title: Membrane-Permeable Mn(III) Complexes for Molecular Magnetic Resonance Imaging of Intracellular Targets.
abstract: Intracellular compartments make up roughly two-thirds of the body, but delivery of molecular imaging probes to these spaces can be challenging. This situation is particularly true for probes designed for detection by magnetic resonance imaging (MRI), a high-resolution but relatively insensitive modality. Most MRI contrast agents are polar and membrane impermeant, making it difficult to deliver them in sufficient quantities for measurement of intracellular analytes. Here we address this problem by introducing a new class of planar tetradentate Mn(III) chelates assembled from a 1,2-phenylenediamido (PDA) backbone. Mn(III)-PDA complexes display T1 relaxivity comparable to that of Gd(III)-based contrast agents and undergo spontaneous cytosolic localization via defined mechanisms. Probe variants incorporating enzyme-cleavable acetomethoxy ester groups are processed by intracellular esterases and accumulate in cells. Probes modified with ethyl esters preferentially label genetically modified cells that express a substrate-selective esterase. In each case, the contrast agents gives rise to robust T1-weighted MRI enhancements, providing precedents for the detection of intracellular targets by Mn(III)-PDA complexes. These compounds therefore constitute a platform from which to develop reagents for molecular MRI of diverse processes inside cells.
authors.affiliation: Departments of †Biological Engineering, ‡Chemistry, §Brain and Cognitive Sciences, and ⊥Nuclear Science and Engineering, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Ali
authors.initials: A
authors.lastname: Barandov
authors.affiliation: Departments of †Biological Engineering, ‡Chemistry, §Brain and Cognitive Sciences, and ⊥Nuclear Science and Engineering, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Bartelle
authors.affiliation: Departments of †Biological Engineering, ‡Chemistry, §Brain and Cognitive Sciences, and ⊥Nuclear Science and Engineering, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Beatriz A
authors.initials: BA
authors.lastname: Gonzalez
authors.affiliation: Departments of †Biological Engineering, ‡Chemistry, §Brain and Cognitive Sciences, and ⊥Nuclear Science and Engineering, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: William L
authors.initials: WL
authors.lastname: White
authors.affiliation: Departments of †Biological Engineering, ‡Chemistry, §Brain and Cognitive Sciences, and ⊥Nuclear Science and Engineering, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lippard
authors.affiliation: Departments of †Biological Engineering, ‡Chemistry, §Brain and Cognitive Sciences, and ⊥Nuclear Science and Engineering, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Alan
authors.initials: A
authors.lastname: Jasanoff
mesh_terms: D002463:Cell Membrane Permeability; D003287:Contrast Media / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008345:Manganese / Q000737:chemistry*
chemical_list: D003287:Contrast Media; D008345:Manganese