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^4-) derivatives have shown potential for molecular imaging with magnetic resonance. DOTA-tetraglycinate (DOTA-4AmC^4-) coordinated with lanthanide metal ions (Ln³⁺) 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_<i>y</i>, where 3 ≥ <i>y</i> ≥ 1) and exchangeable (e.g., -OH or -NH_<i>x</i>, where 2 ≥ <i>x</i> ≥ 1) protons. Herein, we report paramagnetic complexes of divalent transition-metal ions (M²⁺ = Fe²⁺, Co²⁺, Ni²⁺) with DOTA-4AmC^4- that endow a unique amide proton (-NH) moiety for pH/temperature sensing. Crystallographic data reveal that DOTA-4AmC^4- coordinates with M²⁺ through oxygen and nitrogen donor atoms, ranging in coordination numbers from 8-coordinate in Fe(II)DOTA-4AmC^2-, 7-coordinate in Co(II)DOTA-4AmC^2-, and 6-coordinate in Ni(II)DOTA-4AmC^2-. The -CH_<i>y</i> protons in M(II)DOTA-4AmC^2- 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^2- (1.42 ppm/pH), followed by Co(II)DOTA-4AmC^2- (0.21 ppm/pH) and Fe(II)DOTA-4AmC^2- (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^2- was much weaker compared to that of Ln(III)DOTA-4AmC^-. Given its high pH sensitivity and low cytotoxicity, Ni(II)DOTA-4AmC^2- shows promise for use in preclinical BIRDS-based pH imaging.