MRI/MRS scanner showed concentration-dependent brightness. The interaction of human serum albumin (HSA) with 1 and 2 exhibited five times higher r₁-relaxivities (11.3 and 22.0 mM^-1 s^-1 at 1.41 T, respectively).