Synthesis and evaluation of fluorine-18 labeled glyburide analogs as β-cell imaging agents

Abstract

Glyburide is a prescribed hypoglycemic drug for the treatment of type 2 diabetic patients. We have synthesized two of its analogs, namely N-{4-[β-(2-(2′-fluoroethoxy)-5-chlorobenzenecarboxamido)ethyl]benzenesulfonyl}- N′-cyclohexylurea (2-fluoroethoxyglyburide, 8b) and N-{4-[β-(2-(2′-fluoroethoxy)-5-iodobenzenecarboxamido)ethyl]benzenesulfonyl}- N′-cyclohexylurea (2-fluoroethoxy-5-deschloro-5-iodoglyburide, 8a), and their fluorine-18 labeled analogs as β-cell imaging agents. Both F-18 labeled compound 8a and compound 8b were synthesized by alkylation of the corresponding multistep synthesized hydroxy precursor 4a and 4b with 2-[ 18F]fluoroethyl tosylate in DMSO at 120°C for 20 minutes followed by HPLC purification in an overall radiochemical yield of 5-10% with a synthesis time of 100 minutes from EOB. The octanol/water partition coefficients of compounds 8a and 8b were 141.21 ± 27.77 ( n = 8) and 124.33 ± 21.61 ( n = 8), respectively. Insulin secretion experiments of compounds 8a and 8b on rat islets showed that both compounds have a similar stimulating effect on insulin secretion as that of glyburide. In vitro binding studies showed that ∼2% of compounds 8a and 8b bound to βTC3 and Min6 cells and that the binding was saturable. Preliminary biodistribution studies in mice showed that the uptake of both compounds 8a and 8b in liver and small intestine were high, whereas the uptake in other organs studied including pancreas were low. Additionally, the uptake of compound 8b in vivo was nonsaturable. These results tend to suggest that compounds 8a and 8b may not be the ideal β-cell imaging agents.