Journal of medicinal and pharmaceutical chemistry 2014-11-26

Synthesis of 7-halogenated isatin sulfonamides: nonradioactive counterparts of caspase-3/-7 inhibitor-based potential radiopharmaceuticals for molecular imaging of apoptosis.

Panupun Limpachayaporn, Stefan Wagner, Klaus Kopka, Otmar Schober, Michael Schäfers, Günter Haufe

Index: J. Med. Chem. 57(22) , 9383-95, (2014)

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Abstract

N-Alkylated (S)-7-halogen-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatins were developed as a new group of nonradioactive reference compounds for future radiotracers. Inhibitor potency studies of these compounds suggest that the binding pockets readily accommodate both the 7-halogen substituents and aliphatic side chains (methyl to n-butyl) as well as some ω-fluorinated analogues (3-fluoropropyl and 4-fluorobutyl) at the isatin nitrogen. Indeed, compared to the halogen free parent compounds, some 7-halogenated derivatives exhibited slightly improved inhibitory potencies with IC50 values up to 2.6 nM (caspase-3) and 3.3 nM (caspase-7), respectively. Moreover, the 7-position of isatin, a potential cytochrome P450 hydroxylation site, was substituted by I, Br, Cl, and F to potentially enhance the metabolic stability of isatin sulfonamides. As an example, the radiotracer [(18)F]39 that was produced by (19)F/(18)F isotope exchange was shown to be stable in human blood serum after incubation at 37 °C for at least 90 min.