title: Macrocyclic Gd(3+) complexes with pendant crown ethers designed for binding zwitterionic neurotransmitters.
abstract: A series of Gd(3+) complexes exhibiting a relaxometric response to zwitterionic amino acid neurotransmitters was synthesized. The design concept involves ditopic interactions 1) between a positively charged and coordinatively unsaturated Gd(3+) chelate and the carboxylate group of the neurotransmitters and 2) between an azacrown ether appended to the chelate and the amino group of the neurotransmitters. The chelates differ in the nature and length of the linker connecting the cyclen-type macrocycle that binds the Ln(3+) ion and the crown ether. The complexes are monohydrated, but they exhibit high proton relaxivities (up to 7.7 mM(-1)  s(-1) at 60 MHz, 310 K) due to slow molecular tumbling. The formation of ternary complexes with neurotransmitters was monitored by (1) H relaxometric titrations of the Gd(3+) complexes and by luminescence measurements on the Eu(3+) and Tb(3+) analogues at pH 7.4. The remarkable relaxivity decrease (≈80 %) observed on neurotransmitter binding is related to the decrease in the hydration number, as evidenced by luminescence lifetime measurements on the Eu(3+) complexes. These complexes show affinity for amino acid neurotransmitters in the millimolar range, which can be suited to imaging concentrations of synaptically released neurotransmitters. They display good selectivity over non-amino acid neurotransmitters (acetylcholine, serotonin, and noradrenaline) and hydrogenphosphate, but selectivity over hydrogencarbonate was not achieved.
authors.affiliation: Centre de Biophysique Moléculaire, CNRS, Université d'Orléans, 45071 Orléans, Cedex 2 (France).|Department of Physiology of Cognitive Processes, Max Planck Institute for Biological Cybernetics, 72076 Tubingen (Germany).
authors.forename: Fatima
authors.initials: F
authors.lastname: Oukhatar
authors.affiliation: Centre de Biophysique Moléculaire, CNRS, Université d'Orléans, 45071 Orléans, Cedex 2 (France).
authors.forename: Hervé
authors.initials: H
authors.lastname: Meudal
authors.affiliation: Centre de Biophysique Moléculaire, CNRS, Université d'Orléans, 45071 Orléans, Cedex 2 (France).
authors.forename: Céline
authors.initials: C
authors.lastname: Landon
authors.affiliation: Department of Physiology of Cognitive Processes, Max Planck Institute for Biological Cybernetics, 72076 Tubingen (Germany).|Department of Imaging Science and Biomedical Engineering, University of Manchester, Manchester (UK).
authors.forename: Nikos K
authors.initials: NK
authors.lastname: Logothetis
authors.affiliation: Departamento de Química Fundamental, Universidade da Coruña, 15008 A Coruña (Spain).
authors.forename: Carlos
authors.initials: C
authors.lastname: Platas-Iglesias
authors.affiliation: MR Neuroimaging Agents, Max Planck Institute for Biological Cybernetics, 72076 Tubingen (Germany). goran.angelovski@tuebingen.mpg.de.
authors.forename: Goran
authors.initials: G
authors.lastname: Angelovski
authors.affiliation: Centre de Biophysique Moléculaire, CNRS, Université d'Orléans, 45071 Orléans, Cedex 2 (France). eva.jakabtoth@cnrs-orleans.fr.
authors.forename: Éva
authors.initials: É
authors.lastname: Tóth
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D001665:Binding Sites; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D043844:Crown Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D005682:Gadolinium / Q000737:chemistry / Q000378:metabolism*; D008163:Luminescent Measurements; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011199:Potentiometry
chemical_list: D000596:Amino Acids; D056831:Coordination Complexes; D043844:Crown Ethers; D047028:Macrocyclic Compounds; D018377:Neurotransmitter Agents; D005682:Gadolinium
keywords: contrast agents; crown compounds; lanthanides; macrocyclic ligands; neurotransmitters