Synthesis of fluorine-18 labeled sulfonureas as β-cell imaging agents

Article abstract of DOI:10.1002/jlcr.438

Tolbutamide (1) and glyburide (7) are hypoglycemic drugs used to stimulate insulin secretion in type 2 diabetic patients. We have synthesized their fluorine-18 labeled analogs, 1-[(4-[¹⁸F]fluorobenzenesulfonyl)]-3-butyl]urea (p-[¹⁸F]fluorotolbutamide, 3a) and N-{4-[β-(2-[¹⁸F]fluoroethoxybenzene carboxamido)ethyl]benzenesulfonyl}-N′-cyclohexylurea (2-[¹⁸F]fluoroethoxyglyburide, 6a) as β-cell imaging agents. Compound 3a was synthesized via two approaches: One-step synthesis via nucleophilic substitution of p-nitrotolbutamide (2) with K[¹⁸F]/Kryptofix 2.2.2 in either CH₃CN or DMSO gave a complicated mixture; a two-step synthesis via preparation and reaction of 4-[¹⁸F]fluorobenzenesulfonamide with butyl isocyanate in the presence of either copper (I) chloride or borontrifluoride etherate complex in CH₃CN followed by HPLC purification yielded compound 3a in an overall yield of 1-2% with a synthesis time of 120 minutes from EOB. Compound 6a was synthesized by alkylation of the corresponding hydroxy precursor (5) with [¹⁸F]fluoroethyl tosylate in DMSO at 120⁰C for 20 minutes followed by HPLC purification in an overall yield of 5-10% with a synthesis time of 100 minutes from EOB. The lipid/water partition coefficient of compounds 3a and 6a was 3.13±0.28, n=6 and 124.33±21.61, n=8, respectively. The feasibility of using these radiotraces as β-cell imaging agents is under evaluation.