Synthesis and Evaluation of Nanoglobular Macrocyclic Mn(II) Chelate Conjugates As Non-Gadolinium(III) MRI Contrast Agents

摘要

Because of the recent observation of the toxic side effects of Gd(III) based MRI contrast agents in the patients with impaired renal functions, there is a strong interest on developing alternative contrast agents for MRI. In this study, lysine dendrimers with a silsesquioxane core acted as nanoglobular carriers that were conjugated to Mn(II)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate monoamide (Generation 2, 3, 4-DOTA-Mn) to synthesize non-Gd(III) based contrast agents for magnetic resonance imaging (MRI). A generation 3 nanoglobular conjugate of Mn(II)-1,4,7-triaazacyclononane-1,4,7-triacetate-GA amide (G3-NOTA-Mn) was also synthesized and evaluated. The per ion T1 and T2 relaxivities of G2, G3, G4 nanoglobular Mn(II)-DOTA monoamide conjugates decreased with increasing generation of the carriers. The T1 relaxivity of G2, G3, G4 nanoglobular Mn(II)-DOTA conjugates was 3.3, 2.8, 2.4 mM⁻¹sec⁻¹ per Mn(II) chelate at 3 T, respectively. The T1 relaxivity of G3-NOTA-Mn was 3.80 mM⁻¹sec⁻¹ per Mn(II) chelate at 3 T. The nanoglobular macrocyclic Mn(II) chelate conjugates showed good in vivo stability and were readily excreted via renal filtration. The conjugates resulted in much less non-specific liver enhancement than MnCl2 and were effective for contrast enhanced tumor imaging in nude mice bearing MDA-MB-231 breast tumor xenografts at a dose of 0.03 mmol Mn/kg. The nanoglobular macrocyclic Mn(II) chelate conjugates are promising non-gadolinium based MRI contrast agents.