title: Synthesis and evaluation of (S)-2-(2-[18F]fluoroethoxy)-4-([3-methyl-1-(2-piperidin-1-yl-phenyl)-butyl-carbamoyl]-methyl)-benzoic acid ([18F]repaglinide): a promising radioligand for quantification of pancreatic beta-cell mass with positron emission tomography (PET).
abstract: 18F-labeled non-sulfonylurea hypoglycemic agent (S)-2-(2-[(18)F]fluoroethoxy)-4-((3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl)-methyl)-benzoic acid ([(18)F]repaglinide), a derivative of the sulfonylurea-receptor (SUR) ligand repaglinide, was synthesized as a potential tracer for the non-invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta-cells by positron emission tomography (PET) in the context of type 1 and type 2 diabetes. [(18)F]Repaglinide could be obtained in an overall radiochemical yield (RCY) of 20% after 135 min with a radiochemical purity higher than 98% applying the secondary labeling precursor 2-[(18)F]fluoroethyltosylate. Specific activity was in the range of 50-60 GBq/micromol. Labeling was conducted by exchanging the ethoxy-moiety into a 2-[(18)F]fluoroethoxy group. To characterize the properties of fluorinated repaglinide, the affinity of the analogous non-radioactive (19)F-compound for binding to the human SUR1 isoform was assessed. [(19)F]Repaglinide induced a complete monophasic inhibition curve with a Hill coefficient close to 1 (1.03) yielding a dissociation constant (K(D)) of 134 nM. Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide. Finally, biodistribution of [(18)F]repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i.v. injection. Pancreatic tissue displayed a stable accumulation of approximately 0.12% of the injected dose from 10 min to 30 min p.i. 50% of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide, indicating that [(18)F]repaglinide might be suitable for in vivo investigation with PET.
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg-University of Mainz, Fritz Strassmann-Weg 2, D-55128 Mainz, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Wängler
authors.forename: S
authors.initials: S
authors.lastname: Schneider
authors.forename: O
authors.initials: O
authors.lastname: Thews
authors.forename: E
authors.initials: E
authors.lastname: Schirrmacher
authors.forename: S
authors.initials: S
authors.lastname: Comagic
authors.forename: P
authors.initials: P
authors.lastname: Feilen
authors.forename: C
authors.initials: C
authors.lastname: Schwanstecher
authors.forename: M
authors.initials: M
authors.lastname: Schwanstecher
authors.forename: C-Y
authors.initials: CY
authors.lastname: Shiue
authors.forename: A
authors.initials: A
authors.lastname: Alavi
authors.forename: S
authors.initials: S
authors.lastname: Höhnemann
authors.forename: M
authors.initials: M
authors.lastname: Piel
authors.forename: F
authors.initials: F
authors.lastname: Rösch
authors.forename: R
authors.initials: R
authors.lastname: Schirrmacher
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D005240:Feasibility Studies; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D007515:Islets of Langerhans / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D007553:Isotope Labeling / Q000379:methods; D008657:Metabolic Clearance Rate; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009928:Organ Specificity; D010880:Piperidines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D024661:Potassium Channels, Inwardly Rectifying; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014018:Tissue Distribution
chemical_list: D018528:ATP-Binding Cassette Transporters; D002219:Carbamates; D005462:Fluorine Radioisotopes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010880:Piperidines; D024661:Potassium Channels, Inwardly Rectifying; D019275:Radiopharmaceuticals; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; C577507:ABCC8 protein, human; C577509:Abcc8 protein, rat; C072379:repaglinide