title: Synthesis and evaluation of nanoglobular macrocyclic Mn(II) chelate conjugates as non-gadolinium(III) MRI contrast agents.
abstract: Because of the recent observation of the toxic side effects of Gd(III) based MRI contrast agents in patients with impaired renal function, there is strong interest on developing alternative contrast agents for MRI. In this study, macrocyclic Mn(II) chelates were conjugated to nanoglobular carriers, lysine dendrimers with a silsesquioxane core, to synthesize non-Gd(III) based MRI contrast agents. 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 T(1) and T(2) relaxivities of G2, G3, G4 nanoglobular Mn(II)-DOTA monoamide conjugates decreased with increasing generation of the carriers. The T(1) relaxivities of G2, G3, and G4 nanoglobular Mn(II)-DOTA conjugates were 3.3, 2.8, and 2.4 mM(-1) s(-1) per Mn(II) chelate at 3 T, respectively. The T(1) relaxivity of G3-NOTA-Mn was 3.80 mM(-1) s(-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 nonspecific liver enhancement than MnCl(2) 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 nongadolinium based MRI contrast agents.
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, United States.
authors.forename: Mingqian
authors.initials: M
authors.lastname: Tan
authors.forename: Zhen
authors.initials: Z
authors.lastname: Ye
authors.forename: Eun-Kee
authors.initials: EK
authors.lastname: Jeong
authors.forename: Xueming
authors.initials: X
authors.lastname: Wu
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Parker
authors.forename: Zheng-Rong
authors.initials: ZR
authors.lastname: Lu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000175:diagnosis; D002614:Chelating Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D003287:Contrast Media / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D005682:Gadolinium; D006571:Heterocyclic Compounds / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D008279:Magnetic Resonance Imaging; D008345:Manganese / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D057054:Molecular Imaging; D015394:Molecular Structure; D049329:Nanostructures / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D002614:Chelating Agents; D003287:Contrast Media; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D047028:Macrocyclic Compounds; D009942:Organometallic Compounds; D008345:Manganese; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid; D005682:Gadolinium