Stable and Inert Mn(II)-Based and pH-Responsive Contrast Agents

Abstract

Smart/intelligent contrast agent candidates for MRI based on Mn­(II) ion are rare, as it usually forms labile complexes with polyaminocarboxylate-type ligands. Here, we report the first example of a Mn­(II) complex that can be activated by changing the pH of its local environment. The PC2A-EA ligand with an ethylamine pendant arm was found to form a thermodynamically stable (log K MnL = 19.01, pMn = 9.27) and kinetically inert complex with Mn­(II) with respect to trans-chelation with a metal ion such as Cu­(II). The [MnH­(PCA2-EA)] complex displays a relatively slow water exchange rate ((4.0 ± 0.2) × 107 s–1), but the pH-dependent coordination of the ethylamine moiety occurs in the pH range of 6–8 (log K MnL H = 6.88), enabling the complex to exhibit pH-sensitive relaxivity in the biologically relevant pH range.

Modulating the Properties of Fe(III) Macrocyclic MRI Contrast Agents by Appending Sulfonate or Hydroxyl Groups

“…1 H-NMR spectrum of H-L1; Figure S2. 13 C-NMR spectrum of H-L1; Figure S3. LCQ-MS spectrum of [Fe(L1+H+)Cl]Cl; Figure S4.…”

“…These two metal ions are the most promising for the development of Gd-free MRI contrast agents, based on their magnetic properties and their roles as trace elements in human biology. There has been much progress in the development of Mn(II) complexes as MRI probes [9][10][11][12][13]. However, despite the prominent role of iron in human biology, there are significantly fewer studies on Fe(III)-based contrast agents [14][15][16][17][18][19][20].…”

Complexation of Mn(II) by Rigid Pyclen Diacetates: Equilibrium, Ki-netic, Relaxometric, DFT and SOD Activity Studies.

“…28 The log K1 H value of 3,9-PC2A decreases significantly upon functionalization of the secondary NH group with biphenyl (BP) or ethylamine (EA) substituents (log K1 H = 10.45 and 11.34, respectively, vs. 12.25 in 3,9-PC2A). 21,22 The isomeric PC2A ligands were found to be less basic than the DO2A derivatives, as judged by the logKi H values (Table 1). However, the parent PCTA ligand appears to be even less basic, which can be related in part to the formation of a relatively stable complex with the Na + ions present at high concentration in the sample (originating for the ionic strength).…”

Recent Advances of Bioresponsive Nano-Sized Contrast Agents for Ultra-High-Field Magnetic Resonance Imaging

“…Alternatively, nanoparticle with magnetic responsive atom is becoming one of the most promising candidates to be used as contrast agents, such as transition metal ions (Cu 2+ , Fe 2+ /Fe 3+ ,Co 2+ , and Mn 2+ , lanthanide metal ions (Eu 3+ , Gd 3+ , Ho 3+ , and Dy 3+ ) (Tromsdorf et al, 2007;Mahmoudi et al, 2011;Busquets et al, 2015;Ni et al, 2017;Sousa et al, 2017;Guo et al, 2019;Hai et al, 2019;Wahsner et al, 2019;Botar et al, 2020). Furthermore, iron-based nano-system is highly recommended as spin-spin imaging or imaging probe because of its merits of electronic, magnetic, optical properties at nano scale and the excellent in vivo stability as well (Li et al, 2013).…”

“…When employing contrast agents for MRI, contrast agent shall possess the following distinct features for better imaging (Zhou et al, 2019): (a) Nano-size, achieve the maximum recognition; (b) diagnosis with high accuracy; (c) Compatibility, non-cytotoxic and biocompatible; (d) Stability, both chemical and photochemical stable; (e) Metabolism; renal excretion from body (Qin et al, 2007;Huang et al, 2010;Botar et al, 2020).…”