-Methylamide-structured SB366791 derivatives with high TRPV1 antagonistic activity: toward PET radiotracers to visualize TRPV1.

Transient receptor potential cation channel subfamily V member 1 (TRPV1)-targeted compounds were synthesized by modifying the structure of SB366791, a pharmaceutically representative TRPV1 antagonist. To avoid amide-iminol tautomerization, structurally supported -methylated amides (, 3-alkoxy-substitued -meythylamide derivatives of SB366791) were evaluated using a Ca influx assay, in which cells expressed recombinant TRPV1 in the presence of 1.0 μM capsaicin. The antagonistic activities of -(3-methoxyphenyl)--methyl-4-chlorocinnamamide (2) (RLC-TV1004) and -{3-(3-fluoropropoxy)phenyl}--methyl-4-chlorocinnamamide (4) (RLC-TV1006) were found to be approximately three-fold higher (IC: 1.3 μM and 1.1 μM, respectively) than that of SB366791 (IC: 3.7 μM). These results will help reinvigorate the potential of SB366791 in medicinal chemistry applications. The 3-methoxy and 3-fluoroalkoxy substituents were used to obtain radioactive [C]methoxy- or [F]fluoroalkoxy-incorporated tracers for positron emission tomography (PET). Using the C- or F-labeled derivatives, explorative PET imaging trials were performed in rats.