Di-Pyridine-Containing Macrocyclic Triamide Fe(II) and Ni(II) Complexes as ParaCEST Agents

Abstract

Fe(II) and Ni(II) paraCEST contrast agents containing the di-pyridine macrocyclic ligand 2,2′,2″-(3,7,10-triaza-1,5(2,6)-dipyridinacycloundecaphane-3,7,10triyl)triacetamide (DETA) are reported here. Both [Fe(DETA)] 2+ and [Ni-(DETA)] 2+ complexes were structurally characterized. Crystallographic data revealed the seven-coordinated distorted pentagonal bipyramidal geometry of the [Fe-(DETA)]•(BF 4 ) 2 •MeCN complex with five coordinated nitrogen atoms from the macrocyclic ring and two coordinated oxygen atoms from two amide pendant arms. The [Ni(DETA)]•Cl 2 •2H 2 O complex was six-coordinated in nature with a distorted octahedral geometry. Four coordinated nitrogen atoms were from the macrocyclic ring, and two coordinated oxygen atoms were from two amide pendant arms.[Fe(DETA)] 2+ exhibited well-resolved sharp proton resonances, whereas very broad proton resonances were observed in the case of [Ni(DETA)] 2+ due to the long electronic relaxation times. The CEST peaks for the [Fe(DETA)] 2+ complex showed one highly downfield-shifted and intense peak at 84 ppm with another shifted but less intense peak at 28 ppm with good CEST contrast efficiency at body temperature, whereas [Ni(DETA)] 2+ showed only one highly shifted intense peak at 78 ppm from the bulk water protons. Potentiometric titrations were performed to determine the protonation constants of the ligand and the thermodynamic stability constant of the [M(DETA)] 2+ (M = Fe, Co, Ni, Cu, Zn) species at 25.0 °C and I = 0.15 mol•L −1 NaClO 4 . Metal exchange studies confirmed the stability of the complexes in acidic medium in the presence of physiologically relevant anions and an equimolar concentration of Zn(II) ions.

Comparative paraCEST effect of amide and hydroxy groups in divalent cobalt and nickel complexes of tripyridine-based ligands

“…† In the case of the TMTP-Ni, the 1 H proton resonances are very broad due to their long electronic relaxation time and the presence of dynamic equilibrium in the solution state. 38,53 Therefore, in this case, it is difficult to comment on the isomeric state of the complex. The stability of the complexes at higher temperatures and in the physiological pH range was investigated in the presence of a 10 mM complex solution with 20 mM HEPES and 100 mM NaCl in water.…”

“…The bond distances and bond angles of the complexes are provided in Table 2 and Table S1, † respectively. The average 32,33,35,38,42,43 Equilibrium studies…”

“…For the [Ni(TMTP)] 2+ , two CEST peaks were found at both 25 and 37 °C, which were shifted downfield by 75 and 15 ppm from the bulk water resonance at 9.4 T. These two CEST signals are responsible for the two types of exchangeable protons present at 90 and 20 ppm, respectively. Due to the long electronic relaxation time and the presence of dynamic equilibrium in the solution state, 38,53 the [Ni(TMTP)] 2+ complex showed broad peaks in the NMR spectrum as well as in the CEST signals. Both transition metal complexes showed largely shifted peaks from the bulk water proton resonance, comparable to many other reported results.…”

“…These d-d transitions of the [Co (TMTP)] 2+ , and [Ni(TMTP)] 2+ complexes are comparable to the Co(II), and Ni(II) complexes of ligands reported earlier. 26,38,54…”

“…Fe(II), Co(II), and Ni(II)) are used frequently nowadays to develop paraCEST-based contrast agents, and the first transition-metal-based contrast agent was developed by Morrow et al in 2011; 25 many transition-metal-based paraCEST agents containing macrocyclic and acyclic backbones have since been reported. [26][27][28][29][30][31][32][33][34][35][36][37][38] Picolinate-based ligands are currently on trend due to their easy functionalization and ability to form kinetically inert and thermodynamically stable complexes. [39][40][41] Herein, two ligands (TDTA and TMTP) have been synthesized, containing a tri-pyridine backbone with amide or alcohol-exchangeable protons.…”