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.
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.
Wängler
Björn
B
Institute of Nuclear Chemistry, University of Mainz, Mainz, Germany.
Beck
Carmen
C
Shiue
Chyng Yann
CY
Schneider
Stephan
S
Schwanstecher
Christina
C
Schwanstecher
Mathias
M
Feilen
Peter Johannes
PJ
Alavi
Abass
A
Rösch
Frank
F
Schirrmacher
Ralf
R
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
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