One-pot two-step radiosynthesis of a new (18)F-labeled thiol reactive prosthetic group and its conjugate for insulinoma imaging.

Abstract

N-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)-6-fluoronicotinamide ([(18)F]FNEM), a novel prosthetic agent that is thiol-specific, was synthesized using a one-pot two-step strategy: (1) (18)F incorporation by a nucleophilic displacement of trimethylammonium substrate under mild conditions; (2) amidation of the resulting 6-[(18)F]fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester with N-(2-aminoethyl)maleimide trifluoroacetate salt. The radiosynthesis of the maleimide tracer was completed in 75 min from [(18)F]fluoride with 26 ± 5% decay uncorrected radiochemical yield, and specific activity of 19-88 GBq/μmol (decay uncorrected). The in vitro cell uptake, in vivo biodistribution, and positron emission tomography (PET) imaging properties of its conjugation product with [Cys(40)]-exendin-4 were described. [(18)F]FNEM-Cys(40)-exendin-4 showed specific targeting of glucagon-like peptide 1 receptor (GLP-1R) positive insulinomas and comparable imaging results to our recently reported [(18)F]FPenM-Cys(40)-exendin-4.

• Authors: Xuyi Yue, Xuefeng Yan, Chenxi Wu, Gang Niu, Ying Ma, Orit Jacobson, Baozhong Shen, Dale O Kiesewetter, Xiaoyuan Chen
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 11 Issue 11 Pg. 3875-84 (Nov 03 2014) ISSN: 1543-8392 [Electronic] United States
• PMID: 24798315 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Fluorine Radioisotopes
• Glp1r protein, mouse
• Glucagon-Like Peptide-1 Receptor
• N-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)-6-fluoronicotinamide
• Receptors, Glucagon
• Succinimides
• Sulfhydryl Compounds
• Niacinamide

Topics

• Animals
• Cell Line, Tumor
• Chromatography, Thin Layer
• Disease Models, Animal
• Female
• Fluorine Radioisotopes (chemistry)
• Glucagon-Like Peptide-1 Receptor
• Inhibitory Concentration 50
• Insulinoma (diagnostic imaging)
• Mice
• Mice, Inbred BALB C
• Niacinamide (analogs & derivatives, chemical synthesis, chemistry)
• Positron-Emission Tomography
• Receptors, Glucagon (metabolism)
• Succinimides (chemical synthesis)
• Sulfhydryl Compounds (chemistry)
• Temperature
• Tissue Distribution