title: Synthesis and in vitro evaluation of (S)-2-([11C]methoxy)-4-[3-methyl-1-(2-piperidine-1-yl-phenyl)-butyl-carbamoyl]-benzoic acid ([11C]methoxy-repaglinide): a potential beta-cell imaging agent.
abstract: The 11C-labeled sulfonylurea receptor 1 (SUR1) ligand (S)-2-([11C]methoxy)-4-[3-methyl-1-(2-piperidine-1-yl-phenyl)-butyl-carbamoyl]-benzoic acid ([11C]methoxy-repaglinide) was synthesized in an overall radiochemical yield of 35% after 55 min with a radiochemical purity higher than 99%. This compound is considered for the noninvasive investigation of the SUR1 receptor status of pancreatic beta-cells by positron emission tomography (PET) in the context of type 1 and type 2 diabetes. The specific activity was 40-70 GBq/micromol. In vitro testing of the nonradioactive methoxy-repaglinide was performed to characterize the affinity for binding to the human SUR1 isoform. Methoxy-repaglinide induced a complete monophasic inhibition curve with a Hill coefficient close to 1 (1.03) yielding a dissociation constant (KD) of 83 nM and an IC50 of 163 nM. Insulin secretion experiments on isolated rat islets were performed to prove biological activity, which was determined to be in the same range as that of original repaglinide.
authors.affiliation: Institute of Nuclear Chemistry, University of Mainz, Mainz, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Wängler
authors.forename: Carmen
authors.initials: C
authors.lastname: Beck
authors.forename: Chyng Yann
authors.initials: CY
authors.lastname: Shiue
authors.forename: Stephan
authors.initials: S
authors.lastname: Schneider
authors.forename: Christina
authors.initials: C
authors.lastname: Schwanstecher
authors.forename: Mathias
authors.initials: M
authors.lastname: Schwanstecher
authors.forename: Peter Johannes
authors.initials: PJ
authors.lastname: Feilen
authors.forename: Abass
authors.initials: A
authors.lastname: Alavi
authors.forename: Frank
authors.initials: F
authors.lastname: Rösch
authors.forename: Ralf
authors.initials: R
authors.lastname: Schirrmacher
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D001667:Binding, Competitive; D019556:COS Cells; D002219:Carbamates / Q000493:pharmacokinetics; D002250:Carbon Radioisotopes; D006801:Humans; D062425:Hydroxybenzoate Ethers; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000000981:diagnostic imaging / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; 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; D011955:Receptors, Drug / Q000378:metabolism; D013237:Stereoisomerism; D064233:Sulfonylurea Receptors
chemical_list: C498375:2-methoxy-4-(3-methyl-1-(2-piperidin-1-ylphenyl)butylcarbamoyl)benzoic acid; C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; C577509:Abcc8 protein, rat; D001565:Benzoates; D002219:Carbamates; D002250:Carbon Radioisotopes; D062425:Hydroxybenzoate Ethers; D007328:Insulin; D010880:Piperidines; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D019275:Radiopharmaceuticals; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; C072379:repaglinide