title: Bifunctional chelates optimized for molecular MRI.
abstract: Important requirements for exogenous dyes or contrast agents in magnetic resonance imaging (MRI) include an effective concentration of paramagnetic or superparamagnetic ions at the target to be imaged. We report the concise synthesis and characterization of several new enantiopure bifunctional derivatives of (α(1)R,α(4)R,α(7)R,α(10)R)-α(1),α(4),α(7),α(10)-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA) (and their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) analogues as controls) that can be covalently attached to a contrast agent delivery system using either click or peptide coupling chemistry. Gd complexes of these derivatives can be attached to delivery systems while maintaining optimal water residence time for increased molecular imaging sensitivity. Long chain biotin (LC-biotin) derivatives of the Eu(III) and Gd(III) chelates associated with avidin are used to demonstrate higher efficiencies. Variable-temperature relaxometry, (17)O NMR, and nuclear magnetic resonance dispersion (NMRD) spectroscopy used on the complexes and biotin-avidin adducts measure the influence of water residence time and rotational correlation time on constrained and unconstrained systems. The Gd(III)-DOTMA derivative has a shorter water residence time than the Gd(III)-DOTA derivative. Compared to the constrained Gd(III)-DOTA derivatives, the rotationally constrained Gd(III)-DOTMA derivative has ∼40% higher relaxivity at 37 °C, which could increase its sensitivity as an MRI agent as well as reduce the dose of the targeting agent.
authors.affiliation: Hillman Cancer Center, University of Pittsburgh Medical Center , 5117 Centre Avenue, Pittsburgh, Pennsylvania 15213, United States.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Wiener
authors.forename: Marie-Caline
authors.initials: MC
authors.lastname: Abadjian
authors.forename: Raghvendra
authors.initials: R
authors.lastname: Sengar
authors.forename: Luce
authors.initials: L
authors.lastname: Vander Elst
authors.forename: Christoffel
authors.initials: C
authors.lastname: Van Niekerk
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Grotjahn
authors.forename: Po Yee
authors.initials: PY
authors.lastname: Leung
authors.forename: Christie
authors.initials: C
authors.lastname: Schulte
authors.forename: Curtis E
authors.initials: CE
authors.lastname: Moore
authors.forename: Arnold L
authors.initials: AL
authors.lastname: Rheingold
mesh_terms: D001710:Biotin / Q000737:chemistry; D002614:Chelating Agents / Q000737:chemistry*; D003287:Contrast Media / Q000737:chemistry*; D005682:Gadolinium / Q000737:chemistry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008958:Models, Molecular; D000644:Quaternary Ammonium Compounds / Q000737:chemistry
chemical_list: D002614:Chelating Agents; D003287:Contrast Media; D000644:Quaternary Ammonium Compounds; C054005:N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium; D001710:Biotin; D005682:Gadolinium