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 macrocy cles (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis (methylene ethy lphosphonic acid), H4DOTEP; 1,4,7,10-tetraazacyclododecane-1,4,7,10-te trakis (methylene phosphonic acid monoethylester), H4DOTPME; and the c orresponding n-butyl ester, H4DOTPMB) were prepared and examined for p ossible use as MRI contrast agents. Although thermodynamically and kin etically less stable than Gd(DOTA)- in saline and HSA solution, the st ability of these new macrocyclic complexes appears to be sufficiently high for In vivo applications. NMRD relaxivity profiles of the three c omplexes indicate that the number of inner sphere water molecules for these chelates is less-than-or-equal-to 1 and that the more hydrophobi c chelate, Gd(DOTPMB), binds to human serum albumin (HSA). Biodistribu tion studies of the radioactive Sm-153 or Gd-159 chelates in rats, gam ma imaging of the Sm-153 chelates in rats, and proton MRI studies of t he nonradioactive. Gd3+ chelates in rabbits all indicate that the DOTP MB complexes accumulate preferentially in the liver, spleen, and small intestines while the more hydrophilic DOTEP and DOTPME complexes appe ar to display renal clearances similar to other low molecular weight c ontrast agents.