title: In vitro and in vivo evaluation of novel glibenclamide derivatives as imaging agents for the non-invasive assessment of the pancreatic islet cell mass in animals and humans.
abstract: Pancreatic islet cell mass (PICM) is a major determinant of the insulin secretory capacity in humans. Currently, the only method for accurate assessment of the PICM is an autopsy study. Thus, development of a technique allowing the non-invasive quantification of PICM is of great interest. The aim of this study was to develop such a non-invasive technique featuring novel fluorine- and (99m)Tc-labelled glibenclamide derivatives. Despite the structural modifications necessary to introduce fluorine into the glibenclamide molecule, all derivatives retained insulin stimulating capacity as well as high affinity binding to human SUR1 when compared to the original glibenclamide. Contrastingly, the lipophilicity of the fluorine-labelled derivatives was altered depending on the particular modification. In the human PET-study a constant but weak radioactive signal could be detected in the pancreas using a fluorine-labelled glibenclamide derivative. However, a reliable assessment and visualisation of the PICM could not be obtained. It can be assumed that the high uptake of the fluorine-labelled tracer e.g. into the the liver and the high plasma protein binding leads to a relatively low signal-to-noise ratio. In case of the presented fluorine-labelled glibenclamide based compounds this could be the result of their invariably high lipophilicity. The development of a (99 m)Tc-labelled glibenclamide derivative with a lower lipophilicity and differing in vivo behaviour, glibenclamide based compounds for non-invasive imaging of the pancreatic islet cell mass may be possible.
authors: Medical Department I, University Hospital Bergmannsheil, University of Bochum, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany. Stephan.Schneider@ruhr-uni-bochum.de
authors: S
authors: S
authors: Schneider
authors: P J
authors: PJ
authors: Feilen
authors: M
authors: M
authors: Schreckenberger
authors: M
authors: M
authors: Schwanstecher
authors: C
authors: C
authors: Schwanstecher
authors: H G
authors: HG
authors: Buchholz
authors: O
authors: O
authors: Thews
authors: K
authors: K
authors: Oberholzer
authors: A
authors: A
authors: Korobeynikov
authors: A
authors: A
authors: Bauman
authors: S
authors: S
authors: Comagic
authors: M
authors: M
authors: Piel
authors: E
authors: E
authors: Schirrmacher
authors: C Y
authors: CY
authors: Shiue
authors: A A
authors: AA
authors: Alavi
authors: P
authors: P
authors: Bartenstein
authors: F
authors: F
authors: Rösch
authors: M M
authors: MM
authors: Weber
authors: H H
authors: HH
authors: Klein
authors: R
authors: R
authors: Schirrmacher
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D003920:Diabetes Mellitus / Q000000981:diagnostic imaging*; D005462:Fluorine Radioisotopes; D005905:Glyburide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D049268:Positron-Emission Tomography; D015221:Potassium Channels / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000378:metabolism; D064233:Sulfonylurea Receptors; D013667:Technetium
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; C577509:Abcc8 protein, rat; D005462:Fluorine Radioisotopes; D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D019275:Radiopharmaceuticals; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D013667:Technetium; D005905:Glyburide