title: On-bead combinatorial synthesis and imaging of europium(III)-based paraCEST agents aids in identification of chemical features that enhance CEST sensitivity.
abstract: The rate of water exchange between the inner sphere of a paramagnetic ion and bulk water is an important parameter in determining the magnitude of the chemical exchange saturation transfer signal from paramagnetic CEST agents (paraCEST). This is governed by various geometric, steric and ligand field factors created by macrocyclic ligands surrounding the paramagnetic metal ion. Our previous on-bead combinatorial studies of di-peptoid-europium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-tetraamide complexes revealed that negatively charged groups in the immediate vicinity of the metal center strongly enhances the CEST signal. Here, we report a solid phase synthesis and on-bead imaging of 76 new DOTA derivatives that are developed by coupling with a single residue onto each of the three arms of a DOTA-tetraamide scaffold attached to resin beads. This single residue predominantly carries negatively charged groups blended with various physico-chemical characteristics. We found that non-bulky negatively charged groups are best suited at the immediate vicinity of the metal ion, while positive, bulky and halogen containing moieties suppress the CEST signal. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 3455 Cullen Blvd, Houston, TX, 77204-5037, USA.
authors.forename: Jaspal
authors.initials: J
authors.lastname: Singh
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 3455 Cullen Blvd, Houston, TX, 77204-5037, USA.
authors.forename: Vineeta
authors.initials: V
authors.lastname: Rustagi
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-8568, USA.
authors.forename: Shanrong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-8568, USA.|Department of Chemistry, University of Texas at Dallas, 800 West Campbell Rd, Richardson, TX, 75083-3021, USA.
authors.forename: A Dean
authors.initials: AD
authors.lastname: Sherry
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 3455 Cullen Blvd, Houston, TX, 77204-5037, USA.|Department of Cancer Systems Imaging, MD Anderson Cancer Center, 1881 East Road, Houston, TX, 77030-4009, USA.
authors.forename: D Gomika
authors.identifier: http://orcid.org/0000-0003-3509-2446
authors.initials: DG
authors.lastname: Udugamasooriya
keywords: CEST-MRI; DOTA; combinatorial