New non-ionic water-soluble porphyrins: evaluation of manganese(III) polyhydroxylamide porphyrins as MRI contrast agents

Abstract

A new series of metalloporphyrins (M = zinc(II) and manganese(III)), utilizing polyhydroxylamide substituents to achieve water solubility, has been synthesized and spectroscopically characterized. Two of these compounds, [Mn III(TPPAS)Cl] and (Mn III (TPPIS)Cl], have been evaluated as potential MRI contrast enhancement agents. The water proton magnetic relaxation rate, (1/ T 1), of aqueous [Mn III(TPPAS)Cl] solutions has been measured as a function of field strength over the range of Larmor frequencies from 0.01 to 30 MHz. Results show a typical relaxation rate pattern, similar to other water-soluble manganese (III) porphyrin compounds, over this frequency range. Conductivity and osmolality measurements for [Mn III(TPPAS)Cl] in water demonstrate complete dissociation of the chloride ion to yield [Mn III(TPPAS)(H 2O) 2) +. The two axial water ligands provide a reasonable explanation as to the source of the greater than expected proton relaxation rate of manganese(III) porphyrin compounds, in general. Variable-temperature NMR studies of the H 2TPPAS and H 2TPPIS free ligands reveal the occurrence of proton tautomerism, as indicated by two temperature dependent H β pyrrole proton signals. Actual magnetic resonance images of Sprague-Dawley rats, to which [Mn III(TPPAS))Cl] had been administered, showed significant image enhancement in the heat, liver, lungs and gastrointestinal tract. However, with an acute toxicity of 0.1 mmol kg −1, the cationic [Mn III(TPPAS)(H 2O) 2] + compound is too toxic for clinical use.