Relaxometry, animal biodistribution, and magnetic resonance imaging studies of some new gadolinium (III) macrocyclic phosphinate and phosphonate monoester complexes

The Gd³⁺ complexes of three new phosphorus containing tetraaza macrocycles (1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetrakis (methylene ethylphosphonic acid), H₄DOTEP; 1,4,7,10‐tetraazacyclododecane‐l,4,7,10‐tetrakis (methylene phosphonic acid monoethylester), H₄DOTPME; and the corresponding n‐butyl ester, H₄DOTPMB) were prepared and examined for possible use as MRI contrast agents. Although thermodynamically and kinetically less stable than Gd(DOTA)⁻ in saline and HSA solution, the stability of these new macrocyclic complexes appears to be sufficiently high for in vivo applications. NMRD relaxivity profiles of the three complexes indicate that the number of inner sphere water molecules for these chelates is ≤1 and that the more hydrophobic chelate, Gd(DOT‐PMB), binds to human serum albumin (HSA). Biodistribution studies of the radioactive ¹⁵³Sm or ¹⁵⁹Gd chelates in rats, gamma imaging of the ¹⁵³Sm chelates in rats, and proton MRI studies of the nonradioactive Gd³⁺ chelates in rabbits all indicate that the DOTPMB complexes accumulate preferentially in the liver, spleen, and small intestines while the more hydrophilic DOTEP and DOTPME complexes appear to display renal clearances similar to other low molecular weight contrast agents.