title: Calcium-responsive paramagnetic CEST agents.
abstract: The assessment of changes in the extracellular calcium concentration by magnetic resonance imaging would be a valuable biomedical research tool to monitor brain neuronal activity. In this perspective, we report here the synthesis of novel ligands consisting of tetraamide and bisamide derivatives of cyclen, L(1) and L(2), respectively, each bearing imino(diacetate) moieties for Ca(2+) binding. Yb(3+) and Eu(3+) complexes are investigated as chemical exchange saturation transfer (CEST) agents that respond to the presence of Ca(2+). A CEST effect is observed for both YbL(1) and EuL(1) complexes (B=11.7T), originating from the slow exchange of the amide protons and those of the coordinated water, respectively, whilst no CEST is detected for complexes of L(2). Upon calcium binding, the CEST effect decreases considerably (from 60% to 20% for YbL(1) and from 35% to 10% for EuL(1)). A similar variation is observed in the presence of Mg(2+). The affinity constants between the lanthanide complexes and the alkaline earth metal ions have been estimated from the variation of the CEST effect to be K(YbL(1)-Ca)(aff) = 8 ± 2M(-1), K(YbL(1)-Mg)(aff) = 23 ± 3M(-1) and K(EuL(1)-Ca)(aff) = 10 ± 3M(-1). These low values imply the coordination of the alkaline earth ions to a single iminodiacetate arm. Ca(2+)/Mg(2+) binding to the lanthanide complexes slows down the exchange of the amide protons on YbL(1) which is responsible for the diminished CEST effect. This has been evidenced by assessing the proton exchange rates from the dependency of the CEST effect on the saturation time and the saturation power, in the absence and in the presence of Ca(2+) and Mg(2+). The applicability of the PARACEST MRI agents for Ca(2+) detection has been evaluated on a 16T MRI scanner.
authors.affiliation: Physiology of Cognitive Processes, Max Planck Institute for Biological Cybernetics, Spemannstr. 38, 72076 Tübingen, Germany. goran.angelovski@tuebingen.mpg.de
authors.forename: Goran
authors.initials: G
authors.lastname: Angelovski
authors.forename: Thomas
authors.initials: T
authors.lastname: Chauvin
authors.forename: Rolf
authors.initials: R
authors.lastname: Pohmann
authors.forename: Nikos K
authors.initials: NK
authors.lastname: Logothetis
authors.forename: Eva
authors.initials: E
authors.lastname: Tóth
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry*; D002118:Calcium / Q000032:analysis* / Q000378:metabolism; D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry*; D000080027:Cyclams; D005063:Europium / Q000737:chemistry; D006571:Heterocyclic Compounds / Q000737:chemistry*; D028581:Lanthanoid Series Elements / Q000737:chemistry; D008024:Ligands; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008962:Models, Theoretical; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D011522:Protons; D014867:Water; D015018:Ytterbium / Q000737:chemistry
chemical_list: D000577:Amides; D003287:Contrast Media; D000080027:Cyclams; D006571:Heterocyclic Compounds; D028581:Lanthanoid Series Elements; D008024:Ligands; D009942:Organometallic Compounds; D011522:Protons; D014867:Water; D005063:Europium; C038072:cyclen; D015018:Ytterbium; D002118:Calcium