title: Multivalent glibenclamide to generate islet specific imaging probes.
abstract: The monitoring of diabetes mellitus, as it develops and becomes clinically evident, remains a major challenge for diagnostic imaging in clinical practice. Here we present a novel approach to beta-cell imaging by targeting the sulphonylurea receptor subtype 1 (SUR1), using multivalent derivatives of the anti-diabetic drug glibenclamide. Since glibenclamide has a high affinity for SUR1 but does not contain a suitable functional group to be linked to an imaging probe, we have synthesized 11 glibenclamide derivatives and evaluated their affinity to SUR1 in MIN6 cells. The most promising compound has been used to obtain multivalent glibenclamide-polyamidoamine (PAMAM) derivatives, containing up to 15 sulphonylurea moieties per dendrimer. The remaining functional groups on the dendrimers can consecutively be used for labeling with reporter groups for different imaging modalities, thus allowing for multifunctional imaging, and for the modification of pharmacokinetic properties. We synthesized fluorochrome-labeled multivalent probes, that demonstrate in cellular assays affinities to SUR1 in the nanomolar range, superior to native glibenclamide. The probes specifically label MIN6 cells, but not HeLa or PANC-1 cells which do not express SUR1. A very low cytotoxicity of the multivalent probes is demonstrated by the persistent release of insulin from MIN6 cells exposed to high glucose concentrations. Furthermore, the probes display positive labeling of beta-cells of primary mouse and human islet-cells ex vivo and of islets of Langerhans in vivo. The data document that multivalent probes based on glibenclamide derivatives provide a suitable platform for further developments of cell-specific probes, and can be adapted for multiple imaging modalities, including those that are now used in the clinics.
authors.affiliation: School of Pharmaceutical Sciences Geneva-Lausanne, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Andrej
authors.initials: A
authors.lastname: Babič
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Smaragda
authors.initials: S
authors.lastname: Lamprianou
authors.affiliation: Department of Radiology, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vinet
authors.affiliation: School of Pharmaceutical Sciences Geneva-Lausanne, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Stransky-Heilkron
authors.affiliation: School of Pharmaceutical Sciences Geneva-Lausanne, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Celine
authors.initials: C
authors.lastname: Xayaphoummine
authors.affiliation: School of Pharmaceutical Sciences Geneva-Lausanne, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Marino A
authors.initials: MA
authors.lastname: Campo
authors.affiliation: Sanofi Germany, Industriepark Höchst, Frankfurt, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Glombik
authors.affiliation: Sanofi Germany, Industriepark Höchst, Frankfurt, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Schulte
authors.affiliation: Sanofi Germany, Industriepark Höchst, Frankfurt, Germany.
authors.forename: Hans-Paul
authors.initials: HP
authors.lastname: Juretschke
authors.affiliation: Department of Radiology, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Xavier
authors.initials: X
authors.lastname: Montet
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Meda
authors.affiliation: School of Pharmaceutical Sciences Geneva-Lausanne, University of Geneva, University of Lausanne, Geneva, Switzerland. Electronic address: norbert.lange@unige.ch.
authors.forename: Norbert
authors.initials: N
authors.lastname: Lange
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry; D003952:Diagnostic Imaging; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry; D005905:Glyburide / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D018613:Microscopy, Confocal; D015335:Molecular Probes / Q000737:chemistry*; D009928:Organ Specificity / Q000187:drug effects; D064233:Sulfonylurea Receptors / Q000378:metabolism
chemical_list: D050091:Dendrimers; D005456:Fluorescent Dyes; D008024:Ligands; D015335:Molecular Probes; C104700:PAMAM Starburst; D064233:Sulfonylurea Receptors; D005905:Glyburide
keywords: Beta-cells; Dendrimers; Diabetes; Imaging; Multivalency; Sulphonylureas