Gear Up for a pH Shift: A Responsive Iron(II) 2-Amino-6-picolyl-Appended Macrocyclic paraCEST Agent That Protonates at a Pendent Group

Abstract

Two high-spin Fe(II) and Co(II) complexes of 1,4,7,10-tetraazacyclododecane (CYCLEN) appended with four 2-amino-6-picolyl groups, denoted as [Fe(TAPC)]2+ and [Co(TAPC)]2+, are reported. These complexes demonstrate C2-symmetrical geometry from coordination of two pendents, and they are present in a single diastereomeric form in aqueous solution as shown by 1H NMR spectroscopy, and by a single-crystal X-ray structure for the Co(II) complex. A highly-shifted, but low intensity CEST (Chemical Exchange Saturation Transfer) signal from NH groups is observed at −118 ppm for [Co(TAPC)]2+ at pH 6.0 and 37 °C. A higher intensity CEST peak is observed for [Fe(TAPC)]2+ which demonstrates a pH-dependent frequency shift from −72 to −79 ppm at pH 7.7 to pH 4.8, respectively, at 37 °C. This shift in the CEST peak correlates with the protonation of the unbound 2-amino-6-picolyl pendents, as suggested by UV-vis and 1H NMR spectroscopy studies at different pH values. Phantom imaging demonstrates the challenges and feasibility of using the [Fe(TAPC)]2+ agent on a low field MRI scanner. The [Fe(TAPC)]2+ complex is the first transition metal-based paraCEST agent that produces a pH-induced CEST frequency change towards the development of probes for concentration independent imaging of pH.

Non‐Macrocyclic Schiff Base Complexes of Iron(II) as ParaCEST Agents for MRI

“…The exchange rate constant k ex for the exchangeable proton of each complex was measured at pH 7.0 using the omega plot method with a 2 second presaturation pulse and presaturation powers of 9.4, 11.8, 14.8, 18.7, and 23.5 µT at 37 °C. The k ex values were found to be higher than that in previous macrocyclic and non‐macrocyclic amine‐bearing paraCEST agents (entry 9–11 Table ) , . The well resolved Z‐spectra minima for [ L 1H3 Fe II ](OTf) 2 and [ L 2H3 Fe II ](OTf) 2 at 85 and 60 ppm, respectively allow the values for k ex to be easily measured, yielding k ex = 1.0 × 10 4 s –1 and 1.3 × 10 4 s –1 (Table entry 1 & 2, S36, S39).…”

“…The k ex values were found to be higher than that in previous macrocyclic and non-macrocyclic amine-bearing paraCEST agents (entry 9-11 Table 1). [32,38] The well resolved Z-spectra minima for [L 1H3 Fe II ](OTf ) 2 and [L 2H3 Fe II ](OTf ) 2 at 85 and 60 ppm, respectively allow the values for k ex to be easily measured, yielding k ex = 1.0 × 10 4 s -1 and 1.3 × 10 4 s -1 ( 2 , the Δω value of 39 ppm found at 25°C and pH 6.8 was chosen to measure CEST efficacy at 37°C and pH 7.0, yielding a k ex value of 1.6 × 10 4 s -1 (Table 1 entry 3, S43). Water T 1 relaxation times were measured by the inversion recovery method using a standard two-pulse sequence (S31-33).…”

“…Many paraCEST agents use electronically anisotropic lanthanide ions installed into macrocyclic ligands appended with exchangeable OH, NH, or C(O)NH 2 functionalities. [15][16][17][18][19][20][21][22] The smaller number of transition metal paraCEST agents employ similar appended macrocycles; [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] exceptions include a few Fe II compounds, [38,39] a Co II complex, [40] a Ni II complex, [41] and a ferromagnetically coupled bimetallic Cu II dimer. [42] Transition metal paraCEST agents are primarily sought to eliminate the use of Ln III based contrast agents.…”

pH Imaging Using Chemical Exchange Saturation Transfer (CEST) MRI

“…This method should be quite reliable as determining peak position is not as demanding as determining peak width or peak intensity. Unfortunately, presently only two agents have been found which display this property, including a newly discovered high spin Fe(II) complex …”

“…Unfortunately, presently only two agents have been found which display this property, including a newly discovered high spin Fe(II) complex. [81] 5. CEST MRI pH Imaging Applications…”