Complexes of Iron(II), Cobalt(II), and Nickel(II) with DOTA-Tetraglycinate for pH and Temperature Imaging Using Hyperfine Shifts of an Amide Moiety.

Paramagnetic complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA) derivatives have shown potential for molecular imaging with magnetic resonance. DOTA-tetraglycinate (DOTA-4AmC) coordinated with lanthanide metal ions (Ln) demonstrates pH/temperature sensing with Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) and Chemical Exchange Saturation Transfer (CEST), respectively, detecting nonexchangeable (e.g., -CH, where 3 ≥ ≥ 1) and exchangeable (e.g., -OH or -NH, where 2 ≥ ≥ 1) protons. Herein, we report paramagnetic complexes of divalent transition-metal ions (M = Fe, Co, Ni) with DOTA-4AmC that endow a unique amide proton (-NH) moiety for pH/temperature sensing. Crystallographic data reveal that DOTA-4AmC coordinates with M through oxygen and nitrogen donor atoms, ranging in coordination numbers from 8-coordinate in Fe(II)DOTA-4AmC, 7-coordinate in Co(II)DOTA-4AmC, and 6-coordinate in Ni(II)DOTA-4AmC. The -CH protons in M(II)DOTA-4AmC displayed modest pH/temperature sensitivities, but -NH protons exhibited higher intensity, suggesting prominent BIRDS properties. The pH sensitivity was the highest for Ni(II)DOTA-4AmC (1.42 ppm/pH), followed by Co(II)DOTA-4AmC (0.21 ppm/pH) and Fe(II)DOTA-4AmC (0.16 ppm/pH), whereas temperature sensitivities were comparable (i.e., 0.22, 0.13, and 0.17 ppm/°C, respectively). The CEST image contrast for -NH in M(II)DOTA-4AmC was much weaker compared to that of Ln(III)DOTA-4AmC. Given its high pH sensitivity and low cytotoxicity, Ni(II)DOTA-4AmC shows promise for use in preclinical BIRDS-based pH imaging.